NEUROBIOLOGY AND COGNITIVE SCIENCES

UNIT I NEUROANATOMY What are central and peripheral nervous systems; Structure and function of neurons; types of neurons; Synapses; Glial cells; myelination; Blood Brain barrier; Neuronal differentiation; Characterization of neuronal cells; Meninges and Cerebrospinal fluid; Spinal Cord.

UNIT II NEUROPHYSIOLOGY

Resting and action potentials; Mechanism of action potential conduction; Voltage dependent channels; nodes of Ranvier; Chemical and electrical synaptic transmission; information representation and coding by neurons.

UNIT III NEUROPHARMACOLOGY Synaptic transmission, neurotransmitters and their release; fast and slow neurotransmission; characteristics of neurites; hormones and their effect on neuronal function.

UNIT IV APPLIED NEUROBIOLOGY Basic mechanisms of sensations like touch, pain, smell and taste; neurological mechanisms of vision and audition; skeletal muscle contraction.

UNIT V BEHAVIOUR SCIENCE Basic mechanisms associated with motivation; control of feeding, sleep, hearing and memory; Disorders associated with the nervous system.

UNIT II NEUROPHYSIOLOGY

Neurotransmitters

Neurotransmitters are endogenous chemicals which relay, amplify, and modulate signals between a neuron and another cell. Neurotransmitters are packaged into synaptic vesicles that cluster beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse. Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may follow graded electrical potentials. Low level "baseline" release also occurs without electrical stimulation.

Identifying neurotransmitters

According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:

There are precursors and/or synthesis enzymes located in the presynaptic side of the synapse.

The chemical is present in the presynaptic element. It is available in sufficient quantity in the presynaptic neuron to affect the

postsynaptic neuron; There are postsynaptic receptors and the chemical is able to bind to them. A biochemical mechanism for inactivation is present.

Types of neurotransmitters

Major neurotransmitters:

Amino acids: glutamate, aspartate, serine, γ-aminobutyric acid (GABA), glycine Monoamines: dopamine (DA), norepinephrine (noradrenaline; NE, NA),

epinephrine (adrenaline), histamine, serotonin (SE, 5-HT), melatonin Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.

In addition, over 50 neuroactive peptides have been found, and new ones are discovered on a regular basis. Many of these are "co-released" along with a small-molecule transmitter, but in some cases a peptide is the primary transmitter at a synapse.

Single ions, such as synaptically released zinc, are also considered neurotransmitters by some, as are a few gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO).

Excitatory and inhibitory

Some neurotransmitters are commonly described as "excitatory" or "inhibitory". The only direct effect of a neurotransmitter is to activate one or more types of receptors. The effect on the postsynaptic cell depends, therefore, entirely on the properties of those receptors. It happens that for some neurotransmitters (for example, glutamate), the most important receptors all have excitatory effects: that is, they increase the probability that the target cell will fire an action potential. For other neurotransmitters (such as GABA), the most important receptors all have inhibitory effects. There are, however, other neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory receptors exist; and there are some types of receptors that activate complex metabolic pathways in the postsynaptic cell to produce effects that cannot appropriately be called either excitatory or inhibitory.

Actions

The only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors that the transmitter binds to.

Here are a few examples of important neurotransmitter actions:

Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain.

GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA. Correspondingly glycine is the inhibitory transmitter in the spinal cord.

Acetylcholine is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain, but using different types of receptors.

Dopamine has a number of important functions in the brain. It plays a critical role in the reward system, but dysfunction of the dopamine system is also implicated in Parkinson's disease and schizophrenia.

Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine (approximately 90%), and the remainder in central nervous system neurons. It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and endocrine system. It is speculated to have a role in depression, as some depressed patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.

Substance P undecapeptide responsible for transmission of pain from certain sensory neurons to the central nervous system.

A brief comparison of the major neurotransmitter systems follows:

Neurotransmitter systemsSystem Origin Effects

Noradrenaline system

locus coeruleus arousal

rewardLateral tegmental field

Dopamine system

dopamine pathways: mesocortical pathway mesolimbic pathway nigrostriatal pathway

tuberoinfundibular pathway

motor system, reward, cognition, endocrine, nausea

Serotonin system

caudal dorsal raphe nucleus Increase (introversion), mood, satiety, body temperature and sleep, while decreasing nociception.rostral dorsal raphe nucleus

Cholinergic system

pontomesencephalotegmental complex

learning short-term memory arousal

reward

basal optic nucleus of Meynert

medial septal nucleus

Common neurotransmitters

Category   Name   Abbreviation   Metabotropic   Ionotropic  

Small: Amino acids Aspartate - -

NeuropeptidesN-Acetylaspartylglutamate

NAAG

Metabotropic glutamate receptors; selective agonist of mGluR3

-

Small: Amino acids

Glutamate (glutamic acid) Glu

Metabotropic glutamate receptor

NMDA receptor, Kainate receptor, AMPA receptor

Small: Amino acids

Gamma-aminobutyric acid GABA GABAB

receptor

GABAA, GABAA-ρ receptor

Small: Amino acids Glycine Gly - Glycine

receptor

Small: Acetylcholine Acetylcholine Ach

Muscarinic acetylcholine receptor

Nicotinic acetylcholine receptor

Small: Monoamine (Phe/Tyr)

Dopamine DA Dopamine receptor -

Small: Monoamine (Phe/Tyr)

Norepinephrine (noradrenaline) NE Adrenergic

receptor -

Small: Monoamine (Phe/Tyr)

Epinephrine (adrenaline) Epi Adrenergic

receptor -

Small: Monoamine (Phe/Tyr)

Octopamine - -

Small: Monoamine (Phe/Tyr)

Tyramine -

Small: Monoamine (Trp)

Serotonin (5-hydroxytryptamine) 5-HT

Serotonin receptor, all but 5-HT3

5-HT3

Small: Monoamine (Trp) Melatonin Mel Melatonin

receptor -

Small: Monoamine (His) Histamine H Histamine

receptor -

PP: Gastrins Gastrin - -

PP: Gastrins Cholecystokinin CCK Cholecystokinin receptor -

PP: Neurohypophyseals

Vasopressin AVP Vasopressin receptor -

PP: Neurohypophyseals

Oxytocin Oxytocin receptor -

PP: Neurohypophyseals

Neurophysin I - -

PP: Neurohypophyseals

Neurophysin II - -

PP: Neuropeptide Y Neuropeptide Y NY Neuropeptide Y

receptor -

PP: Neuropeptide Y Pancreatic polypeptide PP - -

PP: Neuropeptide Y Peptide YY PYY - -

PP: OpioidsCorticotropin (adrenocorticotropic hormone)

ACTH Corticotropin receptor -

PP: Opioids Dynorphin - -PP: Opioids Endorphin - -PP: Opioids Enkephaline - -

PP: Secretins Secretin Secretin receptor -

PP: Secretins Motilin Motilin receptor -

PP: Secretins Glucagon Glucagon receptor -

PP: Secretins Vasoactive intestinal peptide VIP

Vasoactive intestinal peptide receptor

-

PP: Secretins Growth hormone-releasing factor GRF - -

PP: Somtostatins Somatostatin Somatostatin receptor -

SS: Tachykinins Neurokinin A - -SS: Tachykinins Neurokinin B - -SS: Tachykinins Substance P - -

PP: Other Bombesin - -

PP: Other Gastrin releasing peptide GRP - -

Gas Nitric oxide NO Soluble guanylyl cyclase -

Gas Carbon monoxide CO -Heme bound to potassium channels

Other Anandamide AEA Cannabinoid receptor -

Other Adenosine triphosphate ATP P2Y12 P2X receptor

Precursors of neurotransmitters

While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is mixed as to whether neurotransmitter release (firing) is increased. Even with increased neurotransmitter release, it is unclear whether this will result in a long-term increase in neurotransmitter signal strength, since the nervous system can adapt to changes such as increased neurotransmitter synthesis and may therefore maintain constant firing. Some neurotransmitters may have a role in depression, and there is some evidence to suggest that intake of precursors of these neurotransmitters may be useful in the treatment of mild and moderate depression.

Norepinephrine precursors

For depressed patients where low activity of the neurotransmitter norepinephrine is implicated, there is only little evidence for benefit of neurotransmitter precursor administration. L-phenylalanine and L-tyrosine are both precursors for dopamine, norepinephrine, and epinephrine. These conversions require vitamin B6, vitamin C, and S-adenosylmethionine. A few studies suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much room for further research in this area.

Serotonin precursors

Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of serotonin in the brain. It is significantly more effective than a placebo in the treatment of mild and moderate depression. This conversion requires vitamin C.

5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is also more effective than a placebo and nearly as effective or of equal effectiveness to some antidepressants. Interestingly, it takes less than 2 weeks for an antidepressant response to occur, while antidepressant drugs generally take 2-4 weeks. 5-HTP also has no significant side effects.

Administration of 5-HTP bypasses the rate-limiting step in the synthesis of serotonin from tryptophan. Also, 5-HTP readily passes through the blood-brain barrier, and enters the central nervous system without need of a transport molecule. Note, however, that there is some evidence to suggest that a postsynaptic defect in serotonin utilization may be an important factor in depression, not only insufficient serotonin.

It is important to note that not all cases of depression are caused by low levels of serotonin. However, in the subgroup of depressed patients that are serotonin-deficient, there is strong evidence to suggest that 5-HTP is therapeutically useful in treating depression, and more useful than L-tryptophan.

Depression does not have one cause; not all cases of depression are due to low levels of serotonin or norepinephrine. Blood tests for the ratio of tryptophan to other amino acids, as well as red blood cell membrane transport of these amino acids, can be predictive of whether serotonin or norepinephrine would be of therapeutic benefit. Overall, there is evidence to suggest that neurotransmitter precursors may be useful in the treatment of mild and moderate depression.

Degradation and elimination

Neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further excitatory or inhibitory signal transduction. For example, acetylcholine (ACh), an excitatory neurotransmitter, is broken down by acetylcholinesterase (AChE). Choline is taken up and recycled by the pre-synaptic neuron to synthesize more ACh. Other neurotransmitters such as dopamine are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be the target of the body's own regulatory system or recreational drugs.

Chemical synapse

Illustration of the major elements in chemical synaptic transmission. An electrochemical wave called an action potential travels along the axon of a neuron. When the wave reaches a synapse, it provokes release of a puff of neurotransmitter molecules, which bind to chemical receptor molecules located in the membrane of another neuron, on the opposite side of the synapse.

Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie perception and thought. They allow the nervous system to connect to and control other systems of the body.

