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Re: Anticholinergics as antidepressants

Posted by undopaminergic on December 30, 2019, at 14:40:32

In reply to Re: Anticholinergics as antidepressants, posted by linkadge on December 30, 2019, at 8:28:37

> >Well, we can say for sure that they are different, >and also that their effects are likely >substantially different.
> We can?

Say for sure that selective DRIs are different from SNDRIs? Yes. (You yourself seem to be arguing as much.) Nevertheless, I would still insist that the DAT-inhibition is the main thing as far as the "likeability" of mixed monoamine reuptake inhibitors is concerned.

> >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).
> Norepinephrine reuptake inhibition is involved in some of the cognitive / rewarding process involved in stimulant action / abuse.

I agree, but I'm inclined to believe the adverse effects (eg. tachycardia and sweating) from NRI outweigh the rewarding aspects. Well, at least I feel that is true for me, but I seem to have too much noradrenaline, so any elevation is aversive to me. Analogously, there are people who don't enjoy the DRI action of stimulants, probably because they have high dopamine already.

> For example, certain regions of the brain are devoid of dopamine transporters

Sure, all areas of the brain that don't receive afferent dopamine projections.

> and so dopamine is cleared from the synapse by the norepinephrine transporter.

Right. Noradrenergic nerve terminals always take up dopamine, because that is the precursor to noradrenaline.

> The prefrontal cortex has no dopamine transporters.

I don't agree on that. If VTA dopamine projections to the nucleus accumbens have dopamine transporters, why would projections, from the same origin, to the prefrontal cortex lack them? True, they are scarce / low density, but not nonexistent.

I spent a substantial amount of time investigating this, and I found several articles that confirm the existence of DATs in the PFC:
"A cumulative effect of dopamine and norepinephrine transporter blockade on the output of dopamine in dialysates was also observed in .. the prefrontal cortex."
"Increased expression of the DA transporter (DAT) is also seen in the adult infralimbic mPFC ..."
".. [3H]GBR 12935 dopamine transporter (DAT) binding .. in the prefrontal cortex ... intermittent administration of cocaine resulted in a selective alteration of [3H]GBR 12935 binding in the prefrontal cortex .."
"Moderate levels of [3H]GBR 12935 binding were observed in .. prefrontal and singular cortices."
"In the medial prefrontal cortex, cocaine and GBR 12909 could inhibit only about 40% of the [3H]dopamine uptake."
".. revealed .. decreased DRD2 and DAT mRNA and protein expression in the PFC,"
".. neonatal ethanol exposure increased the V(max) for DAT in the PFC, suggesting an increase in DAT function in PFC."
"Furthermore, long-, but not short-access to self-administered methamphetamine resulted in persistent decreases in dopamine transporter (DAT) protein levels in the prefrontal cortex .."
"In mPFC .., total DAT immunoreactivity was not different .."
"The lower dopamine transporter density in the orbitofrontal and dorsolateral prefrontal cortex was significantly correlated with the duration of methamphetamine use and the severity of psychiatric symptoms."
"Dopamine axon varicosities in .. the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter."

In summary, sparse but not nonexistent.

A couple of articles that suggest you may be right:
"Infusions of the selective dopamine uptake blocker GBR 12909 failed to alter dopamine efflux in any prefrontocortical subregion."
".. it appears that [[3H]GBR 12935] in the rat PFC labels mainly 'the piperazine acceptor site' and not the DA transporter."

> The ability of Ritalin (for example) to increase prefrontal dopamine does not depend on DAT inhibition

I agree. The dopamine transporters of the PFC are very sparse, and to inhibit them takes a very high affinity and potent antagonist. Some of the GBR-xxx series of selective DRIs are potent enough to do so. The dose-effect curve of methylphenidate with respect to DAT inhibition flattens long before reaching 100% inhibition. Some of the radio-tracers used in PET to visualise the distribution of DATs do not sufficiently bind to these transporters in the PFC (at the concentrations used), and so it may appear from the images that the transporters are entirely absent.

> (probably a combination of NRI and 5-h1a agonism from d-methylphenidate).

Are you saying d-methylphenidate is a 5-HT1A agonist?

> Serotonin reuptake inhibition too enhances the rewarding effects of dopamine reuptake inhibition (via 5-ht1a/b stimulated dopamine release in the NAc).

I'm inclined to agree, albeit with the qualification that it probably varies between individuals. Some people feel worse rather than better from SSRIs.

Also, some actions of serotonin antagonise dopamine, whereas some some of them synergise. The question is which of them predominates.

> Also, serotonin and dopamine transporters are sometimes promiscuous. For example, in the presence of an SSRI, the dopamine transporter can begin to clear serotonin, and hence combined SERT/DAT inhibition may result in higher levels of serotonin (and possibly dopamine).

Seems to me that the extracellular serotonin would be reduced if the DAT contributes to its clearance?

I think one of the mechanisms behind the serotonergic neurotoxicity of MDMA is that the SERT begins to take up dopamine into serotonergic nerve terminals, and I propose that the latter are ill-equipped to "deal" with dopamine, resulting in oxidative stress.

