Rimonabant attenuates sensitization, cross-sensitization and cross-reinstatement of place preference induced by nicotine and ethanol

doi:10.1016/S1734-1140(10)70340-6

Pharmacological Reports

Volume 62, Issue 5, September–October 2010, Pages 797-807

https://doi.org/10.1016/S1734-1140(10)70340-6 Get rights and content

Abstract

The present study focused on the evaluation of behavioral sensitization, cross-sensitization, and cross-reinstatement processes induced by nicotine and ethanol in rodents. First, we showed that nicotine (0.175 mg/kg, base, intraperitoneally, ip) produced a conditioned place preference in rats. When the nicotine place preference was extinguished, nicotine-experienced animals were challenged with nicotine (0.175 mg/kg, ip) or ethanol (0.5 g/kg, ip), which reinstated a preference for the compartment previously paired with nicotine. In the second series of experiments, we demonstrated that after 9 days of nicotine administration (0.175 mg/kg, subcutaneously, sc) every other day and following its 7-day withdrawal, challenge doses of nicotine (0.175 mg/kg, sc) and ethanol (2 g/kg, ip) induced locomotor sensitization in mice. Finally, when we examined the influence of rimonabant (0.5, 1 and 2 mg/kg, ip), we found that this cannabinoid CB₁ receptor antagonist attenuated reinstatement effect of ethanol priming as well as nicotine sensitization and locomotor cross-sensitization between nicotine and ethanol. Our results indicate that similar endocannabinoid-dependent mechanisms are involved in the locomotor stimulant and reinforcing effects of nicotine and ethanol in rodents, and as such these data may provide further evidence for the use of cannabinoid CB₁ receptor antagonists in treatment of tobacco addiction with or without concomitant ethanol dependence.

Introduction

Drug addiction is a chronic relapsing brain disease characterized by the compulsive use of addictive substances despite adverse consequences. Polydrug use is becoming increasingly more common, and often involves nicotine and alcohol co-abuse. Individuals who are alcohol-dependent present a higher frequency of nicotine dependence than those who do not drink alcohol [25]. Nicotine dependence is also more frequent in alcohol-dependent drinkers [37]. Despite these epidemiological findings, there have been relatively few animal studies on the neurobiological substrates that may underlie this combined nicotine and ethanol addiction.

Functional interactions between nicotine and ethanol within the central nervous system (CNS) have been well documented [23, 41]. Experimental studies provide evidence for the involvement of nicotinic acetylcholine receptors (nAChRs), the primary mediators of the effects of nicotine, in the modulation of ethanol consumption by showing that nicotine increases ethanol self-administration. This effect is suppressed by the nicotinic antagonist mecamylamine [33]. In addition, ethanol increases the number of nicotine binding sites in the brain [18] and also augments nicotine’s locomotor stimulation [50] or reinforcing activity [29].

It is commonly accepted that repeated exposure to drugs produces long lasting changes in the circuitry of reinforcement [28, 39]. Such changes affect many neurotransmitter systems and their corresponding intracellular signaling pathways. Substantial data now point to a role of the endocannabinoid system in triggering drug seeking behavior [36]. Accordingly, rimonabant (SR141716A), a CB₁ cannabinoid receptor antagonist/partial agonist [43], has been shown to counteract the acquisition or expression of many drug-induced motivational effects [13, 15, 20, 22, 34].