At a chemical synapse, one neuron releases a neurotransmitter into a small space (the synapse) that is adjacent to another neuron. Neurotransmitters must then be cleared out of the synapse efficiently so that the synapse can be ready to function again as soon as possible.

The adult human brain is estimated to contain from 1014 to 5 × 1014 (100-500 trillion) synapses. Every cubic millimeter of cerebral cortex contains roughly a billion of them.

The word "synapse" comes from "synaptein", which Sir Charles Scott Sherrington and colleagues coined from the Greek "syn-" ("together") and "haptein" ("to clasp"). Chemical synapses are not the only type of biological synapse: electrical and

immunological synapses also exist. However, "synapse" commonly means chemical synapse.

Structure

Synapses are functional connections between neurons, or between neurons and other types of cells. A typical neuron gives rise to several thousand synapses, although there are some types that make far fewer. Most synapses connect axons to dendrites, but there are also other types of connections, including axon-to-cell-body, axon-to-axon, and dendrite-to-dendrite. Synapses are generally too small to be recognizable using a light microscope except as points where the membranes of two cells appear to touch, but their cellular elements can be visualized clearly using an electron microscope.

Chemical synapses pass information directionally from a presynaptic cell to a postsynaptic cell and are therefore asymmetric in structure and function. The presynaptic terminal, or synaptic bouton, is a specialized area within the axon of the presynaptic cell that contains neurotransmitters enclosed in small membrane-bound spheres called synaptic vesicles. Synaptic vesicles are docked at the presynaptic plasma membrane at regions called active zones (AZ).

Immediately opposite is a region of the postsynaptic cell containing neurotransmitter receptors; for synapses between two neurons the postsynaptic region may be found on the dendrites or cell body. Immediately behind the postsynaptic membrane is an elaborate complex of interlinked proteins called the postsynaptic density (PSD).

Proteins in the PSD are involved in anchoring and trafficking neurotransmitter receptors and modulating the activity of these receptors. The receptors and PSDs are often found in specialized protrusions from the main dendritic shaft called dendritic spines.

Between the pre- and postsynaptic cells is a gap about 20 nm wide called the synaptic cleft. The small volume of the cleft allows neurotransmitter concentration to be raised and lowered rapidly. The membranes of the two adjacent cells are held together by cell adhesion proteins.

Signaling in chemical synapses

Here is a summary of the sequence of events that take place in synaptic transmission from a presynaptic neuron to a postsynaptic cell. Note that with the exception of the final step, the entire process may run only a few tenths of a millisecond, in the fastest synapses.

1. The process begins with a wave of electrochemical excitation called an action potential traveling along the membrane of the presynaptic cell, until it reaches the synapse.

2. The electrical depolarization of the membrane at the synapse causes channels to open that are permeable to calcium ions.

3. Calcium ions flow through the presynaptic membrane, rapidly increasing the calcium concentration in the interior.

4. The high calcium concentration activates a set of calcium-sensitive proteins attached to vesicles that contain a neurotransmitter chemical.

5. These proteins change shape, causing the membranes of some "docked" vesicles to fuse with the membrane of the presynaptic cell, thereby opening the vesicles and dumping their neurotransmitter contents into the synaptic cleft, the narrow space between the membranes of the pre- and post-synaptic cells.

6. The neurotransmitter diffuses within the cleft. Some of it escapes, but some of it binds to chemical receptor molecules located on the membrane of the postsynaptic cell.

7. The binding of neurotransmitter causes the receptor molecule to be activated in some way. Several types of activation are possible. In any case, this is the key step by which the synaptic process affects the behavior of the postsynaptic cell.

8. Due to thermal shaking, neurotransmitter molecules eventually break loose from the receptors and drift away.

9. The neurotransmitter is either reabsorbed by the presynaptic cell and then repackaged for future release, or else it is broken down metabolically.

Neurotransmitter release

The release of a neurotransmitter is triggered by the arrival of a nerve impulse (or action potential) and occurs through an unusually rapid process of cellular secretion, also known as exocytosis: Within the presynaptic nerve terminal, vesicles containing neurotransmitter sit "docked" and ready at the synaptic membrane. The arriving action potential produces an influx of calcium ions through voltage-dependent, calcium-selective ion channels at the down stroke of the action potential (tail current). Calcium ions then trigger a biochemical cascade which results in vesicles fusing with the presynaptic membrane and releasing their contents to the synaptic cleft within 180µsec of calcium entry. Vesicle fusion is driven by the action of a set of proteins in the presynaptic terminal known as SNAREs(Soluble N-ethylmaleimide sensitive fusion Attachment Protein receptor).

As calcium ions enter into the presynaptic neuron, they bind with the proteins found within the membranes of the synaptic vesicles that allow the vesicles to "dock." Triggered by the binding of the calcium ions, the synaptic vesicle proteins begin to move apart, resulting in the creation of a fusion pore. The presence of the pore allows for the release of neurotransmitter into the synapse.

The membrane added by this fusion is later retrieved by endocytosis and recycled for the formation of fresh neurotransmitter-filled vesicles.

Receptor binding

Receptors on the opposite side of the synaptic gap bind neurotransmitter molecules and respond by opening nearby ion channels in the postsynaptic cell membrane, causing ions to rush in or out and changing the local transmembrane potential of the cell. The resulting

change in voltage is called a postsynaptic potential. In general, the result is excitatory, in the case of depolarizing currents, or inhibitory in the case of hyperpolarizing currents. Whether a synapse is excitatory or inhibitory depends on what type(s) of ion channel conduct the postsynaptic current display(s), which in turn is a function of the type of receptors and neurotransmitter employed at the synapse.

Termination

After a neurotransmitter molecule binds to a receptor molecule, it does not stay bound forever: sooner or later it is shaken loose by random temperature-related jiggling. Once the neurotransmitter breaks loose, it can either drift away, or bind again to another receptor molecule. The pool of neurotransmitter molecules undergoing this binding-loosening cycle steadily diminishes, however. Neurotransmitter molecules are typically removed in one of two ways, depending on the type of synapse: either they are taken up by the presynaptic cell (and then processed for re-release during a later action potential), or else they are broken down by special enzymes. The time course of these "clearing" processes varies greatly for different types of synapses, ranging from a few tenths of a millisecond for the fastest, to several seconds for the slowest.

Modulation of synaptic transmission

Synaptic transmission can be modulated by e.g. desensitization, homosynaptic plasticity and heterosynaptic plasticity:

Desensitization

Desensitization of the postsynaptic receptors is a decrease in response to the same neurotransmitter stimulus. It means that the strength of a synapse may in effect diminish as a train of action potentials arrive in rapid succession--a phenomenon that gives rise to the so-called frequency dependence of synapses. The nervous system exploits this property for computational purposes, and can tune its synapses through such means as phosphorylation of the proteins involved.

Homosynaptic plasticity

Homosynaptic plasticity is a change in the synaptic strength that results from the history of activity at a particular synapse. This can result from changes in presynaptic calcium as well as feedback onto presynaptic receptors, i.e. a form of autocrine signaling. Homosynaptic plasticity can affect the number and replenishment rate of vesicles or it can affect the relationship between calcium and vesicle release. Homosynaptic plasticity can also be post-synaptic in nature. It can result in either an increase or decrease in synaptic strength.

One example is neurons of the sympathetic nervous system (SNS), which release noradrenaline, which, besides affecting postsynaptic receptors, also affects presynaptic

α2-adrenergic receptors, inhibiting further release of noradrenaline. This effect is utilized with clonidine to perform inhibitory effects on the SNS.

Heterosynaptic plasticity

Heterotropic plasticity is a change in synaptic strength that results from the activity of other neurons. Again, the plasticity can alter the number of vesicles or their replenishment rate or the relationship between calcium and vesicle release. Additionally, it could directly affect calcium influx. Heterosynaptic plasticity can also be post-synaptic in nature, affecting receptor sensitivity.

One example is again neurons of the sympathetic nervous system, which release noradrenaline, which, in addition, generate inhibitory effect on presynaptic terminals of neurons of the parasympathetic nervous system.

Effects of drugs

One of the most important features of chemical synapses is that they are the site of action for the majority of psychoactive drugs. Synapses are affected by drugs such as curare, strychnine, cocaine, morphine, alcohol, LSD, and countless others. These drugs have different effects on synaptic function, and often are restricted to synapses that use a specific neurotransmitter. For example, curare is a poison which stops acetylcholine from depolarising the post-synaptic membrane, causing paralysis. Strychnine blocks the inhibitory effects of the neurotransmitter glycine, which causes the body to pick up and react to weaker and previously ignored stimuli, resulting in uncontrollable muscle spasms. Morphine acts on synapses that use endorphin neurotransmitters, and alcohol increases the inhibitory effects of the neurotransmitter GABA. LSD interferes with synapses that use the neurotransmitter serotonin. Cocaine blocks reuptake of dopamine and therefore increases its effects.

Integration of synaptic inputs

In general, if an excitatory synapse is strong, an action potential in the presynaptic neuron will trigger another in the postsynaptic cell, whereas, at a weak synapse, the excitatory postsynaptic potential ("EPSP") will not reach the threshold for action potential initiation. In the brain, however, each neuron forms synapses with many others, and, likewise, each receives synaptic inputs from many others. When action potentials fire simultaneously in several neurons that weakly synapse on a single cell, they may initiate an impulse in that cell even though the synapses are weak. This process is known as summation. On the other hand, a presynaptic neuron releasing an inhibitory neurotransmitter such as GABA can cause inhibitory postsynaptic potential in the postsynaptic neuron, decreasing its excitability and therefore decreasing the neuron's likelihood of firing an action potential. In this way, the output of a neuron may depend on the input of many others, each of which may have a different degree of influence, depending on the strength of its synapse with that neuron.

Synaptic strength

The strength of a synapse is defined by the change in transmembrane potential resulting from activation of the postsynaptic neurotransmitter receptors. This change in voltage is known as a postsynaptic potential, and is a direct result of ionic currents flowing through the postsynaptic ion channels. Changes in synaptic strength can be short–term and without permanent structural changes in the neurons themselves, lasting seconds to minutes — or long-term (long-term potentiation, or LTP), in which repeated or continuous synaptic activation can result in second messenger molecules initiating protein synthesis, resulting in alteration of the structure of the synapse itself. Learning and memory are believed to result from long-term changes in synaptic strength, via a mechanism known as synaptic plasticity.

Volume transmission

When a neurotransmitter is released at a synapse, it reaches its highest concentration inside the narrow space of the synaptic cleft, but some of it is certain to diffuse away before being reabsorbed or broken down. If it diffuses away, it has the potential to activate receptors that are located either at other synapses or on the membrane away from any synapse. The extrasynaptic activity of a neurotransmitter is known as volume transmission. It is well established that such effects occur to some degree, but their functional importance has long been a matter of controversy.

