Do selective TAAR agonists have abuse potential?

[Skorpio]

Many well regarded stimulants are agonists of TAAR1.

TAAR1 - Wikipedia

en.m.wikipedia.org

It is a presynaptic receptor with Gs functions that has neat opposite effects to inhibitory presynaptic autoreceptors (5HT1a, a2 adrenergic, and D2short receptors).

It is postulated that low levels of TAAR1 signaling can predisposed to depression, and high levels of signaling can pre dispose to schizoprenia.

This seems like agonizing it would pretty simply lead to monoamine release. However, many TAAR1 agonists are monoamine releasers by other means.

Do you think that a selective TAAR1 agonist would have recreational/stimulant effects (assuming this hypothetical compound has a good pharmacokinetic profile)?

I am unsure of the answer (or if there is a specific one).

@G_Chem @4meSM (i remember you mentioning this receptor in the past few days).

 

[G_Chem]

I think I’ve been able to get a pretty good read on this receptor site over the years. I’m not quite sure it could viewed upon as recreational but certainly anti-depressant in nature.

I notice that all drugs which have decent affinity/agonism of TAAR1 have long lasting benefits like; less desire for other drugs, more energy, overall better mood, etc. This will vary depending on the half life of the drug how long it will last. These effects last long after the high of the drug is over, an afterglow of sorts. I believe that part of long lasting positive benefits I feel from MDMA and Mescaline also come from agonism of this site but I of course can’t be certain. My brain is just very good and remembering past experiences and drawing together connections.

I actually use Amphetamine and Meth in a somewhat similar manner. I notice my life seems to run a lot better if I use d-Amphetamine and/or d-meth a couple times a year. Usually I’d say overall on average maybe 6 times a year both included, not often. Been using like this for over a decade. The years that I’ve used TAAR1 agonists (including MDMA related drugs and Mescaline) less I notice more desire for other drugs, less happiness with life, etc.

I believe future antidepressants will target this receptor site and could also be great for anti addiction drugs too, if pharmaceutical companies ever decide to make new drugs again..

-GC

 

[thegreenhand]

This seems like agonizing it would pretty simply lead to monoamine release. However, many TAAR1 agonists are monoamine releasers by other means.

TAAR1 is an intracellular receptor so presumably the specific monoamine(s) released would depend on if the ligand can pass through the respective monoamine transporters (or pass through the membrane some other way). Thus a substance agonizing TAAR1 in dopaminergic neurons may be more liable to abuse than say noradrenergic neurons. I’m just speculating though…

I actually use Amphetamine and Meth in a somewhat similar manner. I notice my life seems to run a lot better if I use d-Amphetamine and/or d-meth a couple times a year. Usually I’d say overall on average maybe 6 times a year both included, not often. Been using like this for over a decade. The years that I’ve used TAAR1 agonists (including MDMA related drugs and Mescaline) less I notice more desire for other drugs, less happiness with life, etc.

I find amphetamine has similar effects for me too when I use it every couple months or so. Only done meth once but same story there too. Perhaps it’s just from cognitive effects of dumping out all my feelings onto my friends while on it, but yeah it’s a nice afterglow.

 

[4meSM]

Well, phenylethylamine and especially tyramine have very high affinities for TAAR1 and they don't seem to be particularly recreational, granted they're not selective and are quickly metabolized by MAO. But my guess is that high selectivity for TAAR1 wouldn't be enough if you're looking for recreational effects, you'd probably want it to hit monoamine transporters as well (like amphetamines).

From what I’ve read it does seem like TAAR1 activation has some anti-abuse effects. Selective TAAR1 agonists have been shown to modulate the effects of meth and other amphetamines, decreasing self-administration and hyperactivity, plus they also attenuate cocaine-induced drug-seeking behavior.
The following partial TAAR1 agonist (RO5263397) was tested in rats and, IIRC, it increases their attention spam and impulse control, but other procognitive effects were only observed among cognitively impaired rats (pretreated with PCP).

I found this summary of the "recent" (until 2016) findings related to TAAR1:

Trace Amines and the Trace Amine-Associated Receptor 1: Pharmacology, Neurochemistry, and Clinical Implications

 

[Skorpio]

Just reading papers on wikipedia, I am noticing that TAAR1 apparently decreases dopamine release (inhibitory effects driven by potassium channel opening). Taar1 knockout mice are hypersensitve to the stimulating effects of amphetamine. I guess at least part of the effect if TAAR1 is regulatory, lessening the effect of monoamines. I wonder if the TAAR1 agonism of amphetamines contributes to the "smoothness" of the stimulation (such as when compared to something like methylphenidate).

