Posted by linkadge on December 30, 2019, at 18:34:00
In reply to Re: Anticholinergics as antidepressants, posted by undopaminergic on December 30, 2019, at 14:40:32
>I would still insist that the DAT-inhibition is the >main thing as far as the "likeability" of mixed >monoamine reuptake inhibitors is concerned.
Possibly. However, I've never taken a selective dopamine reuptake inhibitor, so I can't say. I believe modafinil has some ability to inhibit DAT (again perhaps at an alternative binding site) yet it has nowhere near the abuse potential of cocaine. Many of the studies you reference (which suggest some function of DAT in the prefrontal cortex) still seem to reinforce my real point - that additional NET blockade can significantly augment the ability of DAT inhibitor to increase dopamine levels.
Your first link suggests:
"Administration of reboxetine, a selective blocker of the norepinephrine transporter, 20 min after the administration of GBR 12909, a selective blocker of the dopamine transporter, produced an increase of dopamine output in the nucleus accumbes shell (+408% above basal) greater than that obtained by GBR 12909 alone (+308% above basal)."
This would seem to suggest that NET inhibition contributes to the rewarding effects of these drugs (if elevated dopamine is, in fact, the key mechanism).
Keep in mind too, that the infralimbic prefrontal cortex is a sub-region of the prefrontal cortex.
"This study shows that dopamine extracellular concentration can be elevated by norepinephrine transporter blockade, even in areas where the dopamine transporter is predominant, when the latter is pharmacologically blocked."
Again, there is the possibility that monoamine transporters are promiscuous and can replace each other's roles in deficiency states. For example, this study suggests that after long term SSRI administration, the dopamine transporter begins to take up serotonin as well. The authors postulate depression is relived by when presynaptic neurons start to co-release dopamine and serotonin at the same time.
https://www.eurekalert.org/pub_releases/2005-04/cp-sai040105.php
Some evidence of the (relative) lack of dopamine transporters in the prefrontal cortex:
"have tested this hypothesis by comparing the effects of inhibitors selective for the three monoamine transporters with those of a nonspecific inhibitor, cocaine, on uptake of 3H-dopamine into synaptosomes from frontal cortex, caudate nucleus, and nucleus accumbens from wild-type, NET, and dopamine transporter (DAT) knock-out mice. Dopamine uptake was inhibited by cocaine and nisoxetine, but not by GBR12909, in frontal cortex synaptosomes from wild-type or DAT knock-out mice."
https://pdfs.semanticscholar.org/e32b/b1abc682dc7490aea0d6039136bf1edd0139.pdf
(again, not really my main point).
>Are you saying d-methylphenidate is a 5-HT1A >agonist?
Yes (see link below). My hunch is that (if one is targeting increased dopamine in the prefrontal cortex) then a combination of 5-ht1a agonism and NET inhibition would be (likely) synergistic.
https://www.ncbi.nlm.nih.gov/pubmed/19322953
Of course too, one needs to ensure they have adequate levels of omega-3 polyunsaturated fats in their diet which increase both dopamine content and cellular responsiveness to dopamine.
There are some studies that buspirone (5-ht1 agonist) can be effective for ADHD and can augment atomoxetine for ADHD.
https://www.ncbi.nlm.nih.gov/pubmed/20517641
There is a serotonergic theory for ADHD that many of the stimulants are working via 5-ht mechanisms (or some other unknown mechanism) to calm hyperactive individuals. For example, DAT knockout mice are hyperactive! Yet, DAT inhibitors like Ritalin calm DAT knockout mice down. Interestingly cocaine also calms down hyperactive DAT knockout mice.
https://science.sciencemag.org/content/288/5463/11
Interestingly, in the study they were perplexed by the fact that Ritalin calmed the mice only after a lag of 30 minutes (whereas serotonin enhancing drugs calmed the mice much faster). Perhaps this is the lag required for d-methylphenidate to kick in (with 5-t1a receptor agonism)??
>I'm inclined to agree, albeit with the >qualification that it probably varies between >individuals. Some people feel worse rather than >better from SSRIs.
Again, SSRIs alone have other issues (i.e. dopamine suppression via 5-ht2c receptors). By themselves they are not rewarding (actually in DAT knockout mice they are!). However (not sure if you've taken an SSRI + Ritalin), it is substantially more 'reinforcing' than Ritalin alone. Some studies suggest a very similar pattern of NAc cfos activity following SSRI + Ritalin to cocaine.
>Alternatively, this article suggests that sigma->agonism may be a mechanism through which cocaine >could enhance DA release:
Right. I was going to mention that, but wasn't sure how significant the effect was. I think the effect is due to sigma-2 more so than sigma-1 (or vice versa). I think sig-1 receptor agonists display more antipsychotic effects (i.e. fluvoxamine in psychotic depression). Interestinly, the sensitization of cocaine appears to be due to sigma receptor mechanisms. Sigma receptor modulation can reduce the addictive and sensitizing effects of cocaine.
Here's a study suggesting that sigma receptors themselves can alter (perhaps enhance) the way that cocaine inhibits DAT (and as you mention also increase dopamine release). Sigma receptors also modulate glutamate and gaba release, which again could enhance the rewarding effects of cocaine.
https://www.ncbi.nlm.nih.gov/pubmed/28495886
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4830437/
In fact, the study suggests that agents which inhibit DAT AND block sigma receptors appears to have much lower abuse potential (if any) (and may even aid in cocaine withdrawal).
https://www.ncbi.nlm.nih.gov/pubmed/12801223
Sigma receptors may be some of the link between stimulant abuse and schizophrenia (or stimulant induced psychosis). I believe quetiapine has actions on sigma receptors, which may explain its antipsychotic effects at doses too low to achieve significant d2 antagonism.
Ok. Enough for tonight. Take care!
Linkadge
poster:linkadge
thread:1107464
URL: http://www.dr-bob.org/babble/20191019/msgs/1107552.html