Lecture Serotonin ACh and Histamine
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Transcript of Lecture Serotonin ACh and Histamine
Psych 215Lecture 5a: Serotonin
Lecture 5a: 5-HT Objectives• Explain the derivation of the name “serotonin”• Describe the chemical features of 5-HT that distinguish it from catecholamines• Describe the two general 5-HT systems in the brain in terms of their projections• Distinguish between the projections of the D and M ascending 5-HT systems based on
morphology and sensitivity to toxins• Outline the pathway through which 5-HT is made from tryptophan, indicate which enzyme is the
rate-limiting step in 5-HT synthesis and highlight known regulatory mechanisms• Explain why altering dietary tryptophan levels can affect 5-HT levels• Describe the mechanisms of action of PCPA, fenfluramine, methamphetamine, MDMA (ecstasy),
LSD, reserpine, ondansetron, fluoxetine, paroxetine and sertraline as they relate to 5-HT transmission
• Explain how one could demonstrate that serotonin releasers such as fenfluramine act on non-vesicular stores of 5-HT
• Explain the effects of agonists and antagonists at 5-HT1A and/or 5-HT1B/1D receptors upon extracellular levels of 5-HT
• Describe the intracellular signaling pathway for 5-HT1 receptors and relate this signaling to their role in regulating 5-HT release.
• Describe the intracellular signaling pathway for 5-HT2 receptors and relate this signaling to their hallucinogenic profile.
• Describe some of the oddities observed regarding the regulation of 5-HT2 receptor expression by agonists and antagonists
• Distinguish 5-HT3 receptors from other 5-HT receptors in terms of structure, function, and localization in brain
• Explain the neuronal consequences of the repeated administration of 5-HT releasers and predict which brain regions/behaviors would be most likely affected
Indolamine-Serotonin
Isolated from blood and induced muscle contraction in heart=“serum” + “tone”=serotonin
Isolated from intestinal mucosa and induced muscle contraction=enteramine (secreted by enterochromaffin cells in GI tract)
-90% in GI; 8%-10% in blood platelets & 1-2% in brain (but several 100, 000 5-HT neurons in your brain)
-cannot cross the BBB
catecholamines
5-HT projections in brain
Nine 5-HT containing cell body groups located in the brain stem (B1-9)Two systems: caudal versus rostral systems
Caudal system: B1-4; medulla and central pons; project down spinal cord in several pathways (ventral horn, dorsal horn, preganglionic sympathetic cells rolein sensory, motor and autonomic functioning)Rostral system: B5-9; rostral pons and mesencephalon (dorsal and medial raphe, B6-B8, provide 80% of forebrain 5-HT) innervate cortex, basal ganglia, habenula, thalamus, hypothalamus, limbic system
Synthesis Tryptophan hydroxylase=rate-limiting step-made in cell bodies and transported to terminal for 5-HT synthesis-tryptophan crosses BBB and can be regulated by diet-regulated by PKA, CaMKII-gene regulated by cAMP/CREB although no CRE site-no end-product feedback-PCPA=irreversible antagonist (2 weeks)
AADC=very rapid enzyme (same as for converting DOPA to dopamine; found in terminal)
5-HT metabolism:2 processes:1-deamination & 2-oxidation
1. MAO-A: oxidative deamination of catecholamines-enzyme localized in synapse as well as in terminal; cytosolicMAO responsible for majority of break-down after re-uptake
2. Aldehyde dehydrogenase:5-HIAA which diffuses out of
terminals and into CSF-spinal tap for index of 5-HT release/reuptake
MAO-Ainhibitors
5-HT projections in brain
2 types of 5-HT fibers in the brain:
1-Thin; very numerous; many varicositiesthe “D” system (from dorsal raphe)More vulnerable to toxins (e.g., PCA & MDMA)Make less direct synaptic contact (varicosities) modulatory effects upon frontal cortex, striatal structures
2-Thick, large varicositiesthe “M” system (from medial raphe)Make more conventional synaptic contacts
hippocampus and septum
Terminals & Release:Resirpine: Blocks VMATDepletes 5-HT stores
5-HT releasers: PCA and fenfluramine, MDMA, methamphetamine and at very high doses amphetamine
-non-vesicular mechanism of releasing action because not blocked by reserpine-involves transporter because blocked by re-uptake inhibitors
5-HT toxicity:“D” fibers are particularly sensitive to releaser-type neurotoxins:
Releaser Releaser
5,7-DHT
Terminal degeneration; cell body sparing; get both M and D systems; Regrowth; Super-sensitivity to agonists
MDMA or fenfluramine: Selective for D system; Regrowth?
