Dear researchers,
Apparently, TAAR1 agonists, which increase its signal, cause a decrease in firing to dopaminergic neurons, thus a depletion in dopamine production.
TAAR1 antagonists, on the other hand, cause dopamine release and increased effects if psychostimulants (cocaine or amphetamine) are administered simultaneously.
So how come, if amphetamine enhances TAAR1 signal causes dopamine release?
Hi,
Regarding TAAR1 agonist's mechanism of action, there is some good literature. Given a ling below:
Dedic N, Dworak H, Zeni C, Rutigliano G, Howes OD. Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies. Int J Mol Sci. 2021;22(24):13185. Published 2021 Dec 7. doi:10.3390/ijms222413185
However, Antagonist literature is sparse:
Bradaia A., Trube G., Stalder H., Norcross R.D., Ozmen L., Wettstein J.G., Pinard A., Buchy D., Gassmann M., Hoener M., et al. The selective antagonist EPPTB reveals TAAR1-mediated regulatory mechanisms in dopaminergic neurons of the mesolimbic system. Proc. Natl. Acad. Sci. USA. 2009;106:20081–20086. doi: 10.1073/pnas.0906522106.
Recently, another paper:
Lam VM, Mielnik CA, Baimel C, Beerepoot P, Espinoza S, Sukhanov I, Horsfall W, Gainetdinov RR, Borgland SL, Ramsey AJ and Salahpour A (2018) Behavioral Effects of a Potential Novel TAAR1 Antagonist. Front. Pharmacol. 9:953. doi: 10.3389/fphar.2018.00953
From the conclusions in the paper by Lam: "In conclusion, our in vivo studies have shown compound 22 (TAAR 1 Antagonist) to potentiate the locomotor stimulating effects of both amphetamine and cocaine. Our original hypothesis was that compound 22 mediated these effects through the antagonism of TAAR1. However, these findings were also observed in the TAAR1-KO mice, suggesting that compound 22 is not mediating the potentiation of amphetamine- and cocaine-induced locomotor response through TAAR1. In collaboration with PDSP, we attempted to determine the target for compound 22; however, the target for compound 22 remains unknown. Therefore, compound 22 appears to be a potent modulator of dopamine signaling within the brain, through a yet unknown mechanism."
Bhogaraju Anand
Thanks for your prompt reply, but I know and I've read these studies and question still remains: why amphetamine: why should it release dopamine, if enhances TAAR1 signal?
Thank you.
Hi,
Yes, they do act through TAAR1 GPCRs.TAAR1 mediates the effects of AMPH on both GTPase RhoA and cAMP signaling.
Citation
Underhill, S.M., Hullihen, P.D., Chen, J. et al. Amphetamines signal through intracellular TAAR1 receptors coupled to Gα13 and GαS in discrete subcellular domains. Mol Psychiatry 26, 1208–1223 (2021). https://doi.org/10.1038/s41380-019-0469-2
Kohno, M., Dennis, L.E., McCready, H. et al. Dopamine dysfunction in stimulant use disorders: mechanistic comparisons and implications for treatment. Mol Psychiatry 27, 220–229 (2022). https://doi.org/10.1038/s41380-021-01180-4
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