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Monoamine neurotransmitters (+ Acetylcholine and Histamine) Paul Glue

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Text of Monoamine neurotransmitters (+ Acetylcholine and Histamine) Paul Glue

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  • Monoamine neurotransmitters (+ Acetylcholine and Histamine) Paul Glue
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  • Biogenic amines/monoamines
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  • Cortical Innervation - Monoamine Pathways Ventral Tegmental Area Substantia Nigra DOPAMINE Common features: Cell bodies arising in upper brainstem Radiate to most cortical areas Intense arborization of dendritic terminals Consistent with modulatory role Substantia Nigra NOREPINEPHRINE DOPAMINE Common features: Cell bodies arising in upper brainstem Radiate to most cortical areas Intense arborization of dendritic terminals Consistent with modulatory role SEROTONIN DOPAMINE NE Common features: Relatively small numbers of cell bodies arising in upper brainstem Radiate to most cortical areas Intense arborization of dendritic terminals Consistent with modulatory role on other cortical synapses
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  • Dopamine Pathways in the Brain (A9) (A10) (A9) (A10) Localization: - nigrostriatal: substantia nigra (A9) striatum - mesolimbic: ventral tegmental area (A10) limbic structures - tuberoinfundibular pathway pituitary Effects/timecourse: - nigrostriatal: initiation and control of voluntary movement - mesolimbic: interactive and reactive behavior - tuberoinfundibular: prolactin, GH secretion
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  • Dopamine receptors Density in CNS: D1>D2>D3>D4>D5 D1, D5 linked to adenylate cyclase D2, D3, D4 (not linked to AC) Functions: Only D2 antagonism linked to antipsychotic effects D2/3 agonists for Parkinsons Disease D1 antagonists ?anticraving effects No known function for D4/5 ligands
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  • Functions of DA in the brain Motor control: movement initiation and cessation Reward/Motivation: dependence liability of compounds correlated with degree of DA release in Nucleus Accumbens Endocrine: Inhibition of prolactin release Mood: DA releasers/reuptake inhibitors (e.g. cocaine, amphetamine) cause euphoria; D2 antagonists anhedonia in HVs Psychosis: DA releasers/reuptake inhibitors may produce psychotic symptoms (paranoid delusions; hallucinations; etc); all antipsychotics are D2 antagonists Sleep: VTA inhibits ventrolateral preoptic area Attention/Learning/Working memory
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  • Peripheral DA activity Blood vessel smooth muscle beds (vasorelaxation) Atria ( myocardial contractility, cardiac output) Kidneys (nephrons, prox tubule epithelium) sodium excretion Gut wall plexus Lymphocytes
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  • Parkinsons Disease and Dopamine Symptoms: tremor; rigidity/stiffness; bradykinesia; postural imbalance Rates onset in 50s; highest in elderly; protracted course with high disability/morbidity; dementia 25-40% Pathophysiology: loss of nigrostriatal dopaminergic neurons MPTP (DA neurotoxin) produces PD Treatment: Increase synaptic dopamine concentrations (L-DOPA; DA agonists; MAO-B/COMT inhibs) gradual loss of efficacy over time Side effects of treatment: Dyskinesia; psychosis, nausea 18F-L-DOPA PET image
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  • Schizophrenia and Dopamine Symptoms: delusions; hallucinations; disturbances of thought; bizarre behavior; personality change; apathy; withdrawal; etc; episodic or progressive patterns Rates: peak onset in late teens-early 30s; ~ 1% lifetime prevalence Pathophysiology: mesolimbic dopaminergic dysfunction/overactivity (hypothesized) cocaine/amphetamine produce psychotic symptoms increased DA release relative to controls (no differences in brain DA concs, DA receptor density, etc. ) Treatment: All effective drugs are dopamine D2 antagonists (+ other pharmacological effects); potency correlates with daily dose Side effects: Tremor, stiffness; restlessness; akathisia Laruelle M, Biol Psych 1999
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  • Relationship between D2 antagonist potency and average daily dose
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  • Dopaminergic Effects/Side Effects Drugs that increase DA neurotransmission ( synaptic DA) most are effective symptomatic treatments for PD may precipitate/worsen psychosis/dyskinesia potentially addictive other s/e: nausea, GI symptoms Postsynaptic agonists (DA from L-DOPA; bromocriptine, pramipexole) Inhibitors of enzymes which degrade DA (MAOIs (selective MAO-B-I: deprenyl); COMT inhibitors (entocapone) Inhibitors of DA reuptake or inducers of DA release (cocaine, d- amphetamine - not yet shown to help PD) Block DA neurotransmission (postsynaptic antagonism) worsen PD; may induce reversible Parkinsonian sx improve psychotic symptoms antiemetic, prokinetic Typical neuroleptics - D2 antagonists (haloperidol etc plus newer agents) Atypical neuroleptics (D2 antagonism + ?: clozapine)
