Monoamine neurotransmitters (+ Acetylcholine and Histamine) Paul Glue.
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Transcript 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 AreaSubstantia Nigra
DOPAMINE
Common features: Cell bodies arising in upper brainstemRadiate to most cortical areasIntense arborization of dendritic terminals
Consistent with modulatory role
Substantia Nigra
NOREPINEPHRINE
DOPAMINE
Common features: Cell bodies arising in upper brainstemRadiate to most cortical areasIntense arborization of dendritic terminals
Consistent with modulatory role
SEROTONIN
DOPAMINENE
•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 Parkinson’s 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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Parkinson’s Disease and Dopamine
• Symptoms: – tremor; rigidity/stiffness; bradykinesia; postural
imbalance
• Rates – onset in 50’s; 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 30’s; ~ 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 bundleventral 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
– 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-HT1 Gi/Go-protein coupled. Decreases cAMP. Inhibitory
5-HT2 Gq/G11-protein coupled. Increases IP3 and DAG. Excitatory
5-HT3 Ligand-gated Na+ and K+ Depolarizing plasma Excitatory
cation channel. membrane.
5-HT4 Gs-protein coupled. Increases cAMP. Excitatory
5-HT5 Gi/Go-protein coupled. Decreases cAMP. Inhibitory
5-HT6 Gs-protein coupled. Increases cAMP. Excitatory
5-HT7 Gs-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:– γ-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 actionHigh 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)
+/- (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 Alzheimer’s dis.
• [organophosphorus insecticides (e.g. Malathion) and nerve gas (Sarin)]
• Muscarinic antagonists • orphenadrine, procyclidine, others - tremor in Parkinson’s disease
• scopolamine - pre-anesthesia
• Muscarinic agonists • pilocarpine - glaucoma;
• (experimental for Alzheimer’s disease)
• Nicotinic agonists (nicotine)• improves memory; addictive (via DA)
• Nicotinic neuromuscular blocking agents • tubocurarine; pancuronium, others - surgical paralysis