Auto-inhibition: Gi-coupled 5-HT receptors
-cell body level: 5-HT1A-terminal level: 5-HT1B/1D
Re-uptake:
Non-selective re-uptake inhibitors-bind DAT, NET and SERT
SSRI
Paroxetine=Paxil, Aropax, Oxetine, Aroxat, Cebrilin, Deroxat, Motivan, Paroxetina, Optipar, Paroxat, Pondera, Seroxat, Posivil, Pexot, Paraxyle, Plasare, Paradise CR
Sertraline=Zoloft, Sertralin, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton, Xydep, Serlain, Concorz
Fluoxetine=Prozac
5-HT receptor subtypes:
5-HT1 receptors:
Anti-depressant Rx’s can reduce 5-HT1A and 5-HT1D/1B autoreceptor function
5-HT2 receptors:Antagonists Agonists
Agonists very rapid down-regulation; chronic state of super-sensitivity???Antagonists down-regulation of receptor function???inverse agonists?
5-HT3 receptors:
Antagonists
SSRIMDMA
methamphetaminefenfluramine
MDMAmethamphetamine
fenfluramine
reserpine
PCPA
MAO-A I’s*/*
*/*@ somatodendritic5-HT1A receptors
*/**/*LSD/anti-psychotics
ondansetron
Lecture 5b: Acetylcholine
Lecture 5b: ACh Objectives• Describe how Acetylcholine (ACh) is synthesized. • Describe the sources for the Acetyl CoA and Choline used for ACh
synthesis and discuss what limits ACh synthesis in brain.• Explain the role of acetylcholinesterase (AChE) in terminating ACh activity,
describe the factors regulating it and describe the neurochemical and behavioral effects of inhibition
• Compare and contrast muscarinic and nicotinic receptors in terms of their effectors systems and distribution and provide examples of agonists and antagonists of each
• Explain the structure of the nicotinic receptor and how it can give rise to at least 9 different subtypes.
• Explain and illustrate how drugs may interfere with ACh activity by effecting its synthesis, release, degradation or receptor activity.
• Explain why atropine can ameliorate the effects of AChE inhibitors.
Lecture 5c: Histamine Objectives• Describe how histamine can be synthesized • Compare and contrast the 3 histamine receptors and explain (1) why H1
antagonists make you drowsy and (2) why H2 compounds cannot be used currently to treat neuropsychiatric disorders
Acetylcholine (ACh)
The first neurotransmitter to be discovered.Otto Loewi, 1921
– All muscular movement is accomplished by the release of acetylcholine.
– Appears to be involved in regulating REM sleep, perceptual learning, and memory.
ACh Synthesis• ACh is synthesized in the cytoplasm from
Acetyl CoA and choline in a reaction catalyzed by the enzyme cholineacetyltransferase (ChAT).
Sources of Acetyl CoAand choline
Choline• Obtained from foods such as egg yolks, kidney, liver, seeds, and
various vegetables. It is also naturally produced by the liver.
• Free Cholie and lipid-bound choline circulating in blood plasma readily
crosses the BBB.
• Cholinergic nerve terminals uptake choline by a either a high affinity or
a low affinity choline transport system.
• The high affinity system is sodium-dependent and carrier mediated and
is unique to cholinergic cells. It is inhibited when the cell is
depolarized.
• Low affinity choline transport operate by passive diffusion; provides
many non-neuronal cells with the choline they require to carry out
processes such as the synthesis of various choline-containing
phospholipids
ACh synthesis
• Factors regulating ACh synthesis:
• negative feedback: ACh binds to ChAT and inhibits its catalytic ability.
• Law of mass action: ACh concentration is proportional to the availability of
Acetyl CoA, choline and choline acetylcholietransferase.
• The most important limiting factor is the rate of choline high affinity uptake.
• Drugs inhibiting Ach synthesis
• Juglone: ChAT inhibitor
• Triethylcholine (TEC): Inhibits high affinity choline uptake
• The latter is more effective, reflecting the major function of choline uptake in
synthesis
Termination of ACh activity
-Upon release, acetylcholine is hydrolyzed into choline and acetate by acetylcholinesterase (AChE), and, to a much lesser extent, by other nonspecific cholinesterases.
• AChE has an anionic subsite which attracts the positive charge of ACh and an estertic site which possess the serine residue that breaks the ester bond.
• Extremely efficient enzyme, hydrolyzes 5000 molecules of ACh per molecule of enzyme per one second.