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  • Norepinephrine Pathways in the Brain dorsal bundle ventral bundle diffuse innervation of most cortical and subcortical areas extensive distribution in blood vessels, lungs, heart, urethra, GI tract Effects/timecourse: inhibit/facilitate spontaneous neuronal discharge; slow onset and long duration; modulatory Receptors: 1, 2 and subtypes; 1, 2, 3
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  • Agonist effects at NE receptors Smooth muscle contraction (blood vessels, urethra, bronchioles, etc) Central autoreceptor (presynaptic inhibition of NE release) Endocrine ( insulin, glucagon release in pancreas) GI (sphincter contraction) Platelet aggregation Increased cardiac output (contractility, Endocrine (ghrelin, renin secretion) Smooth muscle relaxation (uterus, bladder, blood vessels, bronchi Lipolysis 1: 2: 1: 2: 3: NE in the periphery: sympathetic nervous system (fight or flight)
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  • Functions of NE in the brain Disorders associated with altered central NE Alertness/Arousal/Sleep: LC inhibits ventrolateral preoptic area Memory Mood Attention/Learning/Working memory Depression Anxiety/panic disorder NE= anxiety; MHPG concs (NE metabolite) correlate with anxiety ADHD Schizophrenia Akathisia (+); negative symptoms (-)
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  • NE Effects/Side Effects Increase NE neurotransmission by increasing synaptic NE most are effective symptomatic treatments for major depression may cause adrenergic side effects (increased blood pressure, heart rate, dry mouth, tremor) Presynaptic reuptake blockers (imipramine; venlafaxine; etc; cocaine is not! ) Indirect effects on NE neurotransmission (fluoxetine and other SSRIs - neuronal crosstalk; lithium and ECT) Enzyme inhibitors (MAOIs: phenelzine etc) Decrease NE neurotransmission risk of inducing or worsening depression adrenergic side effects sedation, bradycardia, hypotension (esp. postural), bronchoconstriction Inhibit NE formation/release (reserpine; -methyldopa) Post-synaptic -adrenoceptor antagonists (e.g. propranolol - uncommon)
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  • 5HT Pathways in the Brain cord ascending - raphe nuclei (pons/upper brain stem) and descending - medullary cell bodies diffuse fibers innervate many cortical/subcortical structures extensive location in gut (enterochromaffin cells), platelets, etc Effects/timecourse: inhibit/facilitate spontaneous neuronal discharge; slow onset and long duration; modulatory Receptors: 14 identified; 5HT1-7 plus subtypes
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  • 14 serotonin receptors in 6 families Family Type Mechanism Potential 5-HT 1 G i /G o -protein coupled. Decreases cAMP. Inhibitory 5-HT 2 G q /G 11 -protein coupled. Increases IP 3 and DAG. Excitatory 5-HT 3 Ligand-gated Na + and K + Depolarizing plasmaExcitatory cation channel. membrane. 5-HT 4 G s -protein coupled. Increases cAMP. Excitatory 5-HT 5 G i /G o -protein coupled.Decreases cAMP. Inhibitory 5-HT 6 G s -protein coupled. Increases cAMP. Excitatory 5-HT 7 G s -protein coupled. Increases cAMP. Excitatory
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  • Serotonin 1/2 receptors 5HT1a: buspirone (partial agonist) anxiolytic, antidepressant 5HT1b: triptans (agonists) vasoconstriction; antimigraine (5HT1c no such receptor) 5HT1d: triptans (agonists) vasoconstriction; antimigraine 5HT1e: methysergide - ? effect 5HT1f: triptans (agonists) vasoconstriction; antimigraine 5HT2a: LSD, psilocybin (agonists) perception SGAs (antagonists) - ?reduced EPSE 5HT2b: Fenfluramine (agonist) anorexia Tegaserod (antagonist) -reduced GI motility/IBS 5HT2c: Mirtazapine (antagonist) -anxiolytic.antidepressant
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  • Serotonin 3-7 receptors 5HT3: ondansetron (antagonist) anti-nausea, vomiting 5HT4: cisapride, tegaserod (agonists) - altered GI motility 5HT5a: ? function 5HT6:? function 5HT7:? function
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  • Drugs that modulate 5HT Increase 5HT neurotransmission by increasing synaptic 5HT most are effective symptomatic treatments for major depression may cause serotonergic side effects (nausea/GI discomfort; anxiety; tremor; insomnia) Selective presynaptic reuptake blockers ( SSRIs fluoxetine; paroxetine; etc) Nonselective presynaptic reuptake blockers (imipramine etc) Indirect effects on 5HT neurotransmission (lithium and ECT) Enzyme inhibitors (MAOIs: phenelzine etc) Decrease 5HT neurotransmission Most serotonin antagonists have no obvious side effects Subtype selective effects may affect GI motility, nausea, vomiting, EPSE General 5HT depletion risk of inducing or worsening depression experimental depletion of brain 5HT (L-tryptophan-free amino acid drink)
