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

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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.

Introduction

Nicotine self-administration and by extension tobacco addiction has been linked to the neural effect of nicotine-induced dopamine release, particularly via activation of dopamine projections from the ventral tegmental area to the nucleus accumbens, but the this projection is just part of a complex circuit underlying motivated behavior in general and addiction in particular (Corrigall, 1991, Di Chiara, 2000, Di Chiara et al., 2004, Koob, 1999, Mansvelder and McGehee, 2002, Picciotto and Corrigall, 2002). A wide variety of neurotransmitter systems are involved in these neural circuits involving the midbrain, limbic system, basal ganglia and frontal cortex. In addition, dopamine is not the only neurotransmitter system affected by nicotine. Nicotine also induces the release of serotonin, norepinephrine, histamine, GABA, glutamate, and acetylcholine, the endogeneous ligand for nicotinic receptors (Kenny et al., 2000, Li et al., 1998, Wonnacott et al., 1989). The roles of other transmitter systems, in addition to dopamine and acetylcholine, in the neural bases of nicotine reinforcement are important areas of investigation. Discovering their involvement in the neural basis of nicotine self-administration will not only provide a more comprehensive understanding of the neural bases of tobacco addiction, but could lead to the development of new approaches to help people quit smoking.

Often in drug development research, clues to new therapeutic avenues can come from serendipitous findings from people taking medications for other reasons. Antipsychotic drugs taken by people with schizophrenia may provide important clues for new types of smoking cessation treatment. People with schizophrenia have some of the highest smoking rates in our society, double to triple the general population rate (Barnes et al., 2006, Dalack et al., 1998, Hughes et al., 1986). Interestingly, less smoking is seen with patients with schizophrenia who are taking atypical antipsychotic drugs (Barnes et al., 2006), in particular clozapine (McEvoy et al., 1995). Clozapine is a complex drug with actions on a variety of different neurotransmitter receptors. There may be a subcomponent of clozapine actions that underlies its efficacy in reducing smoking. We have found that clozapine's serotonin 5-HT2 receptor antagonist effects are particularly relevant to blocking nicotine-induced cognitive enhancement (Levin and Rezvani, 2007).

Nicotine actions on cognitive function have been found in our studies to be reduced by ketanserin, which is an antagonist at 5-HT2A and 5-HT2C receptors. Nicotine-induced improvements in spatial working memory in the radial-arm maze (Levin et al., 2005) and sustained attention in a signal detection operant task (Rezvani et al., 2005) are reversed by ketanserin. The role of 5-HT2 receptors in mediating nicotine actions is clearly seen with cognitive and reinforcing effects, but this action does not seem to extend to all of nicotine's effects. Damaj et al. (1994) did not find ketanserin to attenuate the reduction in activity or antinociceptive effects of nicotine in mice.

There has been some work on a possible neural effect that could underlie ketanserin blockade of nicotine effects. Ketanserin blocked nicotine effects of reducing thalamo-cortical high voltage spindles (Jakala et al., 1997). There is evidence that serotonin and serotonergic receptor acting drugs such as ketanserin can act directly on nicotinic receptors. Ketanserin and other serotonergic ligands as well as serotonin itself have been found to block and enhance desensitization of the muscle nicotinic receptor (Garcia-Colunga and Miledi, 1999). It would be interesting to see if this direct action of ketanserin occurs on neuronal nicotinic receptors as well.

The current study examined the interactive role of 5-HT2A and 5-HT2C receptor systems with nicotine self-administration. Serotonergic systems have been found to play an important role in nicotine dependence (Olausson et al., 2002). In addition to stimulating the release of serotonin (Li et al., 1998), nicotine may also have direct effects on presynaptic re-uptake of serotonin. There is in vitro evidence that nicotine can increase the activity of the serotonin transporter in frontal cortical neurons (Awtry et al., 2006). Serotonergic projections from the raphe to the VTA inhibit dopaminergic neuronal activity. Serotonin 5-HT2C receptor antagonists enhance mesocorticolimbic dopamine activity and 5-HT2C receptor agonists suppress it and in contrast 5-HT2A receptors appear to play the opposite role with 5-HT2A receptor agonist treatment potentiating nicotine-induced dopamine release (Di Matteo et al., 2002).