• BUT expresses “excess substrate inhibition”-inhibited by high concentration of ACh
Irreversible acetylcholinesteraseinhibitors =“nerve gas”
Treatment•PAM: (2 pyridine aldoxime methiodide): displaces the inhibitor from the active site. However ,doesn’t cross the BBB. •Atropine: doesn’t effect the inhibitor at all, but balances the effect of AChE by blocking the muscarinic ACh receptors. Currently the most commonly used.
•Headache•Convulsions•Coma•Respiratory arrest •Confusion•Slurred speech•Depression•Respiratory d
•Reduced Vision•Small pupil size•Drooling•Sweating •Diarrhea•Nausea•Abdominal pain•Vomiting
•Twitching•Weakness•Paralysis•Respiratory failure
Central NervousSystem Effects
Autonomic NervousSystem Effects
Neuromuscular Effects
organophosphorous compounds –which form highly stable phosphorlyated complexes with AChE that persist for hours or more
Other pharmacological goodies• Botulinum toxin A:
prevents ACh
release paralysis
• α-latrotoxin (black widow
spider venom): promotes
massive vesicular ACh
release
• Hemicholinium and
vesamicol: prevent
choline reuptake lowers
ACh synthesis and stores
Cholinergic pathway: CNSAcetylcholine is widely distributed in the peripheral and central nervous
system. In the CNS, cholinergic neurons can be divided to several groups. :
Main groups of ACh groups
and pathways in the CNS
1. Interneurons within striatal
complex; regulated by
glutamate and dopamine
2. Basal forebrain (including
nucleus basalis, medial
septal nucleus, substantia
inominata); source of
projection neurons to
limbic system and cortex
Cholinergic pathway: PNSMotor systemsCholinergic neurons are found in the spinal ventral horn and
in cranial nerves 3-7 and 12. Thus, ACh is secreted in all neuromuscular junctions and stimulates muscle contraction.
Autonomic nervous systemThe principle transmitter by the parasympathetic and
sympathetic pregangalionic fibers.
Released by most of the parasympathetic post ganglionicinnervating glands and smooth muscles which will be excited or inhibited depending on the type of receptor they present.
Cholinergic receptorsCholinergic receptors can be divided into 2
major categories. Muscarinic receptorsoriginally were distinguished from nicotinic receptors by the selectivity of the agonists muscarine and nicotine respectively.
Basic differences between muscarinic and nicotinic receptors
All striated musclesPostganalionic
parasympathetic and sympathetic neurons
CNS
Parasympatheticallyinnervated cardiac and smooth muscles (heart, iris, stomach, bronchitis bladder etc).
Salivary, tear and sweat glands
CNS
distribution
TubocurarineAtropine, ScopolamineTypical antagonists
ExcitatoryMixedExcitatory/inhibitory
9 subtypes M1, M3, M5 =Gq coupledM2, M4=Gi coupled
Receptor subtype
IonotropicMetabotropicReceptor type
Fast (10<ms)Slow (100-250 ms)Response time
NicotineMuscarineAgonist
Nicotinic receptors antagonists: Curare
Curare was used as an arrow poison by indigenous forest peoples of South America to paralyze their prey.
The main active ingredient was tubocurarine-antagonists at the nicotinic receptor.
-alpha forms ACh and nicotinebinding site-cation channel-rapidly desensitizes upon agonist stimulation
Nicotinic ACh Receptor
EpibatidineABT-418
EpibatidineEpibatidineAgonists
α-BungarotoxinMecamylamine
Dihydro-β-erythroidine
Mecamylamine
Hexamethoniumα-BungarotoxinAntagonists
α7,α8,α9α3,α4,β2,β4α3,α5,α7,β2,β4α1,β1,δ,γ(ε)Subunits
CNSCNSAutonomic ganglion
Skeletal muscleReceptor
Nicotinic Acetylcholine Receptors
Muscarinic receptors
PLCβAdenylylcyclaseinhibition
PLCβAdenylylcyclaseinhibition
PLCβIntracellular response
Gαq/11Gi/oGαq/11Gi/oGαq/11G protein
CDD-0097Xanomelin
Selective Agonist
pF-HHSiDAF-DX 116ePirenzepineSelective Antagonists
Substantianigra
NeostriatumExocrine glands, GI tract
HeartCortex, hippocampus
Distribution
M5M4M3M2M1
Muscarinic Acetylcholine Receptors
Nerve gasPAM
vesamicol
NicotineCurare
Mecamylamine
MuscarineAtropine
Scopolamine
botulinum-Aα-latrotoxin
H1 antagonists: “anti-histamines” drowsiness; H2 antagnoists=anti-nausea; H3 antagonists increase wakefulness
AADC