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