Antagonizing serotonin 2A (5-HT_2A) receptors attenuates methamphetamine-induced reward and blocks methamphetamine-induced anxiety-like behaviors in adult male rats.

Abstract

Methamphetamine is a highly addictive and abused psychostimulant. Symptoms of methamphetamine withdrawal including drug craving and anxiety that can drive relapse. Currently, there is no FDA approved treatment for methamphetamine use disorder, highlighting the need for research examining the neural mechanisms underlying psychostimulant-induced behaviors. Research indicates that the 5-HT_2A receptor antagonist M100907 attenuates several psychostimulant-induced behaviors, including conditioned place preference (CPP). However, these findings have not been extended to methamphetamine. The present study investigated the effects of M100907 on acquisition of methamphetamine-CPP and methamphetamine-induced anxiety-like behavior. Adult male rats were tested across eight consecutive days. Prior to methamphetamine administration (0 or 1 mg/kg, i.p.), rats were pretreated with their assigned dose of M100907 (0, 0.0025 .025 or 0.25 mg/kg, i.p.) and were placed into their initially non-preferred chamber. After four methamphetamine conditioning sessions, the effects of M100907 on methamphetamine-induced CPP were assessed. Following CPP testing, rats were screened for anxiety-like behaviors in the elevated plus-maze. Pretreatment with M100907 attenuated methamphetamine-induced CPP without producing any observable rewarding or aversive effects in methamphetamine naïve rats. Additionally, M100907 blocked methamphetamine-induced increases in anxiety-like behavior and attenuated some indices of anxiety in methamphetamine naïve rats. Results suggest that blocking 5-HT_2A receptors with the selective antagonist M100907 attenuates the rewarding effects of methamphetamine and does not produce any rewarding or aversive effects alone. Further, M100907 pretreatment blocked the anxiety-inducing effects of methamphetamine. Collectively, these data suggest that the 5-HT_2A receptor subtype represents a novel target for treating methamphetamine use disorder.