Recent work indicates that volume transmission may be the predominant mode of interaction for some special types of neurons. In the mammalian cerebral cortex, a class of neurons called neurogliaform cells can inhibit other nearby cortical neurons by releasing the neurotransmitter GABA into the extracellular space. Approximately 78% of neurogliaforms do not form classical synapses. This may be the first definitive example of neurons communicating chemically where synapses are not present.

Relationship to electrical synapses

An electrical synapse is a mechanical and electrically conductive link between two abutting neurons that is formed at a narrow gap between the pre- and postsynaptic cells known as a gap junction. At gap junctions, cells approach within about 3.5 nm of each other, rather than the 20 to 40 nm distance that separates cells at chemical synapses. As opposed to chemical synapses, the postsynaptic potential in electrical synapses is not caused by the opening of ion channels by chemical transmitters, but by direct electrical coupling between both neurons. Electrical synapses are therefore faster and more reliable than chemical synapses. Electrical synapses are found throughout the nervous system, yet are less common than chemical synapses.

Neurotransmission (Latin: transmissio = passage, crossing; from transmitto = send, let through), also called synaptic transmission, is an electrical movement within synapses caused by a propagation of nerve impulses. As each nerve cell receives neurotransmitter from the presynaptic neuron, or terminal button, to the postsynaptic neuron, or dendrite,

of the second neuron, it sends it back out to several neurons, and they do the same, thus creating a wave of energy until the pulse has made its way across an organ or specific area of neurons.

Nerve impulses are essential for the propagation of signals. These signals are sent to and from the central nervous system via efferent and afferent neurons in order to coordinate smooth, skeletal and cardiac muscles, bodily secretions and organ functions critical for the long-term survival of multicellular vertebrate organisms such as mammals.

Neurons form networks through which nerve impulses travel. Each neuron receives as many as 15,000 connections from other neurons. Neurons do not touch each other; they have contact points called synapses. A neuron transports its information by way of a nerve impulse. When a nerve impulse arrives at the synapse, it releases neurotransmitters, which influence another cell, either in an inhibitory way or in an excitatory way. The next neuron may be connected to many more neurons, and if the total of excitatory influences is more than the inhibitory influences, it will also "fire", that is, it will create a new action potential at its axon hillock, in this way passing on the information to yet another next neuron, or resulting in an experience or an action.

An example of propagation among neurons is the heart beat. A beat is made when a signal is sent from the Sinoatrial node in a sequence that causes the heart to fully contract emptying all the blood in it and refilling with all new blood. It is important that the pulse is sent out from the SA node because the direction of the pulse between the neurons is what drives the muscle to fully contract. If the pulse comes in from the AV node the heart will stutter and not empty all the blood into the body.

Stages in neurotransmission at the synapse

1. Synthesis of the neurotransmitter. This can take place in the cell body, in the axon, or in the axon terminal.

2. Storage of the neurotransmitter in storage granules or vesicles in the axon terminal.

3. Calcium enters the axon terminal during an action potential, causing release of the neurotransmitter into the synaptic cleft.

4. After its release, the transmitter binds to and activates a receptor in the postsynaptic membrane.

5. Deactivation of the neurotransmitter. The neurotransmitter is either destroyed enzymatically, or taken back into the terminal from which it came, where it can be reused, or degraded and removed.

Summation

Each neuron is connected with numerous other neurons, receiving numerous impulses from them. Summation is the adding together of these impulses at the axon hillock. If the neuron only gets excitatory impulses, it will also generate an action potential; but if the neuron gets as many inhibitory as excitatory impulses, the inhibition cancels out the

excitation and the nerve impulse will stop there. Summation takes place at the axon hillock.

Spatial summation means several firings on different places of the neuron, that in themselves are not strong enough to cause a neuron to fire. However, if they fire simultaneously, their combined effects will cause an action potential.

Temporal summation means several firings at the same place, that won't cause an action potential if they have a pause in between, but when there are several firings in rapid succession, they will cause the neuron to reach the threshold for excitation.

Convergence and divergence

Neurotransmission implies both a convergence and a divergence of information. First one neuron is influenced by many others, resulting in a convergence of input. When the neuron fires, the signal is sent to many other neurons, resulting in a divergence of output. Many other neurons are influenced by this neuron.

Cotransmission

Cotransmission is the release of several types of neurotransmitters from a single nerve terminal. Cotransmission allows for more complex effects at postsynaptic receptors, and thus allows for more complex communication to occur between neurons.

In modern neuroscience, neurons are often classified by their cotransmitter, for example striatal GABAergic neurons utilize opioid peptides or substance P as their primary cotransmitter.

Examples of neuron types releasing two or more neurotransmitters at the same time and include:

GABA-glycine co-release. Dopamine-glutamate co-release. Acetylcholine-glutamate co-release. Acetylcholine (ACh) and vasoactive intestinal peptide (VIP) co-release. Acetylcholine (ACh) and calcitonin gene-related peptide (CGRP) co-release. Glutamate and dynorphin co-release (in the hippocampal synapses). NANCs and noradrenaline/acetylcholine/etc.

Excitable cells

Excitable cells are those that can be stimulated to create a tiny electric current.

Muscle cells and

nerve cells (neurons)are excitable

The Resting Potential

All cells (not just excitable cells) have a resting potential: an electrical charge across the plasma membrane, with the interior of the cell negative with respect to the exterior. The size of the resting potential varies, but in excitable cells runs about -70 millivolts (mv).

The resting potential arises from two activities:

The sodium/potassium ATPase . This pump pushes only two potassium ions (K+) into the cell for every three sodium ions (Na+) it pumps out of the cell so its activity results in a net loss of positive charges within the cell.

Some potassium channels in the plasma membrane are "leaky" allowing a slow facilitated diffusion of K+ out of the cell (red arrow).

Ionic Relations in the Cell

The sodium/potassium ATPase produces a concentration of Na+ outside the cell

that is some 10 times greater than that inside the cell

a concentration of K+ inside the cell some 20 times greater than that outside the cell.

The concentrations of chloride ions (Cl-) and calcium ions (Ca2+) are also maintained at greater levels outside the cell EXCEPT that some intracellular membrane-bounded compartments may also have high concentrations of Ca2+ (green oval)

Depolarization

Certain external stimuli reduce the charge across the plasma membrane. mechanical stimuli (e.g., stretching, sound waves) activate mechanically-gated

sodium channels certain neurotransmitters (e.g., acetylcholine) open ligand-gated sodium channels.

In each case, the facilitated diffusion of sodium into the cell reduces the resting potential at that spot on the cell creating an excitatory postsynaptic potential or EPSP.

If the potential is reduced to the threshold voltage (about -50 mv in mammalian neurons), an action potential is generated in the cell.

Action Potentials

If depolarization at a spot on the cell reaches the threshold voltage, the reduced voltage now opens up hundreds of voltage-gated sodium channels in that portion of the plasma membrane. During the millisecond that the channels remain open, some 7000 Na+ rush into the cell. The sudden complete depolarization of the membrane opens up more of the voltage-gated sodium channels in adjacent portions of the membrane. In this way, a wave of depolarization sweeps along the cell. This is the action potential (In neurons, the action potential is also called the nerve impulse.)

Action potentials play multiple roles in several types of excitable cells such as neurons, myocytes, and electrocytes. The best known action potentials are pulse-like waves of voltage that travel along axons of neurons.

The refractory period

The refractory period in a neuron occurs after an action potential and generally lasts one millisecond.

A second stimulus applied to a neuron (or muscle fiber) less than 0.001 second after the first will not trigger another impulse. The membrane is depolarized and the neuron is in its refractory period. Not until the -70 mv polarity is reestablished will the neuron be ready to fire again.

Repolarization is first established by the facilitated diffusion of potassium ions out of the cell. Only when the neuron is finally rested are the sodium ions that came in at each impulse actively transported back out of the cell.

In some human neurons, the refractory period lasts only 0.001-0.002 seconds. This means that the neuron can transmit 500-1000 impulses per second.

The action potential is all-or-noneThe strength of the action potential is an intrinsic property of the cell. So long as they can reach the threshold of the cell, strong stimuli produce no stronger action potentials than weak ones. However, the strength of the stimulus is encoded in the frequency of the action potentials that it generates.

Myelinated Neurons

The axons of many neurons are encased in a fatty sheath called the myelin sheath. It is the greatly expanded plasma membrane of an accessory cell called the Schwann cell. Where the sheath of one Schwann cell meets the next, the axon is unprotected. The voltage-gated sodium channels of myelinated neurons are confined to these spots (called nodes of Ranvier).

The inrush of sodium ions at one node creates just enough depolarization to reach the threshold of the next. In this way, the action potential jumps from one node to the next. This results in much faster propagation of the nerve impulse than is possible in nonmyelinated neurons.

Saltatory conduction (from the Latin saltare, to hop or leap) is the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials without needing to increase the diameter of an axon.

Multiple sclerosisThis autoimmune disorder results in the gradual destruction of myelin sheaths. Despite this, transmission of nerve impulses continues for a period as the cell inserts additional voltage-gated sodium channels in portions of the membrane formerly protected by myelin.

Hyperpolarization

Despite their name, some neurotransmitters inhibit the transmission of nerve impulses. They do this by opening

chloride channels and/or potassium channels in the plasma membrane.

In each case, opening of the channels increases the membrane potential by letting negatively-charged chloride ions (Cl-) IN and positively-charged potassium ions (K+) OUT

This hyperpolarization is called an inhibitory postsynaptic potential (IPSP).

Although the threshold voltage of the cell is unchanged, it now requires a stronger excitatory stimulus to reach threshold.

Example: Gamma amino butyric acid (GABA). This neurotransmitter is found in the brain and inhibits nerve transmission by both mechanisms:

binding to GABAA receptors opens chloride channels in the neuron. binding to GABAB receptors opens potassium channels.

Integrating Signals

A single neuron, especially one in the central nervous system, may have thousands of other neurons synapsing on it. Some of these release activating (depolarizing) neurotransmitters; others release inhibitory (hyperpolarizing) neurotransmitters.

The receiving cell is able to integrate these signals. The diagram shows how this works in a motor neuron.

1. The EPSP created by a single excitatory synapse is insufficient to reach the threshold of the neuron.

2. EPSPs created in quick succession, however, add together ("summation"). If they reach threshold, an action potential is generated.

