Posted by undopaminergic on December 29, 2019, at 20:03:39
In reply to Re: Anticholinergics as antidepressants, posted by linkadge on December 29, 2019, at 13:30:50
> >From what I've read, it does bind to the dopamine >transporter, but it is atypical, and does not >bind to the same site as cocaine or >methylphenidate. If it did, we can be pretty sure >it would be even more of a drug of abuse.
>
> Well, if we're going to pick :) It's hard to know whether a drug of abuse would be 'more' abusable under different circumstances.
>Well, whilst that is true, we can make reasonable predictions. I read there was an opioid (alfentanil IIRC) that is dysphorigenic, but that doesn't change the fact that most (mu) opioids are the opposite. There are individual differences too. I found methoxetamine (MXE, a NMDA-antagonist) the most strongly dysphorigenic drug I ever tried, even though most reports suggest it is a euphoriant. Meanwhile, I enjoyed memantine a *lot*.
> Pure dopamine reuptake inhibitors likely don't have the same abuse potential as cocaine (a triple reuptake inhibitor with monoamine releasing capacity).
>Well, we can say for sure that they are different, and also that their effects are likely substantially different.
Still, the main difference in my view, is that pure DRIs are free of noradrenergic side effects, which would tend to render them more "likeable". I don't know about the serotonin, but from what I've read it seems the serotonergic action of cocaine attenuates the locomotor response (in rodents).
I believe I experienced a selective (and potent) DRI once, but the circumstances were so improbable that I have to say reason suggests it was a purely psychodynamic experience. Anyway, for what it's worth, based on the effects (of whatever origin), my working memory, self-confidence, and motor functions, were improved in a way that does not take place with methyl- or ethylphenidate. And that was on top of (hypo)mania. For me, that substance (if it was a substance) was more pleasant than mixed noradrenaline- and dopamine reuptake inhibitors. But that's just me; there are indications I have excessive noradrenaline. I agree that some people enjoy the noradrenaline boost from cocaine, and likewise serotonin.
It does seem absolutely clear that the *amount* of dopamine elevation does not explain everything about what makes drugs "likeable". For example, this study claims buprenorphine (low abuse potential) can elevate dopamine by 200%, whereas cocaine (high abuse potential) "only" achieves 180%:
https://www.ncbi.nlm.nih.gov/pubmed/1988653
Part of the reason is of course that cocaine achieves the elevation fast, and with buprenorphine it happens slowly.As for the monoamine releasing action of cocaine, have you come across any quantifications of that? Ie. how much of 180% elevated dopamine is attributable to the enhanced release as opposed to reuptake inhibition?
> Even in DAT knockout mice, cocaine still exhibits rewarding effects, arguing against the notion that the dopamine transporter is solely responsible for cocaine's actions.
>I agree, but you have to be careful in interpreting the results of experiments performed on DAT-KO animals. They are different from "wild type" animals in more ways than just lacking the DAT.
> Yes, I head that benztropine acts on the dopamine transporter in a different way from cocaine, but this doesn't mean that it doesn't still increase dopamine levels in the synapse.
>I agree.
> I found benztropine much 'better' than say dimenhydrinate (which I find pretty discussing to be honest).
>
> I've used the scopolamine patch ... Again, not as 'good' as benztropine.
>It's my understanding that the differences in effects between individual anticholinergics are usually attributable to the specific affinities for different muscarinic receptors. For example, scopolamine is more euphoriant than atropine. But benztropine may be a special case, in having effects on the DAT.
> >I read that 5-HT2A antagonists acutely increase >dopamine release in the prefrontral cortex, but >with chronic administration, this effect is not >sustained.
>
> Hmm. Any references on that?No, nothing exact, I read it many years ago. It was on PubMed and I'm pretty sure the drug was olanzapine. I failed to locate it now. While searching, I noticed a few things suggesting that it may be hasty to come to this conclusion from a single study. One article suggested the 5-HT1A receptor, rather than 5-HT2A, is required to increase dopamine.
In my personal experience, I have sometimes noticed a short-lived reduction of apathy upon starting olanzapine. I imagine this is the 5-HT2A antagonism increasing prefrontal dopamine.
> Atypcal antipsychotics can 'normalize' cognition in schizophrenia (in some studies)
>Some aspects maybe, but there are other aspects that scarcely respond to antipsychotics at all. For example, working memory deficits.
> an effect that is presumably due to 5-ht2a antagonism.
When it comes to psychotic aspects of cognition (thought disorder), it is probably the dopamine antagonism too.
> I haven't heard of this effect 'wearing off' but who knows. 5-ht2a and 5-ht2c antagonists can also produce neurotrophic effects, and increase slow wave sleep / melatonin release.
>That is interesting.
The 5-HT2C receptor is particularly antidopaminergic.
I seem to recall that most antidepressants suppress REM-sleep, but trimipramine does not, and may even enhance it.
> >It does, acutely, and then there is a rebound >(ie. increased cortisol) effect.
>
> Any references to this? Do you mean a rebound when the drug wears off, or when it is still in the system?
>The term "rebound" was my interpretation. I meant, that when the drug is taken at night / prior to sleep, the cortisol secretion is suppressed, and then it returns in the morning (rebound), quite possibly because the levels of the drug are lower.
> Ideally you want cortisol to be lower in the evening / night and then increase in the morning.
>Exactly.
> Persistently low cortisol is not a good thing and can make you feel worse.
>Yes, and there is something called "steroid euphoria" that can be induced by glucocorticoid drugs.
> >I'm afraid not. It did not change the ACTH >(adrenocorticotropic hormone) levels in the >study/ies I read.
>
> Any reference to this?This one reports that cortisol is normalised but ACTH remains elevated:
https://www.ncbi.nlm.nih.gov/pubmed/1661430> Here's a study on the d2/d3 receptor upregulation following trimipramine administration. This sets it apart from mirtazapine, which does not induce this upregulation. I found that trimipramine had a much stronger effect than mirtazapine on my core anhedonia. On paper, mirtazapine and trimipramine should induce similar effects, but they apparently don't. Many antidepressants (and ECT) increase the sensitivity of the d2/d3 receptor system.
>
> https://www.ncbi.nlm.nih.gov/pubmed/9660111I became tolerant to the anti-anhedonic effects of pramipexole (dopamine D3/D2 direct agonist). I wonder if trimipramine could reverse this tolerance.
-undopaminergic
poster:undopaminergic
thread:1107464
URL: http://www.dr-bob.org/babble/20191019/msgs/1107499.html