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

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC 27710, USA.
European journal of pharmacology (Impact Factor: 2.53). 11/2008; 600(1-3):93-7. DOI: 10.1016/j.ejphar.2008.10.016
Source: PubMed


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.

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Available from: Amir H Rezvani, Oct 13, 2014
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    • "). Of these neurotransmitter systems, the serotonin (5-HT) system regulates self-administration of nicotine (Levin et al., 2008), nicotine-induced cognitive enhancement (Levin and Rezvani, 2007), memory (Levin et al., 2005), and smoking progression and cessation (Wang and Li, 2010). The serotonergic system consists of seven major receptor classes; among these, all but the 5-HT 3 receptors are G-protein coupled (Barnes et al., 2009; Boess and Martin, 1994; Connolly and Wafford, 2004). "
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    ABSTRACT: Background: Pharmacologic studies implicate a significant role of genes encoding the serotonin transporter (SLC6A4) and the 5-HT3AB subunits HTR3A and HTR3B in nicotine dependence (ND). However, whether they are involved in ND remains largely unknown. Methods: Here, we examined the impact of variations in the three genes on ND in 1366 individuals from 402 African American (AA) and 671 individuals from 200 European American (EA) families. The ND of each smoker was assessed with smoking quantity (SQ), heaviness of smoking index (HSI), and Fagerström test for nicotine dependence (FTND). Results: Association analysis revealed marginal association of rs10160548 in HTR3A with SQ and HSI in AA, 5-HTTLPR in SLC6A4 with FTND in EA, and rs11606194 in HTR3B with SQ and FTND in the pooled sample. Haplotype-based association analysis revealed a few major haplotypes in HTR3A that were significantly associated with ND in the AA, EA, and pooled samples. However, none of these associations remained significant after correcting for multiple testing except for a haplotype G-C-C-T-A-T formed by SNPs rs1150226, rs1062613, rs33940208, rs1985242, rs2276302, and rs10160548 in HTR3A for the AA sample. Considering biological functions of the three genes, we examined interactive effects of variants in the three genes, which revealed significant interactions among rs1062613 and rs10160548 in HTR3A, rs1176744 in HTR3B, and 5-HTTLPR and rs1042173 in SLC6A4 in affecting ND in the three samples. Conclusions: We conclude that SLC6A4, HTR3A and HTR3B play a significant role in ND through genetic interactions.
    Full-text · Article · Jan 2013 · Drug and alcohol dependence
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    • "In contrast, the selective 5-HT 2A receptor antagonist M100907 did not alter nicotine-induced locomotion, or the discriminative stimulus properties of nicotine (Zaniewska et al., 2009, 2007). Another 5- HT 2A receptor antagonist, ketanserin, reduced intravenous nicotine self-administration (Levin et al., 2008). However, since ketanserin also shows relatively high affinity for 5-HT 1D and a1- adrenergic receptors (Marwood, 1994; Wurch et al., 1998) the effect of 5-HT 2A receptor blockade on nicotine self-administration needs to be confirmed, for example using more selective antagonists . "
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    ABSTRACT: The reinforcing effects of nicotine are mediated in part by brain dopamine systems. Serotonin, acting via 5-HT(2A) and 5-HT(2C) receptors, modulates dopamine function. In these experiments we examined the effects of the 5-HT(2C) receptor agonist Ro60-0175 and the 5-HT(2A) receptor antagonist (M100907, volinanserin) on nicotine self-administration and reinstatement of nicotine-seeking. Male Long-Evans rats self-administered nicotine (0.03 mg/kg/infusion, IV) on either a FR5 or a progressive ratio schedule of reinforcement. Ro60-0175 reduced responding for nicotine on both schedules. While Ro60-0175 also reduced responding for food reinforcement, response rates under drug treatment were several-fold higher than in animals responding for nicotine. M100907 did not alter responding for nicotine, or food, on either schedule. In tests of reinstatement of nicotine-seeking, rats were first trained to lever press for IV infusions of nicotine; each infusion was also accompanied by a compound cue consisting of a light and tone. This response was then extinguished over multiple sessions. Injecting rats with a nicotine prime (0.15 mg/kg) reinstated responding; reinstatement was also observed when responses were accompanied by the nicotine associated cue. Ro60-0175 attenuated reinstatement of responding induced by nicotine and by the cue. The effects of Ro60-0175 on both forms of reinstatement were blocked by the 5-HT(2C) receptor antagonist SB242084. M100907 also reduced reinstatement induced by either the nicotine prime or by the nicotine associated cue. The results indicate that 5-HT(2C) and 5-HT(2A) receptors may be potential targets for therapies to treat some aspects of nicotine dependence.
    Full-text · Article · Feb 2012 · Neuropharmacology
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    • "The work of Levin and colleagues has provided important rationale for the use of ketanserin as a smoking cessation therapy (Levin et al., 2005; Levin et al., 2008; Rezvani et al., 2005). While the 5-HT2A and 2C receptors appear to have opposing effects on dopamine activity in reward related centers of the brain (Di Matteo et al., 2002), blockade of both can significantly reduce nicotine self-administration (Levin et al., 2008) and cocaine's locomotor effects (Filip et al., 2001; McMahon and Cunningham, 2001). Whether 5-HT2A/ C receptor blockade can similarly inhibit the reinforcing properties of cigarette smoke constituents interacting with nicotine still needs to be investigated. "
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    ABSTRACT: Our current study aims to evaluate the mechanisms of tranylcypromine (TCP)-mediated enhancement of nicotine self-administration. We replicated our previous findings which demonstrate that 1 h pretreatment with TCP (3 mg/kg, i.p.) enhances nicotine self-administration (7.5 μg/kg/inj, i.v.) when compared with vehicle-treated rodents. We tested whether TCP-mediated enhancement of nicotine self-administration was due to MAO inhibition or off-target effects by (i) extending the TCP pretreatment time from 1 to 20 h, and (ii) evaluating the role of the individual TCP stereoisomers in nicotine self-administration studies. While 20 h and (-)TCP pretreatment induced significant inhibition of MAO (60-90%), animals found nicotine only weakly reinforcing. Furthermore, while both (+) and (±)TCP treatment induced nearly 100% MAO inhibition, (+)TCP pretreated animals took longer to acquire nicotine self-administration compared to (±)TCP pretreated animals. Stable nicotine self-administration in (+)TCP pretreated animals was influenced by nicotinic receptor activation but not nicotine-paired cues. The opposite was found in (±)TCP pretreated animals. Treatment with (-) or (±)TCP increased dopamine and serotonin overflow, while the (+) and (±)TCP treatment enhanced monoamine overflow subsequent to nicotine. Together, our data suggests TCP enhancement of nicotine self-administration are mediated through mechanisms independent of MAO inhibition, including nicotine-paired cues and monoamine uptake inhibition.
    Full-text · Article · Mar 2011 · Neuropharmacology
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