3. The EPSPs created by separate excitatory synapses (A + B) can also be added together to reach threshold.

4. Activation of inhibitory synapses (C) makes the resting potential of the neuron more negative. The resulting IPSP may also prevent what would otherwise have been effective EPSPs from triggering an action potential.

Normally, the number of EPSPs needed to reach threshold is greater than shown here.

One might expect that depolarization at one point on the plasma membrane would generate an action potential irrespective of inhibitory signals elsewhere. However, this is avoided in many neurons by the axon hillock), the region where the axon emerges from the cell body. The portion of the plasma membrane at the axon hillock has

no synapses of its own and A lower threshold than elsewhere on the cell.

[Neurons can establish such distinctive domains on their plasma membrane by anchoring (with actin filaments) transmembrane proteins as barriers to block the free diffusion of membrane proteins from the cell body to the axon.]

The action potential is usually generated in the axon hillock. Having neither excitatory nor inhibitory synapses of its own, it is able to evaluate the total picture of EPSPs and IPSPs created in the dendrites and cell body.

Only if, over a brief interval, the sum of depolarizing signals minus the sum of the hyperpolarizing signals exceeds the threshold of the axon hillock will an action potential be generated.

This way for the neuron to evaluate a mix of positive and negative signals occurs rapidly. It turns out, however, that neurons also have a long-term way to integrate a mix of positive and negative signals converging on them. This long-term response involves changes in gene activity leading to changes in the number and activity of the cell's many synapses.

UNIT III NEUROPHARMACOLOGY

Neuropharmacology is the study of how drugs affect cellular function in the nervous system. There are two main branches of neuropharmacology: behavioral and molecular. Behavioral neuropharmacology focuses on the study of how drugs affect human behavior (neuropsychopharmacology), including the study of how drug dependence and addiction affect the human brain. Molecular neuropharmacology involves the study of neurons and their neurochemical interactions, with the overall goal of developing drugs that have beneficial effects on neurological function. Both of these fields are closely connected, since both are concerned with the interactions of neurotransmitters, neuropeptides, neurohormones, neuromodulators, enzymes, second messengers, co-transporters, ion channels, and receptor proteins in the central and peripheral nervous systems. Studying these interactions, researchers are developing drugs to treat many different neurological disorders, including pain, neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, psychological disorders, addiction, and many others.

Neurochemical Interactions

To understand the potential advances in medicine that neuropharmacology can bring, it is important to understand how human behavior and thought processes are transferred from neuron to neuron and how medications can alter the chemical foundations of these processes.

Neurons are known as excitable cells because on its surface membrane there are an abundance of proteins known as ion-channels that allow small charged particles to pass in and out of the cell. The structure of the neuron allows chemical information to be received by its dendrites, propagated through the soma (cell body) and down its axon, and eventually passing on to other neurons through its axon terminal.

These voltage-gated ion channels allow for rapid depolarization throughout the cell. This depolarization, if it reaches a certain threshold, will cause an action potential. Once the action potential reaches the axon terminal, it will cause an influx of calcium ions into the cell. The calcium ions will then cause vesicles, small packets filled with neurotransmitters, to bind to the cell membrane and release its contents into the synapse. This cell is known as the pre-synaptic neuron, and the cell that interacts with the

neurotransmitters released is known as the post-synaptic neuron. Once the neurotransmitter is released into the synapse, it can either bind to receptors on the post-synaptic cell, the pre-synaptic cell can re-uptake it and save it for later transmission, or it can be broken down by enzymes in the synapse specific to that certain neurotransmitter. These three different actions are major areas where drug action can effect communication between neurons.

There are two types of receptors that neurotransmitters interact with on a post-synaptic neuron. The first types of receptors are ligand-gated ion channels or LGIC’s. LGIC receptors are the fastest types of transduction from chemical signal to electrical signal. Once the neurotransmitter binds to the receptor it will cause a conformational change that will allow ions to directly flow into the cell. The second types are known as G-protein-coupled receptors or GPCR’s. These are much slower than LGIC’s due to an increase in the amount of biochemical reactions that must take place intracellularly. Once the neurotransmitter binds to the GPCR protein it causes a cascade of intracellular interactions that can lead to many different types of changes in cellular biochemistry, physiology, and gene expression. Neurotransmitter/receptor interactions in the field of neuropharmacology are extremely important because many drugs that are developed today have to do with disrupting this binding process.

Molecular Neuropharmacology

Molecular neuropharmacology involves the study of neurons and the neurochemical interactions, and neuron receptors with the goal of developing new drugs that will treat neurological disorders such as pain, neurodegenerative diseases, and psychological disorders (also known as neuropsychopharmacology).There are a few terminology words that must be defined when relating neurotransmission to receptor action.

1. Agonist- this is when a molecule binds to a receptor protein and activates that receptor

2. Competitive Antagonist- this is when a molecule binds to the same site on the receptor protein as the agonist, preventing activation of the receptor.

3. Non-competitive Antagonist- this is when a molecule binds to a receptor protein on a different site than that of the agonist, but causes a conformational change in the protein that does not allow activation.

The following neurotransmitter/receptor interactions can be affected by synthetic compounds that act as one of the three above. Sodium/Potassium ion channels can also be manipulated throughout a neuron to induce inhibitory effects of action potentials.

GABA

The GABA neurotransmitter mediates the fast synaptic inhibition in the central nervous system. When GABA is released from its pre-synaptic cell it will bind to a receptor (most likely the GABAA receptor) that causes the post-synaptic cell to hyperpolarize (stay

below its action potential threshold). This will counteract the effect of any excitatory manipulation from other neurotransmitter/receptor interactions.

This GABAA receptor contains many binding sites that allow conformational changes and are the primary target for drug development. The most common of these binding sites, benzodiazepine, allows for both agonist and antagonist effects on the receptor. A common drug, diazepam, acts as an allosteric enhancer at this binding site. Another receptor for GABA, known as GABAB, can be enhanced by a molecule called baclofen. This molecule acts as an agonist, therefore activating the receptor, and is known to help control and decrease spastic movement.

Dopamine

The dopamine neurotransmitter mediates synaptic transmission by binding to five specific GPCR's. These five receptor proteins are separated into two classes due to whether the response elicits a excitatory or inhibitory response on the post-synaptic cell. There are many types of drugs, legal and illegal, that effect dopamine and its interactions in the brain. With Parkinson's disease, a disease that decreases the amount of dopamine in the brain, the dopamine precursor Levadopa is given to the patient due to the fact that dopamine cannot cross the blood-brain barrier and L-dopa can. Some dopamine agonists are also given to Parkinson's patients that have a disorder known as restless leg syndrome or RLS. Some examples of these are ropinirole and pramipexole.

Psychological disorders like that of attention deficit hyperactivity disorder (ADHD) can be treated with drugs like methylphenidate (also known as Ritalin) which block the re-uptake of dopamine by the pre-synaptic cell, thereby providing an increase of dopamine left in the synaptic gap. This increase in synaptic dopamine will increase binding to receptors of the post-synaptic cell. This same process is also used by other illegal stimulant drugs like that of cocaine and amphetamines.

Serotonin

The serotonin neurotransmitter has the ability to mediate synaptic transmission through either GPCR's or LGIC receptors. Depending on what part of the brain region serotonin is being acted upon, will depend on whether the output is either increasing or decreasing post-synaptic responses. The most popular and widely used drugs in the regulation of serotonin during depression are known as SSRI's or selective serotonin reuptake inhibitors. These drugs inhibit the transport of serotonin back into the pre-synaptic neuron, leaving more serotonin in the synaptic gap to be used.

Before the discovery of SSRI's, there were also very many drugs that inhibited the enzyme that broke down serotonin. MAOI's or monoamine oxidase inhibitors increased the amount of serotonin in the pre-synaptic cell, but had many side effects including intense migraines and high blood pressure. This was eventually linked to the drug interacting with a common chemical known as tyramine found in many types of food.

Ion Channels

Ion channels located on the surface membrane of the neuron, allows for an influx of sodium ions and outward movement of potassium ions during an action potential. Selectively blocking these ion channels will decrease the likelihood of an action potential to occur. The drug riluzole is a neuroprotective drug that blocks sodium ion channels. Since these channels can not activate, there is no action potential and the neuron does not perform any transduction of chemical signals into electrical signals and the signal does not move on. This drug is used as an anesthetic along with sedative properties.

Behavioral Neuropharmacology

Dopamine and serotonin pathway

One form of behavioral neuropharmacology focuses on the study of drug dependence and how drug addiction affects the human mind. Most research has shown that the major part of the brain that reinforces addiction through neurochemical reward is the nucleus accumbens. The image to the right shows how dopamine and serotonin are projected into this area. Chronic alcohol abuse can cause major dependence and addiction. How this addiction occurs is described below.

Alcoholism

The behavior effects of alcohol are primarily produced through its actions on the brain. Intoxication is a short-term result of alcohol present in the brain that is attributed to changes in neuronal communication. Tolerance and dependence are more long-term results that involve molecular and cellular changes due to increased exposure to alcohol.

Researchers have found many areas in neuronal function that alter due to chronic alcohol exposure. In the GABAergic system, the GABAA receptor is modified effecting the efficiency and timing of inhibitory synaptic transmission. This is also usually accompanied by an increase or decrease in the release of the neurotransmitter GABA causing many of the neurons in the brain to become hyper-excitable during withdrawal from alcohol. Since GABA, for the most part, is an inhibitory neurotransmitter, a decrease in its amount will result in a feeling of anxiety. Along with the GABA neurotransmitter, there have been many links to other neurotransmitters that are affected by long-term use of alcohol including dopamine, serotonin, and glutamate.

Neuropsychopharmacology (Greek: neuron+psyche+pharmacon+logos => nerve - soul/mind - drug - study)

More precisely, neuropsychopharmacology is an interdisciplinary science related to psychopharmacology (how drugs affect the mind) and fundamental neuroscience. It entails research of mechanisms of neuropathology, pharmacodynamics (drug action), psychiatric illness, and states of consciousness. These studies are instigated at the detailed level involving neurotransmission/receptor activity, bio-chemical processes, and neural circuitry. Neuropsychopharmacology supersedes psychopharmacology in the areas of "how" and "why", and additionally addresses other issues of brain function. Accordingly, the clinical aspect of the field includes psychiatric (psychoactive) as well as neurologic (non-psychoactive) pharmacology-based treatments.

Developments in neuropsychopharmacology may directly impact the studies of anxiety disorders, affective disorders, psychotic disorders, degenerative disorders, eating behavior, and sleep behavior.

