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

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 underlie its neurobehavioral actions. Nicotine induces serotonin (5-HT) release, which has not classically been thought to be involved in tobacco addiction. 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 2c 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.

Lorcaserin, a 5-HT2C Agonist, Decreases Nicotine Self-Administration in Female Rats

“…Serotonergic systems are quite complex with a wide variety of receptor subtypes. We have found that ketanserin, a 5-HT 2A and 5-HT 2C antagonist, significantly reduces nicotine self-administration in rats (Levin et al, 2008). The relative involvement of serotonin 5-HT 2A and 5-HT 2C receptors is not clear from this study, but it is known that 5-HT 2C receptors located in the ventral tegmental area provide inhibitory influence over dopaminergic projections that are important for drug reinforcement (Bubar and Cunningham, 2007).…”

“…We previously showed in rats that ketanserin, a 5-HT 2A and 5-HT 2C antagonist, significantly reduces nicotine self-administration (Levin et al, 2008). The differential role of 5-HT 2A versus 5-HT 2C receptors was not clear from that study.…”

Role of Central Serotonin Receptors in Nicotine Addiction

“…Indeed local infusion of M100907 to the VTA blocked amphetamine-and cocaine-induced locomotion [ 47 , 106 ]. Consistently, it has recently been shown that vulnerability of adult male rats to hyperactivity, induced by cocaine, is enhanced following virally mediated overexpression of 5-HT 2A receptors in the VTA [ 108 ]. Due to this evidence, and the relationship between the VTA and reinforcing effects of nicotine, it may be expected that 5-HT 2A receptor antagonists would modify some of the behavioural effects observed following the administration of nicotine.…”

IV nicotine self-administration in rats using a consummatory operant licking response: Sensitivity to serotonergic, glutaminergic and histaminergic drugs

“…This comparison of drug effects on IV nicotine self-administration with the operant lever pressing and licking was conducted to help determine which neural systems are more or less involved in the consummatory aspects of nicotine self-administration. In recent studies with the operant lever press method, we have found that the serotonin 5HT 2A and C antagonist ketanserin (Levin et al, 2008) and the histamine H 1 antagonist pyrilamine (Levin et al, 2011c) were effective in reducing nicotine self-administration. We studied these antagonists of 5HT 2A and C and H 1 receptors because these receptor subtypes are two of the more prominent actions of the antipsychotic drug clozapine, which has been found to reduce smoking significantly in people with schizophrenia (McEvoy et al, 1995, McEvoy et al, 1999).…”