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Re: What do TRD patients take without an MAIO linkadge

Posted by undopaminergic on December 11, 2019, at 10:31:16

In reply to Re: What do TRD patients take without an MAIO, posted by linkadge on December 10, 2019, at 15:36:19

> >As I understand it, it is through one of the trace >amine receptors that amph. (and PEA) reduce the >spontaneous firing of the presynaptic neuron.
>
> Yes, it may be a dopamine autoreceptor agonist

If you mean "indirect autoreceptor agonist", I definitely agree. On the other hand, if you mean direct agonist, I'm quite sure it isn't, because that is something we would have read about already if it were so.

> (or functionally interact via TAAR1). Again, amphetamine can have this property too (within a certain dose range, I believe).
>

Probably. Meth and "regular" amphetamine have very similar pharmacology.

> >Do TAARs interact with the autoreceptor system, >or do these receptors produce their effect >independently of each other?
>
> I'm not sure. TAAR1 agonist have antidepressant and antipsychotic properties.
>

That is interesting. The antipsychotic effect is also consistent with the conclusion that TAARs reduce DA neuronal firing. However, *anti*depressant and reduced DA? That is counterintuitive.

> So, in some ways, amphetamine may counteract some of its psychotomimetic effects.
>

Yes.

> https://www.ncbi.nlm.nih.gov/pubmed/29636691
>
> "In general, TAAR1 agonists specifically inhibited the rewarding and reinforcing effects of drugs of abuse and drug-abuse related behaviors. Details of the mechanism of TAAR1 remain elusive; however, it is thought to be regulated by its interactions with D2 receptors."
>
> https://www.ncbi.nlm.nih.gov/pubmed/29066851
>
> "We show, first, that the full TAAR1 agonist, RO5256390, dose-dependently blocked cocaine-induced inhibition of DA clearance in slices of the nucleus accumbens."
>

I don't understand how TAAR-agonists would inhibit cocaine's effects on clearance. If they did, they would have to activate the DAT in face of cocaine's inhibition thereof. I think that the authors may mean that TAAR-agonists inhibit the cocaine-induced *accumulation* of synaptic dopamine.

> "Second, subthreshold inhibition of PKA or PKC phosphorylation did not prevent TAAR1 suppression of cocaine effects whereas subeffective doses of the DA D2 receptor antagonist, L-741,626, rescued cocaine's ability to produce changes in DA uptake in the presence of full TAAR1 activation, thus indicating that TAAR1 modulation of cocaine effects requires simultaneous DA D2 receptor activation."
>

Yes, I think this goes a long way to establish that these two classes of presynaptic receptors interact.

> It seems that taar1 agonist somehow interact with (likely?) presynaptic d2 receptors to inhibit dopamine release (?).
>

Agreed.

> It suggested that there is an interaction between TAAR1 and gsk-3. Gsk-3 inhibitors (like lithium) have mood stabilizing and (in some cases) antipsychotic qualities and also seems to regulate dopamine systems.
>

Interesting. I haven't read much about the pharmacodynamics of lithium.

I would expect a reduction in mania to result in a reduction of the development of delusions. Then again, this is in rodents, I assume.

> LSD inhibits dopamine firing via TAAR1 receptors.
>

Good to know. I haven't read much about LSD pharmacology either.

> https://www.ncbi.nlm.nih.gov/pubmed/27544651
>
> I've often wondered if cannabis interacts with TAAR1 in some way.
>

If so, it doesn't seem to have been reported yet. This PubMed search: <<cannabinoid[tiab] AND (taar[tiab] OR trace amine[tiab])>> turns up nothing interesting.

> I know that CB2 receptor agonists also inhibit dopamine firing and can prevent sensitization from drugs like cocaine.
>

That is also good to know. I would like to add, however, that cocaine pharmacology is complex, and this drug also induces DA downregulation, and this may happen through increased dynorphin (the primary endogenous kappa-opoid).

> "Postsynaptic D2 dopamine receptor supersensitivity in the striatum of mice lacking TAAR1."
>

If TAARs are presynaptic, how do they produce postsynaptic supersensitivity? Seems to me that it has to be through reducing synaptic dopamine, preventing DA-induced downregulation of the postsynaptic receptors.

> https://www.ncbi.nlm.nih.gov/pubmed/25721394
>
> Hence it seems that TAAR1 receptors also regulate post synaptic d2 receptor sensitivity (as do GSK3 inhibitors like lithium / valproate).
>

Interesting. I think in the case of TAARs, this is indirect, through modulation of synaptic DA.

> There are case reports of amphetamine calming mania. This could be via taar1 agonism. Perhaps some manics have supersentive TAAR1 receptors, leading to an increased sensitivity to this target of amphetamine.
>

Very possible. Such supersensitivity would likely exist in many ADDers too.

> "Low phenethylamine levels and low activation of TAAR1 can cause attention deficit hyperactivity disorder."
>

Maybe lack of PEA leads to less development of TAAR-downregulation (tolerance)? And hence, amphetamines would be more effective in calming subjects with this condition via increased TAAR-activation.

> https://www.bocsci.com/tag/trace-amine-associated-receptor-1-taar1-430.html
>
> " Methamphetamine is a psychostimulant that is known to exhibit moderate affinity for sigma-1 receptors (&#963;-1R) expressed in most neuronal cells "
>
> https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-015-0250-7
>

It seems this article examines meth-induced astrocyte (not neuron) activation by meth?

-undopaminergic


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URL: http://www.dr-bob.org/babble/20191019/msgs/1107186.html