1. Monoamine neurotransmitters (+ Acetylcholine and Histamine)
Paul Glue

2. Biogenic amines/monoamines

3. Cortical Innervation - Monoamine Pathways
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
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 NE
DOPAMINE

4. Dopamine Pathways in the Brain
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

5. 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

6. 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

7. 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

9. 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

10. 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

11. Relationship between D2 antagonist potency and average daily dose

12. 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)

13. Norepinephrine Pathways in the Brain
dorsal bundle
ventral bundle
Norepinephrine Pathways in the Brain
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

14. 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
NE in the periphery: sympathetic nervous system (fight or flight)

15. 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 (-)

17. 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; a-methyldopa)
Post-synaptic b-adrenoceptor antagonists (e.g. propranolol - uncommon)

18. 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
Receptors:
14 identified; 5HT1-7 plus subtypes
cord

19. 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

20. 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

21. Serotonin 3-7 receptors
5HT3: ondansetron (antagonist) – anti-nausea, vomiting
5HT4: cisapride, tegaserod (agonists) - altered GI motility
5HT5a: ? function
5HT6: ? function
5HT7: ? function

22. 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)

23. 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

24. 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

25. SERT in action
High affinity antidepressant binding site in extracellular pocket
?Low affinity binding site on intracellular domain
5HT K+
Na+
Cl-
5HT
Na+
Cl K+

26. 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)

27. 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)

28. Histaminic drugs
H1 antagonists: antiallergy/ local antiinflammatory effects
H2 antagonists: reduced gastric acid secretion
H3 (antagonists) – may enhance transmission of monoamines, histamine – experimental
H4: ??

29. Acetylcholine Localization: Effects/timecourse: Receptors:
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)

30. ACh receptor localization
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
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)

31. 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

32. 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

33. 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