"Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine"

[Nagelfar]

"Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine"

http://www.ncbi.nlm.nih.gov/pubmed/26239766 "Dopamine D3 receptor-preferring agonist enhances the subjective effects of cocaine in humans." Psychiatry Res. 2015 Nov 30;230(1):44-9. doi: 10.1016/j.psychres.2015.07.073. Epub 2015 Jul 29. Newton et al.

I've heard a lot of talk about D2 agonists, well here is something quite interesting from the euphorigenic standpoint considering potentiating factors or down right dopaminergic direct-agonism of higher efficacy in matching indirect agonists (releasers, inhibitors, etc.) considering D3 agonists.

 

[sekio]

Pramipexole isn't totally selective for D3, but this is still cool nonetheless.

 

[AlphaMethylPhenyl]

Pramipexole isn't totally selective for D3, but this is still cool nonetheless.

As if two dopaminergics wouldn't produce an additive effect? Maybe I'm just being a hard-ass. Things only seem obvious on the surface.

Pramipexole isn't considered to be recreational. D2/D3 are considered to be in the same "family", as I recall, though.

This might sound like a stupid question, but does pramipexole ever cause facillitated exchange diffusion? It seems like it could, given that it's similar enough in structure to dopamine to function as a D agonist. I'm trying to guess how this works. I mean, cause it couldn't be elevated levels of pramipexole in the synapse that mostly contributes to this effect in conjunction with cocaine, right? Pramipexole itself isn't recreational.

But can't dopamine, along with the other monoamines, can cause far-reaching effects throughout the brain, which is kind of the exception to the rule when it comes to small neurotransmitters? I'm wondering whether the brain somehow re-routes dopaminergic activity to other parts of the brain (the mesolimbic area) when it gets the message that there is already enough "dopamine" (pramipexole) in areas that pramipexole acts.

Or, perhaps it's a more visceral-like thing, similar to one of my hypotheses of how gabapentin can work to reduce drug cravings (it inhibits substance p, and opiates inhibit substance p, so the brain is kind of tricked into believing that it's being given an opiate). So classical conditioning. Pramipexole creates aspects of stimulant experiences without the euphoria, but because the brain is so used to the euphoria being paired with the other effects, pramipexole alone causes euphoria. I guess the thing to do would be to study this on stimulant-naive (or at least hard stimulants) people (doubt there are many adults in the industrialized world who don't have a caffeine habit).

 

[Nagelfar]

I'm wondering whether the brain somehow re-routes dopaminergic activity to other parts of the brain (the mesolimbic area) when it gets the message that there is already enough "dopamine" (pramipexole) in areas that pramipexole acts.

Well cocaine's rewarding activity is considered mainly localized in the nucleus accumbens, where pramipexole mostly targets as mentioned in the paper itself.

 

[Nagelfar]

Pramipexole creates aspects of stimulant experiences without the euphoria, but because the brain is so used to the euphoria being paired with the other effects, pramipexole alone causes euphoria

D3 agonist 7-OH-DPAT is self-administered stand-alone, in animal models.

 

[AlphaMethylPhenyl]

Any explanations, or just doubts? I can think of at least one reason why that might be.

 

[Cotcha Yankinov]

As I recall D3 antagonism leads to acetylcholine efflux and considering the use of anticholinergics to boost dopamine in Parkinson's or antipsychotic type situations there might be some synergy there maybe? Maybe acetylcholine is opposing dopamine and with the D3 agonism the opposition is lessened allowing dopamine to reign unopposed?

Caveat, acetylcholine can also lead to dopamine as well, so maybe it's a matter of brain region and acetylcholine receptor types, and the Parkinson's type situations the anticholinergics are mostly active in movement related areas

 

[Limpet_Chicken]

Whilst it is in no way a physical stimulant, there are definitely pleasant cognitive effects from it for me at least. In terms of synergy with other prodopaminergic compoundsl then opioids, especially, are very positively affected by coadministration of pramipexole with fr.ex morphine sulfate, or to a lesser extent, oxy (the lesser improvement here probably just has to do with my personal preferences, I'm not a huge fan of it really, as its way too short acting, and more importantly just not very euphoric at allwhen I.Ved, oxy has sod all rush for me (question if I may, while I'm here..do other people who oxy find the same? that is to say, distinctly lacking almost entirely any rush and a pretty poor quality and quantity of euphoriant effects, short action is well known but a lot of people really seem willing to pay ridiculous sums for say, a single OC 80, reading on here, a $ a milligram is not even close to uncommon. Now I could care less what people spend, but it does at least make it clear that oxy itself is seen as a highly desirable drug amongst the phenanthrene opioids. I really don't see it myself, and I've been prescribed the 80mg XR formulation, as well as IR at a lower dose per unit, and have put them in me pretty much every way possible about from IT/ICV, intraocularly and up the eye of my...well the less said and contemplated there, the better

 

[MeDieViL]

I like to combine ropinirole with stims, especially with MDPV, nice sexual synergy.

 

[Limpet_Chicken]

Never tried it, pramipexole is definitely nice though. Speedballs with a bit of glepark (the brand name of the stuff), a couple of tablets makes all the difference, although it can make one puke quite easily if not used to it.

I'd say, not classically recreational as such, on its own. But like for example, tizanidine, it IS pleasant enough to be quite reinforcing, and definitely has recreational potential in some circumstances.