Overview

An implicit premise in neuropsychopharmacology with regard to the psychological aspects is that all states of mind, including both normal and drug-induced altered states, and diseases involving mental or cognitive dysfunction, have a neuro-chemical basis at the fundamental level, and certain circuit pathways in the central nervous system at a higher level. (See also: Neuron doctrine) Thus the understanding of nerve cells or neurons in the brain is central to understanding the mind. It is reasoned that the mechanisms involved can be elucidated through modern clinical and research methods such as genetic manipulation in animal subjects, imaging techniques such as functional magnetic resonance imaging (fMRI), and in vitro studies using selective binding agents on live tissue cultures. These allow neural activity to be monitored and measured in response to a variety of test conditions. Other important observational tools include radiological imaging such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT). These imaging techniques are extremely sensitive and can image tiny molecular concentrations on the order of 10 -10 M such as found with extrastriatal D1 receptor for dopamine.

One of the ultimate goals is to devise and develop prescriptions of treatment for a variety of neuro-pathological conditions and psychiatric disorders. More profoundly, though, the knowledge gained may provide insight into the very nature of human thought, mental abilities like learning and memory, and perhaps consciousness itself. A direct product of neuropsychopharmacological research is the knowledge base required to develop drugs which act on very specific receptors within a neurotransmitter system. These "hyperselective-action" drugs would allow the direct targeting of specific sites of relevant neural activity, thereby maximizing the efficacy (or technically the potency) of the drug within the clinical target and minimizing adverse effects.

The groundwork is currently being paved for the next generation of pharmacological treatments which will improve quality of life with increasing efficiency. For example, contrary to previous thought, it is now known that the adult brain does to some extent grow new neurons - the study of which, in addition to neurotrophic factors, may hold hope for neuro-degenerative diseases like Alzheimer's, Parkinson's, ALS, and types of chorea. All of the proteins involved in neurotransmission are a small fraction of the more than 100,000 proteins in the brain. Thus there are many proteins which are not even in the direct path of signal transduction, any of which may still be a target for specific therapy. At present, novel pharmacological approaches to diseases or conditions are reported at a rate of almost one per week.

Neurotransmission

So far as we know, everything we perceive, feel, think, know, and do are a result of neurons firing and resetting. When a cell in the brain fires, small chemical and electrical swings called the action potential may affect the firing of as many as a thousand other neurons in a process called neurotransmission. In this way signals are generated and carried through networks of neurons, the bulk electrical effect of which can be measured directly on the scalp by an EEG device.

By the last decade of the 20th century, the essential knowledge of all the central features of neurotransmission had been gained. These features are:

The synthesis and storage of neurotransmitter substances, The transport of synaptic vesicles and subsequent release into the synapse, Receptor activation and cascade function, Transport mechanisms (reuptake) and/or enzyme degradation

The more recent advances involve understanding at the organic molecular level; biochemical action of the endogenous ligands, enzymes, receptor proteins, etc. The critical changes affecting cell firing occur when the signalling neurotransmitters from one neuron, acting as ligands, bind to receptors of another neuron. Many neurotransmitter systems and receptors are well known, and research continues toward the identification and characterization of a large number of very specific sub-types of receptors. For the six more important neurotransmitters Glu, GABA, Ach, NE, DA, and 5HT (listed at neurotransmitter) there are at least 29 major subtypes of receptor. Further "sub-subtypes"

exist together with variants, totalling in the hundreds for just these 6 transmitters. It is often found that receptor subtypes have differentiated function, which in principle opens up the possibility of refined intentional control over brain function.

It has previously been known that ultimate control over the membrane voltage or potential of a nerve cell, and thus the firing of the cell, resides with the trans-membrane ion channels which control the membrane currents via the ions K+, Na+, and Ca++, and of lesser importance Mg++ and Cl-. The concentration differences between the inside and outside of the cell determine the membrane voltage.

Abstract simplified diagram showing overlap between neurotransmission and metabolic activity. Neurotransmitters bind to receptors which cause changes to ion channels (black,yellow), metabotropic receptors also affect DNA transcription (red), transcription is responsible for all cell proteins including enzymes which manufacture neurotransmitters (blue).

Precisely how these currents are controlled has become much clearer with the advances in receptor structure and G-protein-coupled processes. Many receptors are found to be pentameric clusters of five trans-membrane proteins (not necessarily the same) or receptor subunits, each a chain of many amino acids. Transmitters typically bind at the junction between two of these proteins, on the parts that protrude from the cell membrane. If the receptor is of the ionotropic type, a central pore or channel in the middle of the proteins will be mechanically moved to allow certain ions to flow through, thus altering the ion concentration difference. If the receptor is of the metabotropic type, G-proteins will cause metabolism inside the cell that may eventually change other ion channels. Researchers are better understanding precisely how these changes occur based on the protein structure shapes and chemical properties.

The scope of this activity has been stretched even further to the very blueprint of life since the clarification of the mechanism underlying gene transcription. The synthesis of cellular proteins from nuclear DNA has the same fundamental machineryfor all cells; the exploration of which now has a firm basis thanks to the Human Genome Project which has enumerated the entire human DNA sequence, although many of the estimated 35,000 genes remain to be identified. The complete neurotransmission process extends to the genetic level. Gene expression determines protein structures through type II RNA polymerase. So enzymes which synthesize or breakdown neurotransmitters, receptors, and ion channels are each made from mRNA via the DNA transcription of their respective gene or genes. But neurotransmission, in addition to controlling ion channels either directly or otherwise through metabotropic processes, also actually modulates gene expression. This is most prominently achieved through modification of the transcription initiation process by a variety of transcription factors produced from receptor activity.

Aside from the important pharmacological possibilities of gene expression pathways, the correspondence of a gene with its protein allows the important analytical tool of gene knockout. Living specimens can be created using homolog recombination in which a specific gene cannot be expressed. The organism will then be deficient in the associated protein which may be a specific receptor. This method avoids chemical blockade which can produce confusing or ambiguous secondary effects so that the effects of a lack of receptor can be studied in a purer sense.

Drugs

The inception of many classes of drugs is in principle straightforward: any chemical that can enhance or diminish the action of a target protein could be investigated further for such use. The trick is to find such a chemical that is receptor-specific (cf. "Dirty Drug") and safe to consume. The 2005 Physicians' Desk Reference lists twice the number of prescription drugs as the 1990 version. Many people by now are familiar with "selective serotonin reuptake inhibitors", or SSRI's which exemplify modern pharmaceuticals. These SSRI anti-depressant drugs, such as Paxil and Prozac, selectively and therefore primarily inhibit the transport of serotonin which prolongs the activity in the synapse. There are numerous categories of selective drugs, and transport blockage is only one mode of action. The FDA has approved drugs which selectively act on each of the major

neurotransmitters such as NE reuptake inhibitor antidepressants, DA blocker anti-psychotics, and GABA agonist tranquilizers (benzodiazepines).

New endogenous chemicals are continually identified. Specific receptors have been found for the drugs THC (cannabis) and GHB , with endogenous transmitters anandamide and GHB. Another recent major discovery occurred in 1999 when orexin, or hypocretin, was found to have a role in arousal, since the lack of orexin receptors mirrors the condition of narcolepsy. Orexin agonism may explain the anti-narcoleptic action of the drug modafinil which was already being used only a year prior.

The next step, which major pharmaceutical companies are currently working hard to develop, are receptor subtype-specific drugs and other specific agents. An example is the push for better anti-anxiety agents (anxiolytics) based on GABAA(α2) agonists, CRF1

blockers, and 5HT2c blockers. Another is the proposal of new routes of exploration for anti-psychotics such as glycine reuptake inhibitors. Although the capabilities exist for receptor-specific drugs, a shortcoming of drug therapy is the lack of ability to provide anatomical specificity. By altering receptor function in one part of the brain, abnormal activity can be induced in other parts of the brain due to the same type of receptor changes. A common example is the effect of D2 altering drugs (neuroleptics) which can help schizophrenia, but cause a variety of dyskinesias by their action on motor cortex.

Modern studies are revealing details of mechanisms of damage to the nervous system such as apoptosis (programmed cell death) and free-radical disruption. PCP has been found to cause cell death in striatopallidal cells and abnormal vacuolization in hippocampal and other neurons. The hallucinogen persisting perception disorder (HPPD), also known as post-psychedelic perception disorder, has been observed in patients as long as 26 years after LSD use. The plausible cause of HPPD is damage to the inhibitory GABA circuit in the visual pathway (GABA agonists such as midazolam can decrease some effects of LSD intoxication). The damage may be the result of an excitotoxic response of 5HT2 interneurons. [Note: the vast majority of LSD users do not experience HPPD. Its manifestation may be equally dependent on individual brain chemistry as on the drug use itself] As for MDMA, aside from persistent losses of 5HT and SERT, long-lasting reduction of serotonergic axons and terminals is found from short-term use, and regrowth may be of compromised function.

Neural circuits

It is a not-so-recent discovery that many functions of the brain are localized to associated areas like motor and speech ability. Functional associations of brain anatomy are now being complemented with clinical, behavioral, and genetic correlates of receptor action, completing the knowledge of neural signalling. The signal paths of neurons are hyper-organized beyond the cellular scale into often complex neural circuit pathways. Knowledge of these pathways is perhaps the easiest to interpret, being most recognizable from a systems analysis point of view, as may been seen in the following abstracts.

Progress has been made on central mechanisms of hallucination believed to be common to psychedelic drugs and psychotic illness. It is likely the effect of partial agonistic action on the serotonin system. The 5HT2A receptor and possibly the 5HT1C are involved by releasing glutamate in the frontal cortex, while simultaneously in the locus coeruleus sensory information is promoted and spontaneous activity decreases. One hypothesis suggests that in the frontal cortex, 5HT2A promotes late asynchronous excitatory post-synaptic potentials, a process antagonized by serotonin itself through 5HT1 which may explain why SSRI's and other serotonin-affecting drugs do not normally cause a patient to hallucinate.

Diagram of neural circuit which regulates melatonin production via actual circuit pathways. Green light in the eye inhibits pineal production of melatonin (Inhibitory connections shown in red). Also shown:reaction sequence for melatonin synthesis.

