Research reportA novel highly selective 5-HT6 receptor antagonist attenuates ethanol and nicotine seeking but does not affect inhibitory response control in Wistar rats

Recent studies suggest a potential role for 5-hydroxytryptamine6 (5-HT6) receptors in the regulation of addictive behavior. In the present study, our aim was to investigate whether the novel highly selective 5-HT6 receptor antagonist compound (CMP) 42 affected nicotine and ethanol seeking behavior in Wistar rats. We have also studied whether CMP 42 had beneficial effects in a model of impulse control, as measured in the 5-choice serial reaction time task (5-CSRTT).Rats were trained to nose poke to receive intravenous infusions of nicotine or an ethanol drop. CMP 42 (3-30 mg/kg intraperitoneally, i.p.) was administered to investigate the effects on nicotine self-administration. Rats were also tested for cue-induced reinstatement of nicotine and ethanol seeking. In addition, the effects of CMP 42 were studied on the number of anticipatory responses in the 5-CSRTT.CMP 42 was effective in reducing nicotine self-administration and reinstatement of nicotine seeking at a dose of 30 mg/kg (i.p.). CMP 42 was also effective in reducing reinstatement of ethanol seeking (30 mg/kg i.p.). In contrast, CMP 42 did not affect anticipatory responding at doses tested, indicating no effects on impulse control.These results add to a body of evidence implicating the 5-HT6 receptor as a viable target for the control of drug abuse. Specifically, we demonstrated for the first time effects on nicotine self-administration and on nicotine and ethanol reinstatement. Further, these effects are probably not mediated by effects on impulse control.

► CMP 42 is a CNS available, selective 5-HT6 antagonist. ► CMP 42 was effective in reducing nicotine self-administration in Wistar rats. ► CMP 42 reduced reinstatement of both nicotine and ethanol seeking. ► The 5-HT6 receptor is a viable pharmacological target for the control of drug abuse. ► CMP 42 did not affect anticipatory responding, showing no effects on impulse control.