Ch5 Catecholamines Flashcards
3 catecholamines, and where
dopamine (DA)
norepinepherine/noradeline (NE)
epinepherine/adrenaline (EPI)
EPI/NE Secreted by adrenal medulla (kidney) into the bloodsteam and act as hormones
Catecholamine synthesis
Tyrosine –> DOPA (made by TH) –> Dopamine (made by AADC) –> Norepinepherine (made by DBH)
Packaging into vesicles
VMAT2 in brain = vesicular monoamine transporter
released via Ca2+-dependent exocytosis (needs AP to release). some drugs of abuse cause DA/NE release INDEPENDENT of cell firing (amphet = Ca2+ independent release)
Block VMAT2 = lower NE release, causes lower BP but also depression (no DA)
Autoreceptors (two types), and what do ant/agonists do
concept of negative feedback
somatodendritic autoreceptors - on cell body/dendrite, and SLOWS FIRING RATE, reducing NT, “impulse modulating”
Terminal autoreceptors - on the pre syn nerve terminal, INHIBIT NT release, “release or synthesis modulating”
Autoreceptor agonists = REDUCE NT
Autoreceptor antagonists = INCREASE NT
DA Autoreceptors
D2 subtype
Somatodendritic - midbrain DA neurons in VTA/SN, ENHANCES K CHANNEL OPENING (hyperpolar) SLOWS FIRING RATE
Terminal - INHIBIT DA synthesis and release by: Enhance K channels, Inhibit Ca entry VGCC, enhancing DA reuptake, Inhibit TH
NE autoreceptors
alpha 2 subtype
Somatodendritic - enhance K channels
Terminal - inhibit VGCC
Agonists reduce NE release (lower BP and lower withdrawl
Antagonists increase NE release (exacerbte withdrawl)
Inactivation
the reuptake transporters DAT/NET (not selective) then repackage into vesicles via VMAT or broken down via MAO/COMT
Transporter Blocking Drugs
SNRI - inhibits re-uptake of both NE and 5-HT
Cocaine - inhibits reuptake of all monoamines (DA/NE/5HT)
Metabolism of catecholamines
COMT (only catechols means DA/NE)/MAO (monoamine oxidase, can do 5HT)
Metabolites
DA - homovanillic acid HVA
NE - MHPG in brain, VMA in PNS
Can measure these metabolites as indirect measure of drug
DA system organization
two major groups in midbrain (VTA/SN)
3 ascending pathways innervate forebrain/release DA
Nigrostriatal
Mesolimbic
Mesocortical
Nigrostriatal Tract
axons from A9 Substantia nigra project to caudate/putamen (striatum)
voluntary movement
Parkinsons has loss of DA neurons in SN, denervates striatum
MPTPin animal models damages this pathway
A10 in VTA and other 2 pathways
A10 in VTA gives rise to these 2 paths
Mesolimbic - VTA to NA, motivated beh’rs, positive schizo symptoms
Mesocortical - VTA to prefrontal, working memory, negative/cog schizo symptoms
Five Receptor Subtypes DA
Metabotropic D1-5
D1-like = D1 & 5, stimulates adenyl cyclase vis Gs
D2-like = D2,3,4, inhibits adenyl cyclase via Gi, enhances K channel (hyperpolar), inhibits VGCC, D2 are autoreceptors and postsyn receptors
DA ant/agonists effects
Antagonists suppress motor beh’r, side effect of most antipsychotics
Agonists increase motor, like psychomotor stimulants
DAT/D1 KO mice
DAT KO mice are hyperactive - no reuptake
D1 KO mice = decreased response to stimulant drug, bc less receptors
Inhibiting DAT = increased extracellular DA
Dopamine hypothesis of schizo, 2 evidences and treatment
excess DA = schizo
high doses of amphet can produce a psychosis in healthy, reversed by DA antagonists
psychosis driven by excess D2 postsyn receptor activation
Antipsychotics target D2 rec. as antagonists - block D2 and reduce positive symptoms
D2 receptor antagonists and schizo for acute administration
increased firing rate after admin
increased DA turnover (synthesis/release/metab)
Enhanced release and post-synaptic block = no worsening of symptoms. No net effect bc activity depends on pre/post effects
D2 receptor antagonists and schizo for chronic admin, 2 theories
Decreased DA turnover
2 theories
1. initial inc. in synaptic DA followed by gradual decrease. block leads to upregulation of autorec. so can respond and negatively regulate DA turnover
2. After initial increase in DA turnover, DA neurons temporarily inactivate = decrease in DA turnover
Motor side effects of D2 receptor antagonists
Extrapyramidal symptoms (PNS)
Parkinsonism (rigidity/tremos) - bc blocking DA (no dopa)
Tardive Dyskinesia - permanent, irregular jerks
DA and HVA in schizo
DA function in patients in inconsistent
HVA levels don’t differ between schizo/healthy
HVA levels don’t differ with symptom type/severity
DA imbalance hypothesis
symptoms due to reduced DA in mesocortical (negative/impaired thinking) and excess DA in mesolimbic (positive symptoms)
Dopamine system stabilizers
partial DA agonists compete with DA for receptors = reduce DA effect, allowing reduction of positive symptoms
Also stimulates DA receptors in brain with too little DA, reduces negative symptoms
Noradrenergic organization
CNS - locus ceruleus ascends to most of forebrain (cortex/thal/hypo/limbic)
PNS - postganglionic NT in sympathetic ANS
Postsyn. receptors throughout forebrain
Alpha family receptor NE
metabotropic
A1 operates via Gq = increase in Ca2 and PKC activation
A2 inhibits adenyl cyclase via Gi, increase K channel, inhibit VGCC like D2
A2 receptors are like autoreceptors in LC and terminals
Beta family receptors NE
metabotropic
B1 and 2 stimulate adenyl cyclase Gs, like D1
LC NE neurons
arousal and fire more in waking
A1/2 NE pharmacology
A1/2 rec. in PFC prefrontal cortex
NE higher affinity for A2 in PFC
activation of post-syn A2 receptors in PFC enhances working memory
Stress = inc. NE, activates A1 receptors which means NEGATIVE effect on cog function bc TOO much NE
ADHD drug is A2 agonist
Cold medicine are peripheral A1 adrenergic agonists. NE/agonist constrict vessel = decongest
B family antagonists NE
Beta blockers
treats hypertension and general anxiety
reduces physical aspects of excess NE (flushing/palpitations)
Psych component still present
Anxiety drugs lengthen time humans spend in height (humanized elevated plus-maze)
OG case of frozen addict what happened
synthetic designer drug of heroin,
L-DOPA treatment reversed symptoms
Restores the Parkinsonism that onset (makes dopamine)
MPPP and MPTP in animal models
MPPP similar to heroin - caused no motor in rats but unfroze 1hr later
MPTP - no effect in rats, monkeys/dogs froze, reverse w/ L-DOPA
True story of MPTP
itself is harmless
the metabolite MPP+ is toxic, used as herbicide
MAO blockers prevent cell death from MPTP (MAO metabolizes it)
MAO inhibitors treat Parkinsons, slow SN death