Circadian rhythm, or sleep/wake cycling, is centered in the suprachiasmatic nucleus (SCN) within the hypothalamus, and is marked by melatonin levels 2000-4,000% higher during sleep than in the day. A circuit is known to start with melanopsin cells in the eye which stimulate the SCN through glutamate neurons of the hypothalamic tract. GABA-ergic neurons from the SCN inhibit the paraventricular nucleus, which signals the superior cervical ganglion (SCG) through sympathetic fibers. The output of the SCG, stimulates NE receptors (β) in the pineal gland which produces N-acetyltransferase, causing production of melatonin from serotonin. Inhibitory melatonin receptors in the SCN then provide a positive feedback pathway. Therefore, light inhibits the production of

melatonin which "entrains" the 24-hour cycle of SCN activity. The SCN also receives signals from other parts of the brain, and its (approximately) 24 hour cycle does not only depend on light patterns. In fact, sectioned tissue from the SCN will exhibit daily cycle in vitro for many days. Additionally, (not shown in diagram), the basal nucleus provides GABA-ergic inhibitory input to the pre-optic anterior hypothalamus (PAH). When adenosine builds up from the metabolism of ATP throughout the day, it binds to adenosine receptors, inhibiting the basal nucleus. The PAH is then activated, generating slow-wave sleep activity. Caffeine is known to block adenosine receptors, thereby inhibiting sleep among other things.

Neurotransmitters are chemical messengers produced by the nervous systems of higher organisms in order to relay a nerve impulse from one cell to another cell. The two cells may be nerve cells, also called neurons, or one of the cells may be a different type, such as a muscle or gland cell. A chemical messenger is necessary for rapid communication between cells if there are small gaps of 20 to 50 nanometers (7.874 × 10 −7 –19.69 ×10 −7

inches), called synapses or synaptic clefts, between the two cells. The two cells are referred to as either presynaptic or postsynaptic. The term "presynaptic" refers to the neuron that produces and releases the neurotransmitter, whereas "postsynaptic" refers to the cell that receives this chemical message.

Neurotransmitters include small molecules with amine functional groups such as acetylcholine , certain amino acids, amino acid derivatives, and peptides. Through a series of chemical reactions, the amino acid tyrosine is converted into the catecholamine neurotransmitters dopamine and norepinephrine or into the hormone epinephrine. Other neurotransmitters that are amino acid derivatives include γ -aminobutyric acid, made from glutamate, and serotonin, made from the amino acid tryptophan.

Peptide neurotransmitters include the enkephalins, the endorphins, oxytocin, substance P, vasoactive intestinal peptide, and many others. The gaseous free radical nitric oxide is one of the more recent molecules to be added to the list of possible neurotransmitters. It is commonly believed that there may be fifty or more neurotransmitters. Although there are many

This diagram shows the transmission and reception of neurons and the role of serotonin in communication between neurons

different neurotransmitters, there is a common theme by which they are released and exert their actions. In addition, there is always a mechanism for termination of the chemical message.

General Mechanism of Action

Neurotransmitters are formed in a presynaptic neuron and stored in small membrane-bound sacks, called vesicles , inside this neuron. When this neuron is activated, these intracellular vesicles fuse with the cell membrane and release their contents into the synapse, a process called exocytosis.

Once the neurotransmitter is in the synapse, several events may occur. It may (1) diffuse across the synapse and bind to a receptor on the postsynaptic membrane, (2) diffuse back to the presynaptic neuron and bind to a presynaptic receptor causing modulation of neurotransmitter release, (3) be chemically altered by an enzyme in the synapse, or (4) be transported into a nearby cell. For the chemical message to be passed to another cell, however, the neurotransmitter must bind to its protein receptor on the postsynaptic side. The binding of a neurotransmitter to its receptor is a key event in the action of all neurotransmitters.

Mechanism of Fast-Acting Neurotransmitters

Some neurotransmitters are referred to as fast-acting since their cellular effects occur milliseconds after the neurotransmitter binds to its receptor. These neurotransmitters exert direct control of ion channels by inducing a conformational change in the receptor, creating a passage through which ions can flow. These receptors are often called ligand -gated ion channels since the channel opens only when the ligand is bound correctly. When the channel opens, it allows for ions to pass through from their side of highest concentration to their side of lowest concentration. The net result is depolarization if there is a net influx of positively charged ions or hyperpolarization if there is a net inward movement of negatively charged ions. Depolarization results in a continuation of the nerve impulse, whereas hyperpolarization makes it less likely that the nerve impulse will continue to be transmitted.

The first ligand-gated ion channel whose structure and mechanism were studied in detail was the nicotinic acetylcholine receptor of the neuromuscular junction. This receptor contains five protein subunits, each of which spans the membrane four times. When two acetylcholine molecules bind to this receptor, a channel opens, resulting in sodium and potassium ions being transported at a rate of 10 7 per second. Acetylcholine's action at these receptors is said to be excitatory due to the resulting depolarization. Other receptors for fast transmitters have a similar amino acid sequence and are believed to have a similar protein structure. Glycine and γ -aminobutyric acid (GABA) also act on ligand-gated ion channels and are fast-acting. However, they cause a net influx of chloride ions, resulting in hyperpolarization; thus, their action is inhibitory .

Mechanism of Slow-Acting Neurotransmitters

Slower-acting neurotransmitters act by binding to proteins that are sometimes called G-protein-coupled receptors (GPCRs). These receptors do not form ion channels upon activation and have a very different architecture than the ion channels. However, the timescale for activation is often relatively fast, on the order of seconds. The slightly longer time frame than that for fast-acting neurotransmitters is necessary due to additional molecular interactions that must occur for the postsynaptic cell to become depolarized or hyperpolarized. The protein structure of a GPCR is one protein subunit folded so that it transverses the membrane seven times. These receptors are referred to as G-coupled protein receptors because they function through an interaction with a GTP -binding protein, called G-protein for short.

The conformational change produced when a neurotransmitter binds to a GPCR causes the G-protein to become activated. Once it becomes activated, the protein subunits dissociate and diffuse along the intracellular membrane surface to open or close an ion channel or to activate or inhibit an enzyme that will, in turn, produce a molecule called a second messenger. Second messengers include cyclic AMP , cyclic GMP , and calcium ions and phosphatidyl inositol. They serve to activate enzymes known as protein kinases. Protein kinases in turn act to phosphorylate a variety of proteins within a cell, possibly including ion channels. Protein phosphorylation is a common mechanism used within a cell to activate or inhibit the function of various proteins.

Termination of Transmission

For proper control of neuronal signaling, there must be a means of terminating the nerve impulse. In all cases, once the neurotransmitter dissociates from the receptor, the signal ends. For a few neurotransmitters, there are enzymes in the synapse that serve to chemically alter the neurotransmitter, making it nonfunctional. For instance, the enzyme acetylcholinesterase hydrolyzes acetylcholine. Other neurotransmitters, such as catecholamines and glutamate, undergo a process called reuptake. In this process, the neurotransmitter is removed from the synapse via a transporter protein. These proteins are located in presynaptic neurons or other nearby cells.

Drugs of Abuse

The actions of neurotransmitters are important for many different physiological effects. Many drugs of abuse either mimic neurotransmitters or otherwise alter the function of the nervous system. Barbiturates act as depressants with effects similar to those of anesthetics. They seem to act mainly by enhancing the activity of the neurotransmitter GABA, an inhibitory neurotransmitter. In other words, when barbiturates bind to a GABA receptor, the inhibitory effect of GABA is greater than before. Opiates such as heroin bind to a particular type of opiate receptor, resulting in effects similar to those of naturally occurring endorphins. Amphetamines can displace catecholamines from synaptic vesicles and block reuptake of catecholamines in the synapse, prolonging the action of catecholamine neurotransmitters.

Neurites

Neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before differentiation is complete.

Neurites are often packed with microtubule bundles, the growth of which is stimulated by Nerve Growth Factor (NGF), as well as tau proteins, MAP1, and MAP2.

The neural cell adhesion molecule N-CAM simultaneously combines with another N-CAM and a fibroblast growth factor receptor to stimulate the tyrosine kinase activity of that receptor to induce the growth of neurites.

Stimulation of the shaft always results in growth of the extension.

Lewy body

Lewy bodies are abnormal aggregates of protein that develop inside nerve cells in Parkinson's disease (PD) and some other disorders. They are identified under the microscope when histology is performed on the brain.

Lewy bodies appear as spherical masses that displace other cell components. There are two morphological types: classical (brain stem) Lewy bodies and cortical Lewy bodies. A classical Lewy body is an eosinophilic cytoplasmic inclusion that consists of a dense core surrounded by a halo of 10-nm wide radiating fibrils, the primary structural component of which is alpha-synuclein. In contrast, a cortical Lewy body is less well defined and lacks the halo. Nonetheless, it is still made up of alpha-synuclein fibrils. Cortical Lewy bodies are a trademark of Dementia with Lewy bodies (DLB) and may occasionally be seen in ballooned neurons characteristic of Pick's disease and corticobasal degeneration.

A Lewy body is composed of the protein alpha-synuclein associated with other proteins such as ubiquitin, neurofilament protein, and alpha B crystallin. Tau proteins may also be present. It is believed that Lewy bodies represent an aggresome response in the cell.

[An aggresome is a proteinaceous inclusion body that forms when cellular degradation machinery is impaired or overwhelmed, leading to an accumulation of protein for disposal. The aggresomal response is believed to be a generalised-protective cell biological response to the presence of a high load of abnormal or damaged protein within the cytosol of a cell which fails to be eliminated by the usual ubiquitin proteasome system for protein degradation].

Lewy neurites

Similarly to Lewy bodies, Lewy neurites are proteinaceous formations found in neurones of the disease brain, comprising abnormal α-synuclein filaments and granular material. They are a feature of α-synucleinopathies such as Dementia with Lewy bodies, Parkinson's disease and multiple system atrophy (MSA), and are found in the CA2-3 region of the hippocampus in Alzheimer's disease.

Hormones and their effect on neuronal function

THE ENDOCRINE SYSTEM

The nervous system coordinates rapid and precise responses to stimuli using action potentials. The endocrine system maintains homeostasis and long-term control using chemical signals. The endocrine system works in parallel with the nervous system to control growth and maturation along with homeostasis.

Hormones

The endocrine system is a collection of glands that secrete chemical messages we call hormones. These signals are passed through the blood to arrive at a target organ, which has cells possessing the appropriate receptor. Exocrine glands (not part of the endocrine system) secrete products that are passed outside the body. Sweat glands, salivary glands, and digestive glands are examples of exocrine glands.

The roles of hormones in selecting target cells and delivering the hormonal message.

Hormones are grouped into three classes based on their structure:

1. steroids 2. peptides 3. amines

Steroids

Steroids are lipids derived from cholesterol. Testosterone is the male sex hormone. Estradiol, similar in structure to testosterone, is responsible for many female sex characteristics. Steroid hormones are secreted by the gonads, adrenal cortex, and placenta.

Structure of some steroid hormones and their pathways of formation.

Peptides and Amines

Peptides are short chains of amino acids; most hormones are peptides. They are secreted by the pituitary, parathyroid, heart, stomach, liver, and kidneys. Amines are derived from the amino acid tyrosine and are secreted from the thyroid and the adrenal medulla. Solubility of the various hormone classes varies.