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  • Monoamine transporters (Example - SERT) A brief history: - 1961: Axelrod: presynaptic uptake of neurotransmitter first reported - 1979: Raisman: SERT is a target for antidepressant drugs - 1981: Langer: linking of SERT to depression - 1991: Blakely: sequence of the transporter gene from rats published
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  • SERT is a member of the neurotransmitter transporter family Neurotransmitter transporters belonging to the solute carrier 6 (SLC6) family, including: -aminobutyric acid (GAT) norepinephrine (NET) serotonin (SERT) dopamine (DAT) transporters All are Na +, Cl -dependent transporters with 12 transmembrane segments Primary function: following neurotransmission, to reset neuronal signaling by transporting neurotransmitter out of the synapse and back into the pre-synaptic neuron
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  • SERT in action High affinity antidepressant binding site in extracellular pocket 5HT K + Na + Cl - 5HT Na + Cl - K+ ?Low affinity binding site on intracellular domain
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  • Monoamine transporters and psychotropics Reuptake Inhibitors: (not substrates for the transporter) SSRIs Mixed monoamine reuptake inhibitors Psychostimulants Substrates: (release 5HT after being taken up by SERT) Amphetamine Fenfluramine Ecstacy/MDMA mCPP (trazodone metabolite)
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  • Histamine Brain histamine neurons arise in tuberomammillary nucleus in the posterior hypothalamus. Project throughout the nervous system May stimulate the cerebral cortex either directly or indirectly (5HT, ACh, galanin, GABA, substance P etc) 4 receptors (H1-4) Histamine is arousing/excitatory; increased release in stressed animals; associated with anxiety related behaviours (no human data)
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  • Histaminic drugs H1 antagonists: antiallergy/ local antiinflammatory effects H2 antagonists: reduced gastric acid secretion H3 (antagonists) may enhance transmission of monoamines, histamine experimental H4: ??
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  • Localization: 8 cell groups which project diffusely to all cortical/ subcortical areas main cortical projection: Nucleus Basalis of Meynert Effects/timecourse: slow onset; prolonged regulatory/modulatory effects on other neuronal activity Receptors: muscarinic M1-M5 (G-protein coupled) majority of brain ACh receptors nicotinic (ligand-gated ion channel; multiple subunit combinations; neuromuscular and ganglionic subtypes) Acetylcholine
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  • ACh receptor localization Brain (m1-5) Autonomic ganglia (m1) Heart (m2) Smooth muscle (m2, m3) Exocrine glands (m3) Lung (m4) Autonomic NS (n) Skeletal muscle (n) Brain (n) Agonists Learning/memory GI motility, nausea HR ( vagal tone) vasodilation; bladder contraction salivation broncho-constriction +/- (dose dependent) attention, performance; tremor Antagonists memory impairment GI motility, constipation HR urinary hesitancy; blurred vision dry mouth paralysis
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  • Functions of ACh in the brain Learning and memory anticholinergics and ACh lesions impair learning and memory Attention/arousal Pain (?) Schizophrenia (?sensory gating) (peripherally) striated muscle activation autonomic innervation parasympathetic NS
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  • Cholinergic Side Effects Muscarinic antagonists [nonselective neuroleptics, antidepressants] impair memory symptoms of peripheral cholinergic blockade constipation urinary hesitancy blurred vision dry mouth Muscarinic agonists nausea, diarrhea drooling improved attention, memory
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  • Therapeutic ACh Compounds Cholinesterase inhibitors (donepezil; rivastigmine; galanthamine) increase brain [ACh]; improves memory, attention in Alzheimers dis. [organophosphorus insecticides (e.g. Malathion) and nerve gas (Sarin)] Muscarinic antagonists orphenadrine, procyclidine, others - tremor in Parkinsons disease scopolamine - pre-anesthesia Muscarinic agonists pilocarpine - glaucoma; (experimental for Alzheimers disease) Nicotinic agonists (nicotine) improves memory; addictive (via DA) Nicotinic neuromuscular blocking agents tubocurarine; pancuronium, others - surgical paralysis