The pure TAAR1 agonists (and partial agonists) in the pipeline are being tested as anti-psychotics.

I wonder if combining a TAAR1 antagonist would increase toxicity of amphetamines relative to the stimulant effects, or if it would increase the stimulant effects relative to toxicity.

 

[ecstacylover]

Just reading papers on wikipedia, I am noticing that TAAR1 apparently decreases dopamine release (inhibitory effects driven by potassium channel opening)

I was reading the page on Wikipedia and it says that TAAR1 agonists increase synaptic monoamine concentrations, right before mentioning that TAAR1 decreases DA neuron firing rate. Unless they found the synaptic monoamine increase in culture, this seems sort of at odds, no?

I think the paradox could be rationalized, at least in the case of 5-HT neurons, if TAAR1 was activating potassium channels proximal to SERT. In that case the local potassium concentrations sensed by SERT would decrease, and there would be a weaker driving force to re-activate an inwardly facing SERT. This reduction in SERT function could increase (or at least maintain) synaptic 5-HT concentrations even in the face of reduced 5-HT firing, and it would amplify the release mediated by VMAT2 substrates such as MDMA.

I'm not sure if DAT's re-activation mechanism exports potassium (Wiki seemed to suggest no), so I wonder how exactly TAAR1 agonism might directly increase synaptic dopamine. Just speaking broadly though, I do like the idea that TAAR1 adds some tonic character to DA transmission and that this interferes with reward encoding. It seems more general than a rate coding mechanism.

 

[Skorpio]

I was reading the page on Wikipedia and it says that TAAR1 agonists increase synaptic monoamine concentrations, right before mentioning that TAAR1 decreases DA neuron firing rate. Unless they found the synaptic monoamine increase in culture, this seems sort of at odds, no?

I think the paradox could be rationalized, at least in the case of 5-HT neurons, if TAAR1 was activating potassium channels proximal to SERT. In that case the local potassium concentrations sensed by SERT would decrease, and there would be a weaker driving force to re-activate an inwardly facing SERT. This reduction in SERT function could increase (or at least maintain) synaptic 5-HT concentrations even in the face of reduced 5-HT firing, and it would amplify the release mediated by VMAT2 substrates such as MDMA.

I'm not sure if DAT's re-activation mechanism exports potassium (Wiki seemed to suggest no), so I wonder how exactly TAAR1 agonism might directly increase synaptic dopamine. Just speaking broadly though, I do like the idea that TAAR1 adds some tonic character to DA transmission and that this interferes with reward encoding. It seems more general than a rate coding mechanism.

The wikipedia source mentioning increases of synaptic monoamine concentrations is from this review (it has a nice schematic showing TAAR effects in a neuron towards the end). It seems TAAR1 agonism in dopamine neurons inhibits DAT. Simultaneously, it causes internalization of dopamine receptors.

One issue I have with one paper cited (many of the papers by those two honestly) (Xie and Miller 2007) is that they use methamphetamine as a TAAR1 agonist, while it is quite unselective. I feel like studies with a selective agonist such as Revel 2011 is less ambiguous as the researchers don't have to build bridges around confounding variables. Also realized that Gregory Miller, wrote the review I am reading, which explains the large amount of his papers cited. I need to read more on this I guess and update later. The physiology here is either hairy, or there are two warring hypotheses that are backed by various groups or a little bit of both.


The review -The Emerging Role of Trace Amine Associated Receptor 1 in the Functional Regulation of Monoamine Transporters and Dopaminergic Activity
- https://sci-hubtw.hkvisa.net/10.1111/j.1471-4159.2010.07109.x
Xie and Miller 2007 -Trace Amine-Associated Receptor 1 Is a Modulator of the Dopamine Transporter
- https://sci-hubtw.hkvisa.net/10.1124/jpet.106.117382
Revel 2011 -TAAR1 activation modulates monoaminergic neurotransmission, preventing hyperdopaminergic and hypoglutamatergic activity
- https://sci-hubtw.hkvisa.net/10.1073/pnas.1103029108

 

[AlphaMethylPhenyl]

I think that they can, but I don't know about selective activators. Clearly most substituted phenethylamines are abusable. I would guess that it's a yes, only because sympathomimetics tend to be dopaminergic, even if it's not their primary mechanism.