Synthesis, Storage, and Secretion

Steroid hormones are derived from cholesterol by a biochemical reaction series. Defects along this series often lead to hormonal imbalances with serious consequences. Once synthesized, steroid hormones pass into the bloodstream; they are not stored by cells, and the rate of synthesis controls them.

Peptide hormones are synthesized as precursor molecules and processed by the endoplasmic reticulum and Golgi where they are stored in secretory granules. When needed, the granules are dumped into the bloodstream. Different hormones can often be made from the same precursor molecule by cleaving it with a different enzyme.

Amine hormones (notably epinephrine) are stored as granules in the cytoplasm until needed.

Evolution of Endocrine Systems

Most animals with well-developed nervous and circulatory systems have an endocrine system. Most of the similarities among the endocrine systems of crustaceans, arthropods, and vertebrates are examples of convergent evolution. The vertebrate endocrine system consists of glands (pituitary, thyroid, adrenal), and diffuse cell groups scattered in epithelial tissues.

More than fifty different hormones are secreted. Endocrine glands arise during development for all three embryologic tissue layers (endoderm, mesoderm, ectoderm). The type of endocrine product is determined by which tissue layer a gland originated in. Glands of ectodermal and endodermal origin produce peptide and amine hormones; mesodermal-origin glands secrete hormones based on lipids.

Endocrine Systems and Feedback Cycles

The endocrine system uses cycles and negative feedback to regulate physiological functions. Negative feedback regulates the secretion of almost every hormone. Cycles of secretion maintain physiological and homeostatic control. These cycles can range from hours to months in duration.

Negative feedback in the thyroxine release reflex.

Mechanisms of Hormone Action

The endocrine system acts by releasing hormones that in turn trigger actions in specific target cells. Receptors on target cell membranes bind only to one type of hormone. More than fifty human hormones have been identified; all act by binding to receptor molecules. The binding hormone changes the shape of the

receptor causing the response to the hormone. There are two mechanisms of hormone action on all target cells.

Nonsteroid Hormones

Nonsteroid hormones (water soluble) do not enter the cell but bind to plasma membrane receptors, generating a chemical signal (second messenger) inside the target cell. Five different second messenger chemicals, including cyclic AMP have been identified. Second messengers activate other intracellular chemicals to produce the target cell response.

The action of nonsteroid hormones.

Steroid Hormones

The second mechanism involves steroid hormones, which pass through the plasma membrane and act in a two step process. Steroid hormones bind, once inside the cell, to the nuclear membrane receptors, producing an activated hormone-receptor complex. The activated hormone-receptor complex binds to DNA and activates specific genes, increasing production of proteins.

The action of steroid hormones.

Endocrine-related Problems 1. Overproduction of a hormone 2. Underproduction of a hormone 3. Nonfunctional receptors that cause target cells to become insensitive to

hormones

The Nervous and Endocrine Systems

The pituitary gland (often called the master gland) is located in a small bony cavity at the base of the brain. A stalk links the pituitary to the hypothalamus, which controls release of pituitary hormones. The pituitary gland has two lobes: the anterior and posterior lobes. The anterior pituitary is glandular.

The endocrine system in females and males.

The hypothalamus contains neurons that control releases from the anterior pituitary. Seven hypothalamic hormones are released into a portal system connecting the hypothalamus and pituitary, and cause targets in the pituitary to release eight hormones.

The location and roles of the hypothalamus and pituitary glands.

Growth hormone (GH) is a peptide anterior pituitary hormone essential for growth. GH-releasing hormone stimulates release of GH. GH-inhibiting hormone suppresses the release of GH. The hypothalamus maintains homeostatic levels of GH. Cells under the action of GH increase in size (hypertrophy) and number (hyperplasia). GH also causes increase in bone length and thickness by deposition of cartilage at the ends of bones. During adolescence, sex hormones cause replacement of cartilage by bone, halting further bone growth even though GH is still present. Too little or two much GH can cause dwarfism or gigantism, respectively.

Hypothalamus receptors monitor blood levels of thyroid hormones. Low blood levels of Thyroid-stimulating hormone (TSH) cause the release of TSH-releasing hormone from the hypothalamus, which in turn causes the release of

TSH from the anterior pituitary. TSH travels to the thyroid where it promotes production of thyroid hormones, which in turn regulate metabolic rates and body temperatures.

Gonadotropins and prolactin are also secreted by the anterior pituitary. Gonadotropins (which include follicle-stimulating hormone, FSH, and luteinizing hormone, LH) affect the gonads by stimulating gamete formation and production of sex hormones. Prolactin is secreted near the end of pregnancy and prepares the breasts for milk production. .

The Posterior Pituitary

The posterior pituitary stores and releases hormones into the blood. Antidiuretic hormone (ADH) and oxytocin are produced in the hypothalamus and transported by axons to the posterior pituitary where they are dumped into the blood. ADH controls water balance in the body and blood pressure. Oxytocin is a small peptide hormone that stimulates uterine contractions during childbirth.

Other Endocrine Organs

The Adrenal Glands

Each kidney has an adrenal gland located above it. The adrenal gland is divided into an inner medulla and an outer cortex. The medulla synthesizes amine hormones, the cortex secretes steroid hormones. The adrenal medulla consists of modified neurons that secrete two hormones: epinephrine and norepinephrine. Stimulation of the cortex by the sympathetic nervous system causes release of hormones into the blood to initiate the "fight or flight" response. The adrenal cortex produces several steroid hormones in three classes: mineralocorticoids, glucocorticoids, and sex hormones. Mineralocorticoids maintain electrolyte balance. Glucocorticoids produce a long-term, slow response to stress by raising blood glucose levels through the breakdown of fats and proteins; they also suppress the immune response and inhibit the inflammatory response.

The structure of the kidney as relates to hormones.

The Thyroid Gland

The thyroid gland is located in the neck. Follicles in the thyroid secrete thyroglobulin, a storage form of thyroid hormone. Thyroid stimulating hormone (TSH) from the anterior pituitary causes conversion of thyroglobulin into thyroid hormones T4 and T3. Almost all body cells are targets of thyroid hormones.

Thyroid hormone increases the overall metabolic rate, regulates growth and development as well as the onset of sexual maturity. Calcitonin is also secreted by large cells in the thyroid; it plays a role in regulation of calcium.

The Pancreas

The pancreas contains exocrine cells that secrete digestive enzymes into the small intestine and clusters of endocrine cells (the pancreatic islets). The islets secrete the hormones insulin and glucagon, which regulate blood glucose levels.

After a meal, blood glucose levels rise, prompting the release of insulin, which causes cells to take up glucose, and liver and skeletal muscle cells to form the carbohydrate glycogen. As glucose levels in the blood fall, further insulin production is inhibited. Glucagon causes the breakdown of glycogen into glucose, which in turn is released into the blood to maintain glucose levels within a homeostatic range. Glucagon production is stimulated when blood glucose levels fall, and inhibited when they rise.

Diabetes results from inadequate levels of insulin. Type I diabetes is characterized by inadequate levels of insulin secretion, often due to a genetic cause. Type II usually develops in adults from both genetic and environmental causes. Loss of response of targets to insulin rather than lack of insulin causes this type of diabetes. Diabetes causes impairment in the functioning of the eyes, circulatory system, nervous system, and failure of the kidneys. Diabetes is the second leading cause of blindness in the US. Treatments involve daily injections of insulin, monitoring of blood glucose levels and a controlled diet.

Other Chemical Messengers

Interferons are proteins released when a cell has been attacked by a virus. They cause neighboring cells to produce antiviral proteins. Once activated, these proteins destroy the virus.

Prostaglandins are fatty acids that behave in many ways like hormones. They are produced by most cells in the body and act on neighboring cells.

Pheromones are chemical signals that travel between organisms rather than between cells within an organism. Pheromones are used to mark territory, signal prospective mates, and communicate. The presence of a human sex attractant/pheromone has not been established conclusively.

Biological Cycles

Biological cycles ranging from minutes to years occur throughout the animal kingdom. Cycles involve hibernation, mating behavior, body temperature and many other physiological processes.

Rhythms or cycles that show cyclic changes on a daily (or even a few hours) basis are known as circadian rhythms. Many hormones, such as ACTH-cortisol, TSH, and GH show circadian rhythms.

The menstrual cycle is controlled by a number of hormones secreted in a cyclical fashion. Thyroid secretion is usually higher in winter than in summer. Childbirth is hormonally controlled, and is highest between 2 and 7 AM.

Internal cycles of hormone production are controlled by the hypothalamus, specifically the suprachiasmic nucleus (SCN). According to one model, the SCN is signaled by messages from the light-detecting retina of the eyes. The SCN signals the pineal gland in the brain to signal the hypothalamus, etc.

Endocrine System

The endocrine system is the internal system of the body that deals with chemical communication by means of hormones, the ductless glands that secrete the hormones, and those target cells that respond to hormones. The endocrine system functions in maintaining the basic functions of the body ranging from metabolism to growth. The endocrine system functions in long term behavior and works in conjunction with the nervous system in regulating internal functions and maintaining homeostasis.

Hormones

Hormones are the chemical messengers released by specialized endocrine cells or specialized nerve cells called neurosecretory cells. Hormones are released by the endocrine system glands into the body’s fluids, most often into the blood and transported throughout the body. Hormones are specified by their different chemical structures which can be classified into four categories

Amines: are small molecules originating from amino acids. Examples of this are epineprine and thyroid hormones.

Prostaglandins:are cyclic unsaturated hydroxy fatty acids synthesized in membranes from 20 carbon fatty acid chains

Steroid hormones: are cyclic hydrocarbon derivatives synthesized in all instances from the precursor steroid cholesterol. Examples of this are testosterone and estrogen.

Peptide and Protein hormones: are the largest and most complex hormone. Example of this is insulin.

Hormones drive the endocrine system and without them the body could not function. Hormones are the communicators of the endocrine system and are responsible for maintaining and controlling cellular activity. 

Hormones function

Hormones regulate bodily functions and are specific in what responses they elicit. As hormones are released into the bloodstream they can only initiate responses in target cells, which are specifically equipped to respond. Each hormone due to its chemical structure is recognized by those target cells with receptors compatible with their structure. Once a hormone is released, the first step is the specific binding of the chemical signal to a hormone receptor, a protein within the target cell or built into the plasma membrane. The receptor molecule is essential to a hormones function. The receptor molecule translates the hormone and enables the target cell to respond to the hormones chemical signal. The meeting of the hormone with the receptor cell initiates responses from the target cell. These responses vary according to target cell and lipid solubility.

