Elsevier

Neuropharmacology

Volume 43, Issue 5, October 2002, Pages 857-867
Neuropharmacology

Lack of CB1 cannabinoid receptors modifies nicotine behavioural responses, but not nicotine abstinence

https://doi.org/10.1016/S0028-3908(02)00118-1Get rights and content

Abstract

Cannabis is the most widely consumed illicit drug and its consumption is currently associated with tobacco, which contains another psychoactive compound, namely nicotine. Interactions between cannabinoids and other drugs of abuse, such as opioids, have been previously reported. The aim of the present study was to evaluate the possible role of CB1 cannabinoid receptor in responses induced by acute and repeated nicotine administration by using knockout mice lacking the CB1 cannabinoid receptor and their wild-type littermates. Acute nicotine (0.5, 1, 3 and 6 mg/kg, sc) administration decreased locomotor activity and induced antinociceptive responses in the tail-immersion and the hot-plate test, in wild-type animals. The antinociceptive effects in the tail-immersion test were significantly enhanced in CB1 knockout mice. In wild-type mice nicotine (0.5 mg/kg, sc) produced a significant rewarding effect, as measured by a conditioned place preference paradigm. This response was absent in CB1 knockout mice. Finally, a model of mecamylamine-induced abstinence in chronic nicotine-treated mice (10 mg/kg/day, sc) was developed. Mecamylamine (1 and 2 mg/kg, sc) precipitated several somatic signs of nicotine withdrawal in wild-type dependent mice. However, no difference in the severity of nicotine withdrawal was observed in CB1 knockout mice. These results demonstrate that some acute effects and motivational responses elicited by nicotine can be modulated by the endogenous cannabinoid system and support the existence of a physiological interaction between these two systems.

Introduction

Marijuana is the most widely consumed illicit drug in humans (Adams and Martin, 1996, Watson et al., 2000), frequently used in association with tobacco (Degenhardt et al., 2001, Schorling et al., 1994). The endogenous cannabinoid system has been reported to be involved in the modulation of many functions within the central nervous system. For example, previous studies in rodents have shown that administration of cannabinoid agonists modifies locomotion, anxiety, memory, nociception and processing of reward signals (Dewey, 1986, Hernandez-Tristan et al., 2000, Ledent et al., 1999, Walker et al., 1999, Zimmer et al., 1999). Similarly, previous studies in rodents have shown that nicotine also modifies locomotion, anxiety, learning and memory, nociception, and its repeated administration produces physical dependence (Clarke and Kumar, 1983, Hildebrand et al., 1999, Marubio et al., 1999, Picciotto et al., 1995). Therefore, a number of common central nervous system functions are affected by cannabinoid agonists and by nicotine, although often in opposite directions. Recent studies carried out with mutant mice lacking the CB1 cannabinoid receptor gene have demonstrated that this receptor mediates the pharmacological effects of cannabinoids in the central nervous system (Ledent et al., 1999, Zimmer et al., 1999). Neuroanatomical studies have shown a high density of CB1 receptors in neurons of the cerebellum, basal ganglia, limbic cortices, hippocampus, hypothalamus and different nuclei of the extended amygdala (Tsou et al., 1998). Interestingly, an overlapping distribution of CB1 cannabinoid receptors and nACh receptors has been reported in several brain structures such as the hippocampus and the amygdala (Picciotto et al., 2000), which suggests the possibility of functional interactions between these two systems.

The aim of the present study was to investigate the involvement of the endogenous cannabinoid system on nicotine pharmacological effects. For this purpose, several well-known behavioural responses induced by acute and repeated nicotine administration (Watkins et al., 2000) were evaluated in CB1 cannabinoid receptor knockout mice and their wild-type littermates. Locomotor effects induced by acute nicotine administration were measured in activity boxes. Acute nicotine antinociceptive responses were assayed using two models where different neural pathways are involved in processing the nociceptive signals, the tail-immersion and the hot-plate test (Grossman et al., 1982, Morgan et al., 1989). The conditioned place preference paradigm was used to evaluate the rewarding properties of nicotine. Finally, the behavioural expression of mecamylamine–precipitated withdrawal was evaluated in chronic nicotine-treated mice.

Section snippets

Animals

Male CB1 knockout mice and wild-type littermates, weighing 26–30 g at the beginning of the experiments, were used. The generation of mice lacking CB1 cannabinoid receptor has been previously described (Ledent et al., 1999). In order to homogenise the genetic background of mice, the first generation heterozygotes were bred for 15 generations on a CD1 background, with selection for the mutant CB1 gene at each generation. All animals used in a given experiment originated from the same breeding

Results

Previous studies have characterized the spontaneous behavioural phenotype of CB1 cannabinoid receptor knockout mice (Ledent et al., 1999, Martin et al., 2002, Valverde et al., 2000). Thus, CB1 knockout mice appear fertile and healthy and exhibit a similar nociceptive threshold to wild-type littermates. However, CB1 cannabinoid receptor knockout mice have been reported to show changes in emotional behaviour, a decrease in the motivational responses induced by morphine as well as a reduction in

Discussion

The present results support the existence of a functional interaction between the endogenous cannabinoid system and nicotine, mediated by the CB1 cannabinoid receptor. Indeed, some behavioural responses induced by nicotine (antinociception in the tail-immersion test and conditioned place preference) were modified in animals lacking CB1 cannabinoid receptors, whereas others (hypolocomotion, antinociception in the hot-plate test and physical dependence) remained unaffected.

Nicotine-induced

Acknowledgements

We thank Dr Patricia Robledo and Hagar Lock for critical reading of the manuscript. This study has been supported by grants from the European Commission (98-2227), the Spanish Ministry of Health (FIS, 99/0624), Spanish Ministry of Science and Technology (SAF 2001-0745) and Laboratorios Dr Esteve. The Fonds Médical Reine Elizabeth and the Pôles S’Attraction Interuniversitaires support C.L. and M.P.. C.L. is Chercheur qualifié of the FNRS.

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