Neurotransmitters. Definition They are chemical messengers which released from neurons to act on...
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Transcript of Neurotransmitters. Definition They are chemical messengers which released from neurons to act on...
NeurotransmittersNeurotransmitters
DefinitionDefinition
They are They are chemical messengerschemical messengers which which released from released from neuronsneurons to act on adjacent to act on adjacent cells which are cells which are usuallyusually also neurons also neurons
Peripherally,adjacent effector's cell Peripherally,adjacent effector's cell may may bebe a muscle or glandular cell a muscle or glandular cell
DifferencesDifferences
HormonesHormones: : produced by ductless produced by ductless glands,secreted into circulation, go to distance glands,secreted into circulation, go to distance target cells,to act via specific protein receptors target cells,to act via specific protein receptors at these cells e.g: at these cells e.g: Aldosterone,Insulin,ADH,ThyroxinAldosterone,Insulin,ADH,Thyroxin
AutacoidsAutacoids : : act on target cells close to act on target cells close to their site of release,called “local hormones” or their site of release,called “local hormones” or “paracrine secretions” e.g: “paracrine secretions” e.g: Histamine,prostaglandinHistamine,prostaglandin
CriteriaCriteria
1.1. The substance must be present within the The substance must be present within the presynaptic neuronpresynaptic neuron
2.2. The substance must be released in response The substance must be released in response to presynaptic depolarization, and the release to presynaptic depolarization, and the release must be Ca2+-dependentmust be Ca2+-dependent
3.3. Specific receptors for the substance must be Specific receptors for the substance must be present on the postsynaptic cellpresent on the postsynaptic cell
Major classes of NTMajor classes of NT
Amino AcidsAmino Acids GlutamateGlutamate ( (excitatoryexcitatory)) GABAGABA ( (inhibitoryinhibitory) )
Acetylcholine Acetylcholine ((excitatoryexcitatory))
Monoamine Monoamine ((excitatoryexcitatory)) Catecholamine: Catecholamine: DopamineDopamine, , NorepinephrineNorepinephrine Indolamine: Indolamine: SerotoninSerotonin
Neural organization of NT systems
Communication
(GLT & GABA)
Coordination
(GLT & GABA)
Modulation
(Ach, NE, DA,5HT
III III
I, II, & III are different CNS areas, e.g.cortex, brainstem, spinal cord
1. Amino acids1. Amino acids
Glutamate (GLT) & ɣ-aminobutyric acid Glutamate (GLT) & ɣ-aminobutyric acid (GABA)(GABA)
Main excitatory (GLT) and inhibitory Main excitatory (GLT) and inhibitory (GABA) NTs in CNS(GABA) NTs in CNS Found throughout CNS in long axon and Found throughout CNS in long axon and
intrinsic neuronsintrinsic neurons Interacts with / modulate activity within other Interacts with / modulate activity within other
NT systemsNT systems
AA synthesis and AA synthesis and metabolismmetabolismGlucose OR glutamine
Glutamate (GLT)
γ- aminobutyric acid (GABA)
Glutamic acid decarboxylase (GAD)
Kribs cycle
• Metabolism• Reuptake by presynaptic neuron and glial cells
• Recycled into glutamate (& GABA)
Glutamate receptors
Ionotropic (fast): Na+ in AMPA: fast excitatory signals Kainate: fast excitatory, autoreceptor (↑ GLT
release) Ionotropic (slow): Na+, Ca2+ in
NMDA: sustained, high-frequency excitatory signals
Activated by repeated excitatory stimulation: escalation
Metabotropic (slow): K+ out; Ca2+ in
Glutamate ReceptorsGlutamate Receptors
GLT function & effectGLT function & effect
Main excitatory NT within CNS Pain perception:
Acute: AMPA / kainate (co-transmission substance P)
Chronic (neuropathic): NMDA
Memory: long-term potentiation (LTP) Epilepsy, excitotoxicity (ischemic episodes)
