Monoamine
neurotransmitters
(+ Acetylcholine and Histamine)
Paul Glue
Biogenic amines/monoamines
Cortical Innervation - Monoamine Pathways
SEROTONIN
DOPAMINE
NOREPINEPHRINE
•Common features:
•Relatively small Common
numbers of
cell bodies
features:
Common
features:
arising in upper brainstem
Cell
Cell bodies
bodies arising
arising in
in upper
upper
brainstem
•Radiate to most cortical
areas
brainstem
Radiate
Radiate to
to most
most cortical
cortical areas
areas
•Intense arborization
of
dendritic
terminals
Intense
Intense arborization
arborization of
of dendritic
dendritic
terminals
terminals role on other
•Consistent with modulatory
cortical synapses
Consistent
Consistent with
with modulatory
modulatory role
role
NE
DOPAMINE
Ventral
Tegmental
Substantia
Nigra Area
Substantia Nigra
DOPAMINE
Dopamine Pathways
in the Brain
(A9)
Localization:
- nigrostriatal:
substantia nigra (A9)
 striatum
- mesolimbic: ventral
tegmental area (A10)
 limbic structures
- tuberoinfundibular
pathway  pituitary
(A10)
(A10)
(A9)
Effects/timecourse:
- nigrostriatal: initiation
and control of
voluntary movement
- mesolimbic:
interactive and reactive
behavior
- tuberoinfundibular:
prolactin, GH secretion
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
•
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
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
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
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
Relationship between D2 antagonist potency
and average daily dose
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, damphetamine - 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)
Norepinephrine
Pathways in the
Brain
•diffuse innervation of most
cortical and subcortical areas
•extensive distribution in
blood vessels, lungs, heart,
urethra, GI tract
dorsal bundle
ventral bundle
Effects/timecourse:
•inhibit/facilitate
spontaneous neuronal
discharge;
•slow onset and long
duration;
•modulatory
Receptors:
•1, 2 and subtypes; 1,
2, 3
Agonist effects at NE receptors
• 1:
• 2:
• 1:
• 2:
• 3:
– 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
NE in the periphery: sympathetic nervous system (fight or flight)
Functions of NE in the brain
• Alertness/Arousal/Sleep:
– LC inhibits ventrolateral preoptic area
• Memory
• Mood
• Attention/Learning/Working memory
Disorders associated with altered central NE
• Depression
• Anxiety/panic disorder
– NE=  anxiety; MHPG concs (NE metabolite) correlate with
anxiety
• ADHD
• Schizophrenia
– Akathisia (+); negative symptoms (-)
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)
5HT Pathways in
the Brain
•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
cord
Receptors:
•14 identified; 5HT1-7
plus subtypes
14 serotonin receptors in 6
families
Family
5-HT1
5-HT2
5-HT3
5-HT4
5-HT5
5-HT6
5-HT7
Type
Gi/Go-protein coupled.
Gq/G11-protein coupled.
Ligand-gated Na+ and K+
cation channel.
Gs-protein coupled.
Gi/Go-protein coupled.
Gs-protein coupled.
Gs-protein coupled.
Mechanism
Decreases cAMP.
Increases IP3 and DAG.
Depolarizing plasma
membrane.
Increases cAMP.
Decreases cAMP.
Increases cAMP.
Increases cAMP.
Potential
Inhibitory
Excitatory
Excitatory
Excitatory
Inhibitory
Excitatory
Excitatory
Serotonin 1/2 receptors
• 5HT1a: buspirone (partial agonist) –
• 5HT1b: triptans (agonists) –
(5HT1c – no such receptor)
• 5HT1d: triptans (agonists) –
• 5HT1e: methysergide • 5HT1f: triptans (agonists) –
anxiolytic, antidepressant
vasoconstriction; antimigraine
• 5HT2a: LSD, psilocybin (agonists) –
SGAs (antagonists) • 5HT2b: Fenfluramine (agonist)
Tegaserod (antagonist) • 5HT2c: Mirtazapine (antagonist) -
perception
?reduced EPSE
anorexia
reduced GI motility/IBS
anxiolytic.antidepressant
vasoconstriction; antimigraine
? effect
vasoconstriction; antimigraine
Serotonin 3-7 receptors
•
•
•
•
•
•
5HT3: ondansetron (antagonist) –
5HT4: cisapride, tegaserod (agonists) 5HT5a:
? function
5HT6:
? function
5HT7:
? function
anti-nausea, vomiting
altered GI motility
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)
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
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
SERT in action
High affinity
antidepressant binding site
in extracellular pocket
5HT
Na+
Cl-
?Low affinity binding site
on intracellular domain
K+
5HT
Na+
Cl-
K+
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)
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)
Histaminic drugs
• H1 antagonists: antiallergy/ local antiinflammatory
effects
• H2 antagonists: reduced gastric acid secretion
• H3 (antagonists) – may enhance transmission of
monoamines, histamine – experimental
• H4: ??
Acetylcholine
– 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)
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
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
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
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