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Behavioural Pharmacology
Ketanserin, a 5-HT2 receptor antagonist, decreases nicotine self-administration in rats

Edward D. Levin, a, , Susan Sladea, Michael Johnsona, Ann Petroa, Kofi Hortona, Paul Williamsa, Amir H. Rezvania and Jed E. Rosea

aDepartment of Psychiatry and Behavioral Sciences, Duke University Medical Center, USA


Received 15 January 2008; revised 25 September 2008; accepted 9 October 2008. Available online 17 October 2008.

Abstract
Nicotine intake constitutes a principal mechanism for tobacco addiction. In addition to primary effects on nicotinic acetylcholine receptors, nicotine has cascading effects, which may also underlie its neurobehavioral actions. Nicotine induces serotonin (5-HT) release, which has not classically been thought to be involved in tobacco addiction as dopamine has. However, addiction can be characterized more as a disorder of compulsion than a disorder of enjoyment. 5-HT mechanisms play key roles in compulsive disorders. Nicotine-induced 5-HT release may be a key to tobacco addiction. Ketanserin, a 5-HT2a and 5-HT2c receptor antagonist, significantly attenuates nicotine effects on attention and memory. These studies were conducted to determine if ketanserin would reduce nicotine self-administration in rats. Male Sprague–Dawley rats (N = 12) were given initial food pellet training and then 10 sessions of nicotine self-administration training (0.03 mg/kg/infusion, i.v.). Then the rats were administered ketanserin (1 or 2 mg/kg, s.c.) or the saline vehicle. Ketanserin (2 mg/kg) significantly decreased nicotine self-administration. This did not seem to be due to sedative or amnestic effects of ketanserin. In a second study, the effects of repeated administration of 2 mg/kg ketanserin (N = 11) vs. saline injections (N = 10) were examined. In the initial phase, the acute effectiveness of ketanserin in significantly reducing nicotine self-administration was replicated. The effect became attenuated during the following several sessions, but the significant effect became re-established during the final phases of this two-week study. 5-HT mechanisms play critical roles in the maintenance of nicotine self-administration. Better understanding of those roles may help lead to new 5-HT-based treatments for tobacco addiction.

Keywords: Nicotine; Self-administration; Serotonin; 5-HT2; Ketanserin; (Rat)