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Re: Downregulating dopamine autoreceptors » zeugma

Posted by karaS on October 16, 2004, at 20:29:15

In reply to Re: Downregulating dopamine autoreceptors, posted by zeugma on October 16, 2004, at 16:55:04

> hi kara and todd,
>
> all of our thoughts have been moving along similar lines. i am convinced, given the nature of my response to strattera and provigil (I believe provigil operates at least partially through noradrenergic mechanisms) and my much less specific and strong response to Ritalin, that my noradrenergic system is at least partially functional, while my dopaminergic system is in dire shape. i tracked down this article about the involvement of alpha-1-b receptors (previously identified as crucial to Provigil's mechanism of action) as mediating the interplay between the NE and DA systems. This search was inspired by the fact that I'm probably going to try dexedrine next, and i know that amphetamines act more potently to release/inhibit reuptake of NE than DA.


If stimulants more potently release/inhibit reuptake of NE, then why is it assumed that those who react paradoxically to stimulants have hypersensitive DA (rather than NE) receptors? (Also, if this is the case, then amphetamines might not put me to sleep like Ritalin did?)


> It was found recently that locomotor and rewarding effects of psychostimulants and opiates were dramatically decreased or suppressed in mice lacking 1b-adrenergic receptors [1b-adrenergic receptor knock-outs (1bAR-KOs)] (Drouin et al., 2002). Here we show that blunted locomotor responses induced by 3 and 6 mg/kg D-amphetamine in 1bAR-KO mice [84 and 74%, respectively, when compared with wild-type (WT) mice] are correlated with an absence of D-amphetamine-induced increase in extracellular dopamine (DA) levels in the nucleus accumbens of 1bAR-KO mice. Moreover, basal extracellular DA levels in the nucleus accumbens are lower in 1bAR-KO than in WT littermates (28%; p < 0.001).
>
> In rats however, prazosin, an 1-adrenergic antagonist, decreases D-amphetamine-induced locomotor hyperactivity without affecting extracellular DA levels in the nucleus accumbens, a finding related to the presence of an important nonfunctional release of DA (Darracq et al., 1998). We show here that local D-amphetamine releases nonfunctional DA with the same affinity but a more than threefold lower amplitude in C57BL6/J mice than in Sprague Dawley rats. Altogether, this suggests that a trans-synaptic mechanism amplifies functional DA into nonfunctional DA release.


By “trans-synaptic mechanism”, you’re referring to the work of the 1-b adrenergic receptors, right? So you’re saying here that hypersensitive DA receptors might not be our problem (or might only be part of the problem) – and that the DA itself could instead be rendered “nonfunctional”?


> Our data confirm the presence of a powerful coupling between noradrenergic and dopaminergic neurons through the stimulation of 1b-adrenergic receptors and indicate that nonfunctional DA release is critical in the interpretation of changes in extracellular DA levels. These results suggest that 1b-adrenergic receptors may be important therapeutic pharmacological targets not only in addiction but also in psychosis because most neuroleptics possess anti-1-adrenergic properties.
>
> http://www.jneurosci.org/cgi/content/full/22/21/9150
>
> am i on the right track here?

It's certainly food for thought. Thanks for posting this. I'm happy if it opens new avenues of exploration. I just wish that we were further along in the process!

Kara


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URL: http://www.dr-bob.org/babble/20041012/msgs/403975.html