Posted by linkadge on December 30, 2019, at 8:28:37
In reply to Re: Anticholinergics as antidepressants, posted by undopaminergic on December 29, 2019, at 20:03:39
>Well, we can say for sure that they are different, >and also that their effects are likely >substantially different.
We can?
>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. For example, certain regions of the brain are devoid of dopamine transporters and so dopamine is cleared from the synapse by the norepinephrine transporter. The prefrontal cortex has no dopamine transporters. The ability of Ritalin (for example) to increase prefrontal dopamine does not depend on DAT inhibition (probably a combination of NRI and 5-h1a agonism from d-methylphenidate).
Serotonin reuptake inhibition too enhances the rewarding effects of dopamine reuptake inhibition (via 5-ht1a/b stimulated dopamine release in the NAc). 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).
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"
https://www.biopsychiatry.com/hyperdopaminergic.html
"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:
https://www.ncbi.nlm.nih.gov/pubmed/16554471
The following study suggests that cocaine increases dopamine release via a cholinergic mechanism (because nicotinergic antagonists were able to block the rewarding effects):
http://grantome.com/grant/NIH/F32-DA040409-01
This also could be one mechanism of tolerance to many drugs (i.e. depletion of cholinergic reserves).
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).
I suppose the firing (and suppression) of the VTA neurons is important in the process of addiction. Dopamine can modulate this firing via inhibition of gaba release in this region. Opiates too block gaba release there and enhance firing. However, overactivity of VTA neurons is also linked to depression. The reward center is meant to help us get through difficult times, 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.
https://www.jneurosci.org/content/22/24/10856
>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.
Yeah. I think M1 and M2 receptor blockade is important. M1/M2 knockout mice display a depression resistant phenotype.
http://jpet.aspetjournals.org/content/jpet/351/2/448.full.pdf
"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."
>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.
That could be. However, 5-ht antagonists can increase 5-ht1 mediated neurotransmission by blocking 'alternative' receptors for serotonin to bind to. 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.
>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.
My only recipe is to keep "changing sh*t up". I know this runs completely contrary to conventional wisdom.
Linkadge
poster:linkadge
thread:1107464
URL: http://www.dr-bob.org/babble/20191019/msgs/1107519.html