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Re: Anticholinergics as antidepressants

Posted by undopaminergic on January 1, 2020, at 14:10:29

In reply to Re: Anticholinergics as antidepressants, posted by linkadge on December 30, 2019, at 18:34:00

> >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.

I agree. But this abstract suggests only "moderate" selectivity for the DAT:

Corroborated by:
"Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 +/- 12% .. 8 mg/kg: 54 +/- 3% ..). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 +/- 7.8% .. 8 mg/kg: 44 +/- 12% ..)."

But in contrast:
"Modafinil was binding to the DAT but insignificantly to SERT or NET and dopamine reuptake was blocked .."

"These results demonstrate that modafinil potentiates brain dopaminergic signals via DAT inhibition by acting at the same binding site of cocaine."

"The atypical stimulant and nootropic modafinil interacts with the dopamine transporter in a different manner than classical cocaine-like inhibitors."

However, DAT inhibiton does not seem to be the only action of modafinil:
"These results suggest that the arousal effect of modafinil does not depend on the availability of the endogenous catecholamines but results from an enhancement of alpha 1- and beta-receptor activity .."

"These effects could be linked to modulation (stimulation) of central alpha 1-adrenoceptors unaccompanied by peripheral sympathetic effects .."

And, with respect to amphetamines:
".. it is concluded that the mechanism underlying the modafinil induced stimulant locomotor effect differs completely from that of (+)amphetamine."

> 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.

Oh, but I agree on that. However, see below.

> 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).

Yes. However, I am wondering about the significance of elevated dopamine in noradrenergic synapses. This dopamine does not necessarily reach dopamine receptors, except where DA and NA receptors are closely co-localised.

> Keep in mind too, that the infralimbic prefrontal cortex is a sub-region of the prefrontal cortex.

Sub-region? You mean analogous to medial or ventrolateral PFC (ie. "subsections")? Or do you mean it is located below/under the PFC without actually being part of the PFC?

> 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.

Interesting. I'm thinking of L-dopa induced dyskinesias in Parkinson's disease. Maybe this happens because L-dopa elevates the extracellular concentrations of dopamine to the point that SERT begins to take up -- and release -- dopamine.

> Some evidence of the (relative) lack of dopamine transporters in the prefrontal cortex:
> (again, not really my main point).

Right. I have already acknowledged that the DAT is sparse in the PFC, but argued that it is not nonexistent. I am still confused as to whether the DAT is sparse because DA terminals are sparse, or whether DA terminals actually express the NAT protein in place of the DAT.

> >Are you saying d-methylphenidate is a 5-HT1A >agonist?
> Yes (see link below).

My intuition suggests that this action of d-MPH takes very high doses. The abstract speaks of 5 to 100 micromol... whereas at the DAT and NAT, d-MPH is active at *nano*molar concentrations.

Indeed, Wikipedia confirms my suspicions -- look at the receptor binding table:
According to that table, the IC50 concentration of d-MPH at the DAT is only 23 nM, whereas the EC50 at 5-HT1A is 6800!

> 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.

I agree on that. Seems methylphenidate and buspirone might be an interesting combination.

> 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.

How common is omega-3 deficiency? I've tried this supplement with no effect.

> There are some studies that buspirone (5-ht1 agonist) can be effective for ADHD and can augment atomoxetine for ADHD.

Pretty much what I suggested above.

> 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.

I'm still trying to figure this out. Methylphenidate stimulates me to be more active, even "hyper"-active, eg. staying up the whole night (or longer) and being less apathetic. Meanwhile, the first doses of PEA that I took, calmed me down to the point that I could have slept, had I not been focussing on watching the news and weather forecast. Perhaps PEA and amphetamines can calm you down through actions at the trace amine-receptors? Or do these drugs simply release so much DA that it hits the autoreceptors strongly enough to calm the presynaptic neuron enough to in turn calm the postsynaptic neuron through absence of DA-agonism?


I agree with the criticism by Volkow et al.

> 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 don't know. It would seem to be a process that starts slowly and then progresses until reaching some kind of "critical mass".

> >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!).

Interesting, regarding the DAT-KO mice. As I said before, they are different in more ways than just lacking the DAT.

Here's another abstract in that context:
"DAT knock-out mice were also unresponsive to the normally robust wake-promoting action of modafinil, methamphetamine, and the selective DAT blocker GBR12909 but were hypersensitive to the wake-promoting effects of caffeine."

> However (not sure if you've taken an SSRI + Ritalin),

I think I've neglected to try that combination.

> it is substantially more 'reinforcing' than Ritalin alone. Some studies suggest a very similar pattern of NAc cfos activity following SSRI + Ritalin to cocaine.

Seems intuitive, but this article suggests that modafinil+escitalopram is not nearly as "good" as cocaine:
".. no treatment significantly reduced choices for cocaine infusions. ... Modafinil attenuated many positive subjective effects produced by cocaine; however, escitalopram combined with modafinil did not enhance the efficacy of modafinil to reduce cocaine effects."

One would intuitively expect the combination -- as a "simulation" of cocaine pharmacodynamics -- to better (than modafinil alone) substitute for cocaine, and thereby reducing interest in cocaine infusions.

Anyway, modafinil differs substantially from Ritalin, so this article may not be entirely relevant to the combination of MPH+SSRI.

> >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).

I thought it was sigma-*ant*agonism that produced antipsychotic-like effects?

> 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.

Do you have any references at hand? I'm very interested in this, and other cocaine trivia. Walking in the footsteps of Freud...

> 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.

I don't have a clear understanding of "conformations" of the DAT. Also, I definitely need to read more about sigma.

> 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).

And by extension, maybe agents that potently a) block the DAT and b) stimulate sigma, would be "particularly" abusable. Especially if they have a fast onset of action -- compare oral methylphenidate with crack cocaine.

> 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.

Interesting speculation. If quetiapine (QTP) is a sigma-ligand, maybe that is the reason why it is the only(?) antipsychotic drug associated with drug-seeking. I don't know if it has been said before here, but there are even people who are into "Q-balls" -- that is a recreational combination of QTP and cocaine, and which is commonly injected. It strikes me now, that the recently popular practice of "augmenting" antidepressive (including stimulants) treatment with antipsychotics is really analogous to Q-balling. Could Abilify+Dexedrine be a recrational combo that is subjectively superior to Dexedrine alone?





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