Behavioral responses related to a relapse in drug taking can be measured in various animal models e.g., in drug self-administration or the conditioned place preference (CPP) paradigm [11]. After extinction of the drug-reinforced behavior, an acute exposure to the drug (non-contingent injection, priming dose) or non-drug contextual stimuli reinstates drug-seeking behavior [21]. An alternative characteristic of addiction and relapse is a phenomenon termed sensitization or reverse tolerance [45]. Using this paradigm it has been shown that after intermittent chronic exposure to a drug, animals began to develop addiction-like symptoms including continued drug seeking behavior and an escalation of drug intake, increased motivation to obtain drugs and a greater propensity to relapse after enforced abstinence [for review, see 45]. The present studies were undertaken to investigate the incidence of behavioral crossover rewarding and the locomotor effects of nicotine and ethanol. First, we used the nicotine-CPP procedure in rats evaluated in our previous studies [2., 3., 4., 6] to further examine the phenomenon of reinstatement of extinguished nicotine-CPP by a priming dose of ethanol. Second, using an experimental procedure previously established in mice [2], we examined whether nicotine-experienced mice develop sensitization to the locomotor stimulating effect of ethanol. Finally, we investigated the influence of rimonabant [43] on the expression of nicotine- and ethanol-induced effects. The results are discussed in the context of behavioral changes induced by subchronic drug treatment that lead to addiction and relapse, especially in connection with the influence of the endocannabinoid system.

Section snippets

Animals

The experiments on the CPP paradigm, including cross-reinstatement procedures, were carried out on naive male Wistar rats weighing 250–300 g and experiments for sensitization and cross-sensitization procedures on naive male Swiss mice (Farm of Laboratory Animals, Warszawa, Poland) weighing 20–25 g at the beginning of the experiments. The animals were kept under standard laboratory conditions (12/12-h light/ dark cycle, temperature 21 ± 1°C, humidity 40–50%) with free access to tap water and lab

CPP

The time spent in the initially less preferred (white) and in the initially more preferred (black) side did not significantly differ between groups on the preconditioning day. This preference was not significantly changed when saline was paired with both compartments during the conditioning sessions.

As shown in Figure 1, in saline- and nicotine-conditioned rats given saline or ethanol injection on the reinstatement test, two-way ANOVA analysis revealed that there was a significant effect of

Discussion

The present study focused on the evaluation of behavioral sensitization, cross-sensitization, and cross-reinstatement processes induced by nicotine and ethanol in rodents. Additionally, we investigated the effects of rimonabant, a cannabinoid CB₁ receptor antagonist/partial agonist, on the behavioral influences of both drugs. First, we used the CPP paradigm to study the extinction and reinstatement of the extinguished nicotine place conditioning. In these experiments, rats were initially

Conclusion

It is reasonable to conclude that the endocannabinoid system may play an important role in the nicotine-and ethanol-induced neural and behavioral plasticity underlying the development of drug addiction and relapse. Because cannabinoid CB₁ receptor antagonists (e.g., rimonabant or AM 251) [9, present study] have been shown to diminish the reward and stimulant properties of addictive drugs, this class of compounds may offer therapeutic advantages in the treatment of tobacco dependence with or

Acknowledgments

The authors would like to thank Sanofi-Synthelabo (Montpellier, France) for the generous gift of rimonabant. This work was supported by the Statutory Funds of the Medical University of Lublin (DS 23/08) and received no special grant from any funding agency in the public, commercial or not-for-profit sectors. All authors declare that they have no conflicts of interest to disclose.

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Rimonabant attenuates sensitization, cross-sensitization and cross-reinstatement of place preference induced by nicotine and ethanol

Abstract

Introduction

Section snippets

Animals

CPP

Discussion

Conclusion

Acknowledgments

Neuroscience

Pharmacol Biochem Behav

Eur J Pharmacol

Alcohol

Pharmacol Rep

Prog Neuropsychopharmacol Biol Psychiatry

Neuropharmacology

Neuropharmacology

Neuron

Neuropharmacology

Alcohol

Pharmacol Biochem Behav

Eur J Pharmacol

Neurosci Biobehav Rev

Alcohol

Pharmacol Rep

Trends Neurosci

J Subst Abuse Treat

Alcohol

Pharmacol Biochem Behav

Pharmacol Biochem Behav

FEBS Lett

Pharmacol Biochem Behav

Neurobiol Learn Mem

Behav Brain Res

Brain Res