GABAGABA Major inhibitory neurotransmitter in CNSMajor inhibitory neurotransmitter in CNS
Hyperpolarizes postsynaptic membraneHyperpolarizes postsynaptic membrane
Two types of GABA Receptors:Two types of GABA Receptors: GABA-AGABA-A
ClCl-- channel channel binding Cl binding Cl-- conductance in presynaptic conductance in presynaptic neuronsneurons
““fast” response (1msec)fast” response (1msec) Benzodiazepines, barbituratesBenzodiazepines, barbiturates
GABA-BGABA-B G-protein coupled receptorG-protein coupled receptor K+ conductanceK+ conductance ““slow” response (1sec)slow” response (1sec)
GABA ReceptorsGABA Receptors
GABA functions & effectGABA functions & effect
Main inhibitory NT within CNSMain inhibitory NT within CNS synchronize local neural activity synchronize local neural activity modulation of motor control in basal gangliamodulation of motor control in basal ganglia broad distribution underlies importance of broad distribution underlies importance of
tonic inhibition in CNStonic inhibition in CNS
Dysfunction = EpilepsyDysfunction = Epilepsy
2. Acetylcholine (Ach)2. Acetylcholine (Ach) Earliest discovered neurotransmitter
NT @ ALL first synapses outside CNS (autonomic ganglia)
Terminal NT: parasympathetic NS; skeletal muscle
2 receptor families Muscarinic: metabotropic
PNS: parasympathetic NS terminals CNS cortex, hippocampus (HC), striatum
Nicotonic: ionotropic (Na+ in) CNS cortex, hippocampus (HC), ventral tegmental area (VTA) PNS: autonomic ganglia, skeletal muscle junctions
ACh synthesis and metabolism
choline
acetylcholine (ACh)
choline [reuptake into presynaptic neuron] + acetate [to blood]
Acetylcholinesterase (AChE)
Choline acetyltransferase (ChAT)
Ach function & effect Ach function & effect (brain)(brain)
1. Pedunculopontine – lateral dorsal pathway Sleep / wake (REM sleep); motor (ACh →DA)
2. Basal forebrain cholinergic pathways Medial septal nucleus →HC + amygdala Learning and memory
3. Nucleus basalis of Maynert → cortex Attention and memory
Ach circuit in brainAch circuit in brain
3. Monoamines3. Monoamines
Catecholamines
Indolamine(s)
Dopamine (DA) Found only in CNS (not PNS): widely
distributed via pathways ascending from midbrain
Can be excitatory or inhibitory [location, receptors,interactions w other NTs]
2 receptor families: D1 (D5) & D2 (D3, D4) D1 striatum; (D5) hippocampus, hypothalamus D2 striatum; substantia nigra (SN) & VTA
[autoreceptors] D3 limbic, striatum, cortex; SN [autoreceptors] D4 limbic, frontal cortex
DA synthesis and metabolism
Tyrosine (amino acid from diet)
Dopa
Dopamine (DA)
DOPAC + HVA
Tyrosine hydroxylase
Dopa decarboxylase on postsynaptic membrane
Monoamine oxidase (MAO) in presynaptic neuron [after reuptake]Catechol-O-methyl transferase (COMT)
Wait a minute !!Wait a minute !!
HO
HO
NH3+
Dopamine
Polar groups Mostly protonatedto the correspondingammonium salt
HO
HO
NH3+
L-DOPA
Polar groups Mostly protonatedto the correspondingammonium saltO O
H
Polar group
If dopamine is too polar to cross the BBB, If dopamine is too polar to cross the BBB, how can L-DOPA cross it?how can L-DOPA cross it?
Answer !Answer !
L-DOPA is transported across the BBB L-DOPA is transported across the BBB by an amino acid transport system (same by an amino acid transport system (same one used for tyrosine and phenylalanine)one used for tyrosine and phenylalanine)
DA function & effectDA function & effect
Nigrostriatal pathwayMotor function
Mesolimbic and Mesocortical pathways Pleasure & Reward, reinforcement, motivation Attentional and behavioural control Endocrine regulation (Prolactin)
PsychosisSchizophrenia, hallucinatory drugs
DA circuit in brainDA circuit in brain
Reward circuitryReward circuitryPrefront
alcortex
dopamine
nucleus accumbe
ns
dopamine
VTA
dopamine
Reward Reward PathwayPathway
?
