Highly selective 5-HT2A receptor antagonist M100907 (Volinanserin), a potential antipsychotic drug, attenuates methamphetamine’s rewarding effects and does not produce any rewarding or aversive effects alone. It also, according to a study published in Drug and Alcohol Dependence, blocked anxiety-inducing effects of meth. The researchers conducted the study using adult male rats.

Having recently been implicated in substance use disorders, 5-HT2A receptors are a target for novel therapies. Previous studies have shown the highly selective 5-HT2A receptor antagonist/inverse agonist (R)-(+)-α-(2,3-Dimethoxyphenyl)-

1-[2-(4-fluorophenyl)ethyl]-4-piperinemethanol (M100907) to be effective in certain cocaine and methamphetamine symptoms such as hyperlocomotion and impulsivity. For this study, the researchers wanted to explore reward properties and anxiety.

The researchers used Long Evans hooded rats. Conditioned place performance (CPP) trials were conducted across 8 days. Researchers defined methamphetamine-induced CPP as a “significant increase in the duration of time spent in the initially nonpreferred Side [of 2 compartments] post-conditioning compared to the pre-conditioning baseline.


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The researchers found rats in the M100907 group exhibited “robust” CPP compared with the saline-receiving rat group. (Veh-Meth group (t(9) = -8.04, P = .000, d=3.76) but not the Veh-Sal group (t(8)=0.883, P =.403, d=0.298). They also found 1 mg/kg to be a “rewarding” dose.

All 3 drug-receiving groups exhibited CPP. All 3 M100907 doses used in the study attenuated methamphetamine-CPP.

“Results from the present study are the first to indicate that blocking 5HT2A receptors with the selective antagonist/inverse agonist M100907 prior to methamphetamine administration attenuates acquisition of methamphetamine-CPP,” the study reported. “The present results are also the first to report that the 5-HT2A receptor antagonist M100907 prevents methamphetamine-induced anxiety-like behavior…Future research should examine how M100907 influences methamphetamine reinforcement in rats.”

Reference

Madden JT, Reyna NC, Pentkowski NS. Antagonizing serotonin 2A (5-HT2A) receptors attenuates methamphetamine-induced reward and blocks methamphetamine-induced anxiety-like behaviors in adult male rats. Drug Alcohol Depend. 2020 Oct 1;215:108178.