Posted by Astounder on October 31, 2007, at 14:02:28
In reply to Re: Dopamine agonists cause sedation. But why?? » linkadge, posted by cactus on October 28, 2007, at 20:13:27
Two things to say about differentiating the effects of dopamine agonists from L-DOPA & psychostimulants:
1.) Unlike DA, DA agonists always have a higher affinity for D2Sh than D2Lh. D2Lh is the postsynaptic receptor that mediates the reinforcing, mood elevating, psychomotor activating, wakefulness promoting, and psychotomimetic effects of the psychostimulants we all know and love. D2Sh is the inhibitory presynaptic autoreceptor; activation of this inhibits exocytotic release of dopamine from the axon terminal into the synaptic cleft.
Psychostimulants get around this autoreceptor because they mimic excessive burst firing; that is, they so quickly cause accumulation of DA in the synaptic cleft that when even the presynaptic receptors are saturated and inhibiting further release from the axon, there's more than enough extracellular DA to activate postsynaptic receptors on the dendrite and initiate the action potential. Methamphetamine reverses the DA transporter, depleting axonal DA and spilling it into the synapse; because neurotransmission now no longer reliant on exocytosis of DA from the terminal, autoreceptor activation does nothing. Cocaine and methylphenidate block the reuptake of the catecholamines; here autoreceptors do nothing because the DA in the cleft will stay there to stimulate postsynaptic receptors until they're catabolized by glial cells--which will take quite a while, as the reuptake inhibitors will also block the high-affinity DA and NE transporters on these glial cells, leaving only the low-affinity uptake2. Nicotine's activation of Ca2+-permeable nAChRs on dopaminergic neurons can directly induce burst firing, even during resting potential. Additionally, NE potentiates DA firing in both the short term, but activating alpha2 heteroreceptors on serotonergic neurons that tonically inhibit DA firing, by competing with DA's uptake into glial cells, and in the long term by increasing extrasynaptic DA levels through blocking uptake2 through its metabolite through way of COMT, normetanephrine.
DA agonists cannot overcome these feedback mechanisms like psychostimulants can, because they are unable to mimic or stimulate burst firing; even tonally they are less efficacious than endogenous DA, due to their higher affinity for the autoreceptor than the postsynaptic receptor.
2.) More importantly, there are peripheral DA receptors. These receptors are not normally activated by DA, because most DA is trapped inside the BBB, while peripheral DA is voraciously metabolized by MAO and COMT in glial cells and platelets. Psychostimulants do not activate these receptors because they are not direct agonists. Even L-DOPA's activation of these receptors can limited by co-administration of carbidopa.
On the sympathetic ganglia, peripheral D2 receptors are inhibitory heteroreceptors. Activation results in vasodilation by preventing release of norepinephrine; the resulting orthostatic hypotension causes the feeling of profound drowsiness and weakness. Agonism of D2 receptors in the CTZ causes nausea and vomiting. There are other peripheral D2 and D3 receptors, but their effects are not well understood.
Finally, many DA agonists are also agonists at the presynaptic alpha2 adrenoceptor and antagonists at the postsynaptic alpha1 adrenoceptor giving them additional indirect and direct anti-noradrenergic/sympatholytic actions, respectively.
poster:Astounder
thread:791344
URL: http://www.dr-bob.org/babble/20071027/msgs/792561.html