Norepinephrine (NE)
Found in both PNS (sympathetic NS), and widely distributed in CNS
3 receptor families (all metabotropic): Alpha-1: excitatory postsynaptic (↑Ca2+ flow) Alpha-2: inhibitory presynaptic [autoreceptor] (↑K+,
↓Ca2+) Beta: excitatory presynaptic [autoreceptors] &
postsynaptic
Synthesized from DA in NE axon terminals; metabolized (after reuptake) by MAO / COMT
NE in PNS:Autonomic (sympathetic) NS
Sympathetic NS terminals and adrenal medulla Fight-or-flight
response
NE pathways in brain
2 major groups of NE neurons ascending from pontine locus coeruleus (LC) and lateral tegmental nuclei (LTN) some overlap, together
innervate whole brain
NE function & effectNE function & effect Arousal: LC sleep/wake state Arousal ↔ attention
Tonic NE activity in LC = vigilant attention Scanning, high behavioural flexibility
Phasic NE activity in LC = focused attention Selective attention, response inhibition
Also involved in nociception, memory, and control of autonomic & endocrine function
Serotonin (5-HT)
5-hydroxytryptamine Found in both PNS and CNS
CNS contains < 2% total 5-HT in bodyOutside CNS: broad range physiological functions
7 (!) receptor subtypes (ionotropic and metabotropic)Not clearly associated with specific brain regionsSome functional specificity (with overlap)
Serotonin ReceptorsSerotonin Receptors 5-HT5-HT1A1A CNS: neuronal inhibition, behavioral effects (sleep, feeding, CNS: neuronal inhibition, behavioral effects (sleep, feeding,
thermoregulation, anxiety) thermoregulation, anxiety) 5-HT5-HT1B1B CNS: presynaptic inhibition, behavioral effects; vascular: CNS: presynaptic inhibition, behavioral effects; vascular:
pulmonary vasoconstriction ergotaminepulmonary vasoconstriction ergotamine 5-HT5-HT1D1D CNS: locomotion; vascular: cerebral vasoconstrictionCNS: locomotion; vascular: cerebral vasoconstriction 5-HT5-HT2A2A CNS: neuronal excitation, behavioral effects; smooth muscle: CNS: neuronal excitation, behavioral effects; smooth muscle:
contraction, vasoconstriction / dilatation; platelets: aggregation α-contraction, vasoconstriction / dilatation; platelets: aggregation α-methyl-5-HTmethyl-5-HT
5-HT5-HT2B2B stomach: contraction α-methyl-5-HTstomach: contraction α-methyl-5-HT 5-HT5-HT2C2C CNS, choroid plexus: (CSF) secretion α-methyl-5-HT, LSDCNS, choroid plexus: (CSF) secretion α-methyl-5-HT, LSD 5-HT5-HT33 CNS, PNS: neuronal excitation, anxiety, emesisCNS, PNS: neuronal excitation, anxiety, emesis 5-HT5-HT44 GIT, CNS: neuronal excitation, gastrointestinal motilityGIT, CNS: neuronal excitation, gastrointestinal motility 5-Ht5-Ht55 CNS: unknown CNS: unknown 5-Ht5-Ht66 CNS: unknown CNS: unknown 5-HT5-HT77 CNS, GIT, blood vessels: unknownCNS, GIT, blood vessels: unknown
5-HT synthesis and metabolism
Tryptophan (amino acid from diet)
5-hydroxytryptophan
Serotonin (5-HT)
5-HIAA
Tryptophan hydroxylase
L-aromatic acid decarboxylase
Monoamine oxidase (MAO) in presynaptic neuron [after reuptake]
Aldehyde dehydrogenase
5-HT functions: ‘body’
Coordinate physiological functioning Physiological regulation
Thermoregulation, appetite and digestion, cardiovascular activity, sexual functioning, pain perception
Circadian rhythms Sleep/wake cycle: precursor of melatonin
(pineal gland)
5-HT functions: ‘mind’
Affect regulation and cognitive function Learned helplessness Anticipatory anxiety Inhibit pain sensation 5-HT contributes to (declarative)
memory, particularly for emotional stimuli
Summary Neural signaling occurs via electrical impulse
down the axon, causing NT release Amino acids glutamate and GABA are the major
excitatory and inhibitory NTs in the CNS, modulating activity via long-axon and intrinsic neurons
Ach, DA, NE, and 5-HT systems originate in subcortical nuclei and project along organized pathways to modulate brain activity; although interactive, each is associated with certain functions and neuromodulatory disorders