> In animal models, dopamine is more involved in reward anticipation (and the motivation to achieve a reward) rather than producing reward themselves.


> In some models, increasing dopamine inhibits opiate release (perhaps creating a sense of dissatisfaction, or increasing goal directed behavior). I remember reading studies on hyperdopaminergic mice. According to the following abstract:
> "hyperdopaminergic mutant mice attribute greater incentive salience ("wanting") to a sweet reward in the runway test. But sucrose taste fails to elicit higher orofacial "liking" reactions from mutant mice"

That is consistent with what I've read. Nevertheless, I did experience more "liking" when I first took pramipexole. For example, music sounded better, and I *liked* it more. Likewise (pun not intended) food and movies.

I also experienced enhanced taste of foods in one of my (hypo)manic episodes.

> "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?"
> I have not. However, here is a little blurb on the possible mechanism of dopamine release by cocaine:

Alternatively, this article suggests that sigma-agonism may be a mechanism through which cocaine could enhance DA release:
"sigma receptor ligands appear to facilitate dopamine release from nigrostriatal, and presumably mesocorticolimbic, neurons through a non-transporter-mediated mechanism."

> The following study suggests that cocaine increases dopamine release via a cholinergic mechanism (because nicotinergic antagonists were able to block the rewarding effects):


> This also could be one mechanism of tolerance to many drugs (i.e. depletion of cholinergic reserves).

Seems this could be tested with acetylcholinesterase inhibitors.

> The following study suggests that 5-ht1b receptor expression in the NAc has something to do with the rewarding effects of cocaine. 5-ht1b expression in the NAc is controlled by the P11 protein (which is apparently low in people with depression).

That's very interesting. As far as I've seen, the 5-HT1B receptor is largely neglected by researchers, because you rarely come across it.

> I suppose the firing (and suppression) of the VTA neurons is important in the process of addiction.

Absolutely. Especially as far as opies go.

> Dopamine can modulate this firing via inhibition of gaba release in this region.

You mean dopamine in the NAc inhibits GABAergic neurons projecting to the VTA?

> Opiates too block gaba release there and enhance firing.

Right. I also read that kappa-opioid receptor antagonism enhances dopamine release in the prefrontal cortex, but I don't have any references at hand -- other than personal experience with buprenorphine.

> However, overactivity of VTA neurons is also linked to depression.

I wasn't aware of that. It's counterintuitive, but I suppose there can be dysregulations of this circuitry, so that it doesn't function normally.

> The reward center is meant to help us get through difficult times,

Amongst other things. It seems particularly important in establishing rewarding habits, some of which can be dysfunctional (eg. taking certain drugs), and may be at odds with helping us through difficult times (such as lack of the drug of choice).

> but it is not really meant (or even capable) of firing 24/7. There will always be some mechanism (even if its death of the neurons themselves) that limits the ability to experience pleasure constant.

Well, that is the conventional wisdom. But I do know consistent pleasure can be sustained for days, if not weeks, on end. It does lose its novelty after some days, and you begin to take it for granted, but you still feel good. More modest (or "normal") well-being can be sustained for even longer.


That's cool.

> Yeah. I think M1 and M2 receptor blockade is important. M1/M2 knockout mice display a depression resistant phenotype.
> "These data establish muscarinic M1 and M2 receptors as sufficient to generate behavioral effects consistent with an antidepressant phenotype and therefore as potential targets in the antidepressant effects of scopolamine."

I'm a bit confused. You say M1/M2 knockouts are resistant to depression, but it seems the article is saying that these receptors, and not their absence, are sufficient *for* an antidepressant phenotype?

> That could be. However, 5-ht antagonists can increase 5-ht1 mediated neurotransmission by blocking 'alternative' receptors for serotonin to bind to.

Oh, yes, that makes sense. Ie. 5-HT2A blockade would enhance the relative "dominance" of the 5-HT1A or -1B receptors, shifting the balance.

> Mirtazapine also exhibits this 'indirect' 5-ht1a agonism even though the molecule displays no direct 5-ht1 agonism on its own right.


> Some research suggests the 5-ht7 receptor may be more involved in the anti-anhedonic effect of certain antipsychotics. 5-ht7 antagonists appear to have rapid acting AD effects.

Very interesting. It's not only antipsychotics:

I'm taking one of them, clozapine, and I wonder if sulpiride and/or trimipramine may share this action too.

> >I became tolerant to the anti-anhedonic effects >of pramipexole (dopamine D3/D2 direct agonist). I >wonder if trimipramine could reverse this >tolerance.
> Possibly. Perhaps worth a try if you have some Mirapex left over.

Sifrol in my case, but alas, I have none left, and at this point it seems my doctor(s) would be unlikely to prescribe it.

> My only recipe is to keep "changing sh*t up". I know this runs completely contrary to conventional wisdom.

Not really. It makes a lot of sense. By changing things, ie. experimenting, you can learn things, and gradually figure out what works or not.





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