catecholamines 1 Flashcards
catecholamines
Dopamine (DA), Norepinephrine (NE) and Epinephrine (EPI), all monoamines made from tyrosine
where are NE and EPI released?
adrenal medlla
how are catecholamines made?
tyrosine + tyrosine hydroxylase (TH) -> L DOPA, LDOPA + dopamine decarboxylase (AADC) -> DA
DA + dopamine beta hydroxylase (DBH) -> NE
what is the rate limiting step in DA synthesis?
tyrosine + tyrosine hydroxylase (TH) -> L DOPA, can avoid by supplementing LDOPA
TH activity is regulated by: pharmacology:
What pharmacological factors help to regulate TH activity?
high catecholamine levels inhibit TH activity through phsphorylation / dephosphroylation; negative feedback
pharmacology:
L-DOPA: precursor of rate limiting step, orally active, can go through BBB
AMPT: blocks TH and prevents synthesis of L DOPA; induces sedation, depression, reduced blood pressure; can be reversed with L-DOPA
Catecholamine packing needs VMAT (vesicular monoamine transporter), which can be affected by
Reserpine blocks VMAT and prevents DA/NE from being packages; if not protected, they are broken down by enzymes in terminals; causes sedation and depression and systemic effects
what are MAO and COMT
monoamine oxidase and catechol-O-methyltransferase; they metabolize catecholamines
HVA (homovanillic acid) is
main metabolite of DA; if you find a lot of this, that means DA is being used
MHPG is
NE metabolite; enters CSF and bloodstrem; elimited via urine
MAO inhibitor
phenelzine (nardil), used to treat clinical depression
COMT inhibitor
tolcapone (tasmar) enhances the effectiveness of L-DOPA in treating later parkinson stages
en passant synapses
many DA and NE neurons have repeated swellings (varicosities) filled with synaptic vesicles that form ENPASSANT “in passing” snypses, allows for widespread transmission of signal
DA and NE membrane transporter proteins
are referred to as DAT and NET; removed from synaptic cleft with membrane transporer proteins; they are sloppy. In frontal lobes, most DA reuptake done by NET
catecholamine reuptake pharmacology
blocking transporter leads to greater extracellular neurotrasmitter levels (due to lack of reuptake)
Cocain inhibits reuptake of all monoamines (DA, NE, 5HT)
Tricyclic antidepressants inhibit NE and 5HT
methylphenidate (ritalin) is more selective for catecholamines
normal catecholamine transmission
DA/NE is released from presynaptic terminal by exocytosis when an impulse reaches terminal, and the NT is quickly taken back by reuptake transporter
amphetamine pharmacological effects
reverses the DA / NE tranporter; instead of taking them back up they now release more; transmitter release independent of cell firing; also not selective: act on DA, NE and 5HT
amphetamine behavioural effects: locomotion
increase locomotor activity by increasing DA in nucleus accumbens (ventral striatum); at higher doses, methamphetamine tweaking instead - lower doses saturate DA release in accumbus but higher doses -> more DA activation in dorsal straitum
amphetamine behavioural effects: sensitization
sensitization: repeated exposure increases sensitivity to effect of drug;
Amphetamine (AMPH)-induced locomotion
Gets low dose AMPH on Day 1 (test dose), then gets daily saline injections for 5 days
Gets test dose AMPH on Day 1, then gets AMPH repeatedly for 5 days
On test day, both groups get same test dose of amphetamine again
stimulant and cognitive enhancers
lower dose d-amphetamine can have therapeutic effects:
powerful stimulant: promote wakefulness but reduce REM sleep
cognitive enhancer: for multiple forms of cognition
side effect: lacking creative thought
catecholamine autoreceptors
DA and NE have D2 and a2 respectively;
monoamine autoreceptors reside on axon terminals and cell bodies
activation enhances opening of voltage gated K+ channels that shorten durations of action potentials
on terminals, this reduces Ca+ influx and transmitter exocytosis
autoreceptors on CELL BODIES reduce neural firing
Catecholamine autoreceptors
For DA (or other monoamine) neuron Firing at cell body causes “somatodendritic” release Local release acts on somatodendritic autoreceptors to reduce neural firing Terminal autoreceptor stimulation reduces transmitter release
Selective knockout of D2 autoreceptors (but not postsynaptic D2) in animals leads to
greater DA-mediated locomotion vs controls - confirming these receptors attenuate DA transmission
lower dose DA / NE saturate ————, but higher dose do ————-
Lower dose saturates autoreceptors (reducing transmitter release), but does not activate enough postsynaptic receptors to affect neuron
Higher dose activate sufficient # of postsynaptic receptors