Serotonergic and nicotinic systems interact in a variety of ways important for neurobehavioral activity (Seth et al., 2002). Behavioral pharmacology studies have found important roles for 5-HT2 receptor systems in the expression of nicotine effects. The discriminative stimulus effects of nicotine have been found to be reduced by 5-HT2A and/or 5-HT2C receptor agonists (Batman et al., 2005, Zaniewska et al., 2007). The effect of the 5-HT2A/2C receptor agonist DOI in reducing nicotine discrimination was reversed by administration of the 5-HT2A/2C receptor antagonist ketanserin (Batman et al., 2005). The effects of more selective 5-HT2A or 5-HT2C receptor agonists in reducing nicotine discrimination were reversed by the respective receptor antagonists for these receptors (Zaniewska et al., 2007). In addition, the effects of nicotine on locomotion were also attenuated by 5-HT2A/2C receptor agonist treatment (Batman et al., 2005). The 5-HT2C receptor agonist R0-60-0175 significantly reduced nicotine self-administration, an effect, which was reversed by the 5-HT2C receptor antagonist SB 242,084 (Grottick et al., 2001). In addition, R0-60-0175 also reduced food-motivated responding, reduced chronic nicotine-induced sensitization of locomotor hyperactivity and attenuated nicotine-induced improvement of attentional function in the 5-choice serial reaction time task (Quarta et al., 2007).

In the current study we assessed the involvement of serotonergic mechanisms in one of nicotine's effects, reinforcement as measured by nicotine self-administration. Ketanserin was chosen for investigation because it provides 5-HT2A and 5-HT2C receptor antagonist activity. Individually 5-HT2A and 5-HT2C ligands have both been found to be important for nicotinic action. Combined 5-HT2A and 5-HT2C antagonism with ketanserin has been found to block nicotine-induced cognitive improvement. However, it is not clear what combined 5-HT2A and 5-HT2C receptor blockade would have on nicotine reinforcement. The current study was conducted to determine whether 5-HT2A and 5-HT2C as well as 5-HT1D blockade with ketanserin may be helpful in reducing nicotine self-administration.

Section snippets

Subjects

The procedures used in this study were approved by the Duke University Animal Care and Use Committee and conform to the 1996 edition of the Animal Care Guide. Young adult male Sprague–Dawley albino rats (Taconic Farms, Germantown, N.Y., USA) were singly housed in approved standard laboratory conditions in a Duke University vivarium facility near the testing room to minimize any stress-induced by transporting the rats. The day–night cycle was reversed cycle (lights on 18:00–6:00) so that they

Study 1

The average number of food pellets earned per session was 60.1 ± 5.4 (mean ± S.E.M.). During the 10 sessions of training with nicotine reinforcement the rats averaged 6.09 ± 0.84 infusions per session. The main effect of ketanserin on nicotine self-administration was significant (F(2,22) = 5.45, P < 0.025). As shown in Fig. 1, comparisons of each dose with control showed that the lower 1 mg/kg ketanserin did not quite cause a significant (P = 0.08) decrease in nicotine self-administration, a decrease of

Discussion

The serotonin 5-HT2 receptor antagonist ketanserin significantly reduced nicotine self-administration in rats. The first study identified an acute dose of 2 mg/kg of ketanserin that significantly reduced nicotine self-administration. This dose has not been seen previously to cause sedative effects or to cause cognitive impairment. However, it has been shown to significantly attenuate nicotine-induced improvements in working memory and attentional performance (Levin et al., 2005, Rezvani et al.,

Acknowledgements

This research was supported by an unrestricted grant from Philip Morris USA and by NIDA grant DA015756.

References (35)

  • ZaniewskaM. et al.

    Effects of the serotonin 5-HT2A and 5-HT2C receptor ligands on the discriminative stimulus effects of nicotine in rats

    Eur. J. Pharmacol.

    (2007)
  • AwtryT.L. et al.

    In vitro regulation of serotonin transporter activity by protein kinase A and nicotinic acetylcholine receptors in the prefrontal cortex of rats

    Synapse

    (2006)
  • BarnesM. et al.

    Smoking and schizophrenia: is symptom profile related to smoking and which antipsychotic medication is of benefit in reducing cigarette use?

    Aust. N. Z. J. Psychiatry

    (2006)
  • BatmanA.M. et al.

    Attenuation of nicotine's discriminative stimulus effects in rats and its locomotor activity effects in mice by serotonergic 5-HT2A/2C receptor agonists

    Psychopharmacology

    (2005)
  • BonaventureP. et al.

    Autoradiographic mapping of 5-HT1B- and 5-HT1D receptors in human brain using 3H]alniditan, a new radioligand

    Recept. Channels

    (1997)
  • CorrigallW.A.

    Understanding brain mechanisms in nicotine reinforcement

    Br. J. Addict.

    (1991)
  • DalackG.W. et al.

    Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings

    Am. J. Psychiatr.

    (1998)
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