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Re: Dopamine agonists cause sedation. But why?? » Astounder

Posted by amigan on November 2, 2007, at 6:36:00

In reply to Re: Dopamine agonists cause sedation. But why?? » linkadge, posted by Astounder on November 1, 2007, at 11:30:46

> > >.) 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.
> >
> > But does it make sense that the theraputic effect of a dopamine agonist would correspond with an overal decrease in post synaptic receptor stimulation?
> >
> > If they do have higher affinity for presynaptic autoreceptors and the sedation does correspond to a decrease in dopamine release, then why would one get improvement in Parkinson's symptoms right after dosing? Wouldn't one expect the net decrease in post synaptic dopamine receptor function to correspond to worsening Parkinsonian symptoms?
> >
> > So I guess what I am saying is why do parkinsons symptoms remit at the same time as an increase in sedation? You obviously are getting a net increase in dopaminergic neurotransmission at this point or else or else parkinsons symptoms wouldn't decrease, yet you are experiencing somnolence at the same time.
> >
> > Also, one would expect the autoreceptors would desensize leading to a net increase in dopamine release overtime. Does the sedation improve over time (I don't know I have never taken it)
> >
> >
> > Linkadge
> >
> >
> >
> >
>
> It's not that they're completely ineffective for their purposes, rather I'm trying to explain why they don't cause the rapid reversal of depressive symptoms like amphetamines do. Though the autoreceptors are activated, the dopamine agonist is still able to activate the postsynaptic receptors, even if less DA is entering the cleft than normal. But their lowered potency compared to pure dopamine (by the ratio of affinity to post- and presynaptic receptors) would explain why L-DOPA eventually becomes preferred over DA agonists in the late stages of Parkinson's, despite its greater incidence of side-effects.
>
> Likely, the autoreceptors do desensitize over time, and this is probably responsible for any delayed antidepressant effects, but by this time you may already be desensitizing the postsynaptic receptors as well. For Parkinson's patients, who have hypersensitive striatal DA receptors, the sedating action of DA agonists are going to be overcome by the psychomotor activation that stimulation of the striatum causes. In depressives who don't have hypersensitive striatal DA receptors (at least, that I know of), there is not going to be psychomotor activation to overcome the sedating effects of the DA agonists.
>
> I haven't taken them, so I don't know how much the sedation improves. You should develop at least partial tolerance to sedation resulting from the alpha1 antagonism and alpha2 agonism, like you do with prazosin and clonidine, respectively. I don't know anything about tolerance to the orthostatic effects of peripheral DA receptors.
>
> Honestly, If I'm going for DA, I'd rather activate the DAergic pathways through augmenting the action of DA itself, instead of trying to mimic it with direct agonists: DL-phenylalanine or microdose L-DOPA + carbidopa, MAO-B or full MAO inhibitors, COMT inhibitors, DRIs, NRIs, glial OCT3/uptake2 blockers, 5HT2A & 5HT2C antagonists, alpha2 antagonists, NMDA antagonists, AMPA agonists, nicotine, intermittent doses of neuroleptics to reverse tolerance, pyridoxal-phosphate, reserpine, tetrabenazine, or kappa-opioid pretreatment, and any other things I can't think of.

I think you pretty much covered them all. :-P
I can only think of adenosine antagonists like caffeine, but i suspect that it is not very potent.
I see that 5HT2A and 5HT2C antagonists increase dopamine. Does this mean that certain antidepressants like mirtazapine are expected to do the job? Are there any more potent 5HT2A/C antagonists than this drug?


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poster:amigan thread:791344
URL: http://www.dr-bob.org/babble/20071027/msgs/792912.html