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

• Published in: Behavioural brain research Vol. 236; no. 1; pp. 157 - 165
• Main Authors: de Bruin, N.M.W.J., McCreary, A.C., van Loevezijn, A., de Vries, T.J., Venhorst, J., van Drimmelen, M., Kruse, C.G.
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier B.V 01-01-2013; Elsevier
• Subjects: 5-Choice serial reaction time task (5-CSRTT); 5-HT6 antagonist; Alcohol Drinking - drug therapy; Alcohol Drinking - psychology; Analysis of Variance; Animals; Behavioral psychophysiology; Biological and medical sciences; Central Nervous System Depressants - administration & dosage; Central Nervous System Depressants - pharmacology; Cue-induced reinstatement of drug seeking; Cues; Data Interpretation, Statistical; Drug abuse; Drug self-administration; Drug-Seeking Behavior - drug effects; Ethanol; Ethanol - administration & dosage; Ethanol - pharmacology; Extinction, Psychological - drug effects; Fundamental and applied biological sciences. Psychology; impulsive behavior; Impulsive Behavior - drug therapy; Impulsive Behavior - psychology; Infusions, Intravenous; Intravenous administration; Male; Nicotine; Nicotine - administration & dosage; Nicotine - pharmacology; Nicotinic Agonists - administration & dosage; Nicotinic Agonists - pharmacology; Nose; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Pyrazoles - pharmacology; Rats; Rats, Wistar; Reaction Time - drug effects; Reaction time task; Receptors, Serotonin - drug effects; Recurrence; Reinstatement; Self Administration; Serotonin Antagonists - pharmacology; Serotonin S6 receptors; Sulfonamides - pharmacology; Tobacco Use Disorder - drug therapy; Tobacco Use Disorder - psychology; Self-administration; 5-HT6 antagonist; Cue-induced reinstatement of drug seeking; 5-Choice serial reaction time task (5-CSRTT); Ethanol; Nicotine; Rat; Rodentia; 5-HT6 serotonin receptor; Self administration; Alkaloid; Vertebrata; Mammalia; Choice reaction time; Animal; Serial reaction time; Antagonist; Inhibition; 5-HT; Cognitive control
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2012.08.048

▸ 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.
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 (3–30mg/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 30mg/kg (i.p.). CMP 42 was also effective in reducing reinstatement of ethanol seeking (30mg/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.