lecture 9 LOs Flashcards
how are DA/NE removed from the synaptic cleft
membrane transporter proteins
commonly referred to as DAT and NET
sloppy
in the frontal lobes most DA reuptake is done by NET
what does blocking transporters lead to
greater accumulation of extracellular NT levels
what is release of reuptake blockers dependent on
activity of the neuron
if neurons are not firing then reuptake blockers will not increase transmitter levels
what does cocaine inhibit the reuptake of
all monoamines (DA, NE, 5-HT)
what does tricyclic antidepressant inhibit the reuptake of
NE and 5-HT
what does methyphenidate (ritalin) selective for
catecholamines
what does amephtamine do to the DA/NE transporter
reverse it so it spits out moleculesm from inside the terminal into the synapse
more transmitter is released and stays out a lot longer
amphetamines are ____ of cell firing
independent
even if the neuron is not firing, amphetamines can still increase transmitter levels
are amphetamines more selective or non selective
non selective, will work on DA, NE, and 5-HT
what do amphetamines that enter the brain invariably do
increase locomotor activity
driven primarily by the increased DA in nuecleus accumbens
what do high doses of amphetamines result in
stereotyped behaviours
snigging, repetitive head/limb movements, licking, biting)
what does the continuum of beh changes from amphetamine doses come from
increase stimulation of DA receptors in the nucleus accumbens and striatum
what is sensitization
repeated exposure increases sensitivity to effects of drug at the same dose
therepeutic effects of small doses of d-amphetamine
powerful stimulat: promotes wakefulness, reduces REM sleep
cognitive enhancer: for multiple forms of cognition
DA and NE receptor subtypes
DA autoreceptor: D2 subtype
NE autoreceptor: alpha 2 subtype
where do monoamine autoreceptors reside
axon terminals (DA and NE)
cell bodies (NE)
what does activation of DA and NE receptors result in
opening of voltage gated K+ channel that shortens duration of action potentials
on terminals this reduces Ca2+ influx and transmitter exocytosis
what do autoreceptors on the cell body do
reduce neural firing
where else can D2/alpha 2 receptors reside
postsynaptic neurons
DA cell groups A1-7
nonadrenergic
DA cell groups A8-16
dopaminergic
where do A9 (nigrostriatal) axons originate from
substantia nigra and extend to caudate putamen (dorsal striatum)
what does the nigrostriatal DA facilitate
voluntary movement
parkinsons involves these neurons
6-OHDA and MPTP are used to destroy these cells in this pathway in animal models for parkinsons
what does dorsal striatum DA aide in
action selection, promotes the best action while expressing the others
the A10 cell group in the VTA gives rise to two pathways
mesolimbic
mesocortical
mesolimbic pathway extension
various limbic system nuclei
nucleus accumbens, amygdala
DA input to accumbens facilitates forward locomotion
what is the mesolimbic pathway heavily linked to
reward and motivational functions
mesocortical DA terminals
have few DA transporters, most DA clearance in the cortex is done by COMT and NET
what do blockages of the mesocortical pathway link to
congnitive functions
blockade of PFC DA receptors impairs executive functions
DA D1receptors more heavily expressed in prefrontal regions (vs D2)
PFC DA modulates ___ witin an optimum range
cognition
dopamine receptor subtypes
D1 to D5
all are metabotropic, interact w G proteins and second messengers
what does D1 activation stimulate
adenylyl cyclase and cAMP synthesis
what does D2 activation do
reduces cAMP
how do D2 receptors function
as both autoreceptors and postsynaptic receptors
how do D2 antagonists increase DA release
by blocking the autoreceptor, but also reduce postsynaptic DA signalling
does D2 or D1 have higher affinity for dopamine
D2
some DA receptors are ___ for glutamate/GABA terminals and modulate…
heteroreceptors
fast transmission presynaptically
dopamine agonist
apomorphine
stimulates D1 and D2 receptors
causes beh similar to what is seen w cocaine or amphetamines
DA receptor agonists are used for treatment of parkinsons
dopamine antagonist
flupenthixol
blocks D1 and D2 receptors
reduces motivation and at higher doses produces catalepsy (lack of spontaneous movement) like all D1 or D2 antagonists
haloperidol
highly selective for D2 vs D1 but will still bind to D2,3,4 w similar affinity