Hormones are either lipid-soluble or lipid-insoluble, depending on their biochemical structure.  The lipid solubility of the hormone determines the mechanism by which it can affect its target cell.

Lipid-soluble hormones are able to penetrate through the cell membrane and bind to receptors located inside the cell. Such hormones diffuse across the plasma membrane and target those receptor cells found within the cytoplasm. Lipid-soluble hormones target the cytoplasmic receptors which readily diffuse into the nucleus and act on the DNA, inhibiting and stimulating certain proteins. DNA function is of great influence over the cellular activities of the body and therefore such hormonal-DNA interaction can have effects as long as hours and in some cases days. Two known types of lipid soluble hormones are steroids and thyroid hormones. Both travel over long courses of time via the bloodstream and both directly effect DNA functions.

Those hormones which are lipid-insoluble are unable to penetrate through the plasma membrane and function with their target cells in a much different and complex manner. Lipid-insoluble hormones must bind with cell-surface receptors which follow a different path involving a second messenger. The hormone's inability to penetrate the membrane requires a second messenger which translates the outer message and functions within the cell.

Once a lipid-insoluble hormone binds with a cell surface receptor, its’ signal is translated into the cell by specific secondary messengers. There are three known and accepted secondary messengers which vary in structure and function, but all three carry out the external signal internally. The three known secondary messengers are (1) cyclic nucleotide compounds (cNMPs), cAMP, and cGMP; (2) inositol phospholipids; and (3) Ca2+ ions. After a hormone binds with a receptor molecule it via a transducer protein sends the hormones signal through the membrane. The protein receptor initiates the formation of a second messenger, whether it be it be cAMP or an inositol phospholipid, which then binds to an internal regulator. The internal regulator controls the target cells’ response to the hormone's signal.

Each different type of secondary messenger evokes different responses by those cells they affect. cAMP has wide range of tissues it targets and those responses it elicits. cAMP pathways can increase the heart rate and force a contraction in a heart, it can decrease lipid breakdown in fat cells, and it can stimulate resorption of water in a kidney. An inositol phospholipid pathway can initiate breakdown of liver glycogen and DNA synthesis in fibroblasts. Ca2+ pathways are linked to initiating responses in striated muscles most notably contraction. These responses, however, are short lived responses; much shorter then those by lipid soluble affected cells. Although the cellular mechanisms of hormones vary according to solubility and first and second messengers, such hormones function in eliciting responses from their target cells.

Hormones more or less function as a stimulant, promoting an action in a target cell which can be magnified in stimulating organs or even systems. Hormone stimulation varies from growth and metabolic functions to ova and sperm production.

Signals transmitted by the endocrine system

There are two ways in which the endocrine system affects the rest of the organism. The first method of transmission, is called local signaling. This is when regulators are released by a gland or cell into the interstitial fluids and are absorbed by nearby cells. The second method of transmission is called long distance signaling. Long distance signaling takes place when an endocrine cell or neurosecretory cell releases hormones into the bloodstream. Once in the bloodstream the hormones travel to the receptor cell. When they reach their destination the receptor cell integrates the signal and reacts to its design. 

Growth factors in the endocrine system

Growth factors affect the development of new cells. There are specific hormones that correspond with the development of specific cells. For example, epidermal growth factor is required to grow epithelial cells. The rate of growth can also be affected, for example an experiment on fetal mice was done to see if rate of growth of skin would change with an influx of hormones. It was found that by injecting the fetal mice with EGF that skin developed faster.

The role of the hypothalamus and pituitary gland

The hypothalamus and pituitary gland are two parts of the brain that have important roles in integrating the nervous and endocrine system. The hypothalamus is found in the lower part of the brain in the midbrain where it functions in receiving messages from nerves and integrating that into endocrine gland responses. The hypothalamus is more or less the communication link between the nervous system and the endocrine system. The hypothalamus regulates the secretion of various hormones by controlling the main hormonal gland the pituitary gland

The pituitary gland releases hormones that control many of the endocrine system's functions. The pituitary gland releases hormones when signaled by the hypothalamus. The pituitary gland has numerous functions which are performed by its’ two parts. Pituitary’s two separate parts are essential to the production of many hormones but, their function in relation to the hypothalamus and endocrine system vary greatly.

The posterior pituitary is an extension of the brain and secretes two types of hormones, oxytocin and antidiuretic hormone(ADH), both of which are produced by the hypothalamus and released into the posterior pituitary. Neurosecretory cells in the hypothalamus produce oxytocin and ADH and are transported down an axon to the posterior pituitary where it is stored. The posterior pituitary releases these hormones when needed via the bloodstream and bind to their target cells. The posterior pituitaries hormones elicit specific responses from the kidneys, by means of ADH, and the mammary glands, by means of oxytocin. ADH acts directly on the ability of the kidneys to reabsorb water, whereas oxytocin causes mammary glands to release milk.

The anterior pituitary also relies on the hypothalamus to control and regulate its hormonal release, but in a less direct manner.  The release of hormones by the anterior pituitary is driven by neurosecretory cells located in the hypothalamus. When the hypothalamus receives a signal for the need of a hormone produced by the anterior pituitary, it sends releasing hormones through short portal vessels and into a second capillary network within the anterior pituitary, where it acts on a specific hormone. Besides releasing stimulatory hormones the hypothalamus also releases inhibiting hormones which prevent the release of certain hormones from the anterior pituitary. The anterior pituitary produces and releases several different hormones with many different functions. Its hormones range from growth hormones that act on bones, to prolactin which stimulates mammary glands. A unique function of those hormones released by the anterior posterior, is that some of them act on other endocrine glands and signal them to produce and release other hormones. Tropic hormones are responsible for this, such as thyroid stimulating hormone which stimulates the thyroid and its production of hormones. 

Pheromones and their function

Pheromones are chemical signals that function as external communicators whereas hormones are internal. Pheromones communicate between separate individuals, not within one individual as hormones do. Pheromones are communicating chemicals that act between animals of the same species. Pheromones are dispersed into the environment and are used in attraction, defense, and marking territories. Pheromones play a great role in the insect world, but their importance in human interaction is disputed. Some scientist question the presence of chemical influence on human behavior while an entire industry, the fragrance industry, bases its existence on the appreciation for external scents. Pheromones most likely play a hidden role in the interaction of humans with each other. 

The Endocrine System related to the Nervous System

The nervous and endocrine systems are related in three main areas, structure, chemical, and function. The endocrine and nervous system work parallel with each other and in conjunction function in maintaining homeostasis, development and reproduction. Both systems are the communication links of the body and aid the body’s life systems to function correctly and in relation to each other.

Structurally many of the endocrine systems glands and tissues are rooted in the nervous system, Such glands as the hypothalamus and posterior pituitary are examples of nerve tissues that influence the function of a gland and it’s secretion of hormones. Not only does the hypothalamus secrete hormones into the bloodstream, but it regulates the release of hormones in the posterior pituitary gland. Those that are not made of nervous tissue once were. The adrenal medulla is derived from the same cells that produce certain ganglia.

Chemically both the endocrine and nervous system function in communication by means of the same transmitters but use them in different ways. Hormones are utilized by both systems in signaling an example of this can be seen in the use of Norepinephrine.

Norepineprine functions as a neurotransmitter in the nervous system and as an adrenal hormone in the endocrine system.

Functionally the nervous and endocrine system work hand in hand acting in communicating and driving hormonal changes. They work in maintaing homeostasis and respond to changes inside and outside the body. Besides functioning in similar manners they work in conjunction. An example of this can be seen in a mothers release of milk. When a baby sucks the nipple of its mother, sensory cells in the nipple sends signals to the hypothalmus, which then responds by releaing oxytocin from the posterior pituitary. The oxytocin is released into the bloodstream where it moves to its’ target cell, a mammary gland. The mammary gland then responds to the hormones signal by releasing milk through the nipple. Besides working in conjunction with each other, both systems affect one another. The adrenal medulla is under control the control of nerve cells, but the nervous systems development is under the control of the endocrine system. 

Growth hormone

Growth hormone (GH) is a peptide hormone produced by the anterior lobe of the pituitary gland in response to GH-releasing hormone from the hypothalamus. Release of growth hormone is inhibited bysomatostatin, which also is produced by the hypothalamus.  GH enhances the metabolism of fats for energy. It also enhances amino acid uptake and protein synthesis, which help in growth of cartilage and bone.  Secretion of growth hormone is increased by exercise, stress, lowered blood glucose, and by insulin. 

The hormones that influence our attitudes and behaviors

There are many hormones that in one way or another effect attitude and behavior, but in the interest ot time and space, this section will mostly discuss the gonadal, placenta, and thyroid hormones.

A variety of hormones are produced by the gonads and placenta. Estrogens, such as estradiol, function in the development and maintenance of the female reproductive tract, in the simulation of the mammary glands, in the development of secondary sex characteristics, and in the regulation of behavior. Androgens, such as testosterone, influence the development and maintenance of the male reproductive tract, secondary sex characteristics, and behavior.

There has been a great deal of interest in the relationship between hormones and behavior and it has been found that the natural variation in the amount of hormones present is correlated with variation in behavior. For example, during the female menstrual period the "average" female shows a decreased body temperature, decrease in food and water intake, decrease in body weight, and she becomes sexually receptive. These variations within the body cause the females behavior to change. It's been found that it can result in changing of mood, performance in cognitive tasks, sensory sensitivity, and sexual activity. Unfortunately, due to the possible implications of gender issues this research is

controversial. The same can happen with males. Research has shown that there is some suggestion of a relationship between androgens, like testosterone, and dominance-related behavior. For example, men with high levels of testosterone are prone to be more competitive and have a higher level of aggression.

Thyroid hormones can also influence a person's mood due to the changes in the thyroid's activity. Little is known about the mechanisms by which thyroid hormones elevate mood, but it has a connection to the neural functions in the brain, which have influence over hormone release.

Many psychological disorder are directly related to certain impairments of brain functioning (chemical and hormonal imbalances), while others are more behaviorally orientated. Affective Disorders, for example, are those in which there is a disturbance of mood. One form of this disorder is depression which has been related to a number of hormones like melatonin and thyroid hormones.

Headaches, which can dramatically make a person irritable, snappy, and emotional can be another consequence of a hormone. During the female menstrual period, around ovulation time, estrogen rises to a peak. When estrogen is high a message goes out to produce a hormone called serotonin. This hormone makes the blood vessels in the brain narrow. This doesn't cause any pain, but when the estrogen, and hence serotonin, levels drop, blood vessels in the head begin to expand and put pressure on nerves. This causes the pain you feel when you have a headache.