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adrenal medulla (kidney)
secretes EPI and NE into the bloodstream
act as hormones
vesicular monoamine transporter (VMAT)
packages monoamines into vesicles
VMAT1 - adrenal medulla; VMAT2 - brain
DA, NE, 5-HT
independent release
some drugs of abuse cause DA and NE release independent of cell firing (Ca2+ - independent release)
somatodendritic autoreceptors
on cell bodies or dendrites
slows rate of neuron firing
reduces rate of NT release
“impulse modulating”
terminal autoreceptors
on presynaptic nerve terminal
inhibit further NT release
“release or synthesis modulating”
somatodendritic DA autoreceptors
midbrain in VTA and SN
enhances opening of K+ channels
slows firing rate
terminal DA autoreceptors
enhances opening of voltage-gated K+ channels
inhibits Ca2+ entry to VGCCs
enhancing DA uptake via DAT
inhibiting TH
somatodendritic NE autoreceptors
enhance opening of K+ channels
terminal NE autoreceptors
inhibit VGCCs
clonidine
treats high blood pressure and opioid withdrawal
NE autoreceptor agonist
reduces NT release
yohimbine
antagonizes NE autoreceptors
increases NE release
exacerbates opioid withdrawal
membrane transporters
DAT and NET
non-selective, each can take up the other NT
SNRI
inhibits reuptake of both NE and 5-HT
cocaine
inhibits reuptake of all monoamine NTs: DA, NE, 5-HT
catchecol-O-methyltransferase (COMT) and monoamine oxidase (MAO)
metabolize catecholamines
DA → HVA
NE → MHPG in the brain
NE → VMA in the PNS
ascending DA pathways
innervate forbrain regions and release DA
nigrostriatal
mesolimbic
mesocortial
nigrostriatal dopamine tract
substantia nigra → caudate-putamen (striatum)
facilitates voluntary movement
Parkinson’s Disease
massive loss of DA neurons in SN
denervation of the striatum
mesolimbic dopamine pathway
ventral tegmental area → nucleus accumbens
motivated behaviors
positive symptoms in schizophrenia
mesocortical dopamine pathway
ventral tegmental area → prefrontal cortex
working memory
negative and cognitive symptoms in schizophrenia
dopamine receptor subtypes (metabotropic)
D1 and D5 (D1-like)
stimulates AC via Gs
D2, D3, D4 (D2-like)
inhibits AC via Gi
enhances K+ channel opening
inhibits VGCCs
D2 are autoreceptors and postsynaptic receptors
dopamine hypothesis of schizophrenia (1967)
excess DA function results in symptoms of schizophrenia
high doses of amphetamine can produce psychotic reaction in health individuals » can be reversed by DA antagonists
psychotic behavior driven by excess post-synaptic D2 receptor activation
“typical” antipsychotic drugs: D2 receptor antagonists
D2 receptor antagonists: acute administration
increased firing rate after antipsychotic administration
increased DA turnover (synthesis, release, metabolism)
enhanced release accompanied by post-synaptic blockade
no worsening of symptoms
D2 receptor antagonist: chronic administration
decreased DA turnover
two theories:
initial increase in synaptic DA followed by gradual decrease
chronic blockade leads to up regulation of autoreceptors
regulation of DA turnover
after initial increase in DA turnover, DA neurons temporarily inactivate (depolarization block)
resulting decrease in turnover
D2 receptor antagonist: side effects
extrapyramidal symptoms (EPS)
dystonia (continuous spasms + muscle contractions)
akathisia (motor restlessness)
Parkinsonism (rigidity, bradykinesia, and tremor)
tardive dyskinesia » permanent
irregular, jerky movements
dopamine system stabilizers
partial DA agonists: compete with DA for receptors, reduces DA effect » reduces positive symptoms
stimulates DA receptors in brain regions with too little DA » reduces negative symptoms
noradrenergic system
CNS: brainstem » locus ceruleus (LC)
ascending fibers project to many forebrain structures
PNS: post-ganglionic NT in sympathetic division of ANS
noradrenergic receptors (metabotropic)
α1: operates via Gq, increase in Ca2+ ions in post-synaptic cell, PKC activation
α2: inhibits AC via Gi, increase K+ channel opening, inhibit VGCCs (like D2)
ß1 and ß2: stimulates AC via Gs (like D1)
postsynaptic receptors throughout cortex, thalamus, hypothalamus, cerebellum, limbic system
α2 receptors function as autoreceptors in LC and nerve terminals
α1 and α2 receptors in PFC
NE has higher affinity for α2 than α1 in PFC
activation of post-synaptic α2 in PFC enhances working memory
stress stimulates NE release in the PFC
activation of α1 receptors » negative effect on cognitive functions of the PFC
ß-antagonists (beta blockers)
hypertension, cardiac arrythmias
generalized anxiety disorder (GAD): propranolol
reduce physical component associated with excess NE activity
psychological component still present