D9-tetrahydrocannabinol decreases somatic and motivational manifestations of nicotine withdrawal in mice

GRACIELA N. BALERIO, ESTER ASO, FERNANDO BERRENDERO, PATRICIA MURTRA AND RAFAEL MALDONADO.

Stockholm, Sweden

Congreso; 17th ECNP Congreso. European College of Neuropsychopharmacology; 2004

 GN. Balerio, E. Aso, F. Berrendero, P. Murtra and R. Maldonado. Universitat Pompeu Fabra, Laboratori de Neurofarmacologia. Facultat de Ciències de la Salut i de la Vida, Barcelona, Spain.  D9-tetrahydrocannabinol decreases somatic and motivational manifestations of nicotine withdrawal in mice  The possible interactions between D9-tetrahydrocannabinol (THC) and nicotine remain unclear in spite of the current association of cannabis and tobacco in humans. The aim of the present study was to explore the interactions between these two drugs of abuse by evaluating the consequences of THC administration on the somatic manifestations and the aversive motivational state associated to nicotine withdrawal in mice.  To induce nicotine dependence, mice were implanted subcutaneously with osmotic minipumps containing 25 mg/kg/day nicotine hydrogen tartrate salt. Six days after minipump implantation, withdrawal syndrome was precipitated by injection of mecamylamine. The aversive motivational state associated to nicotine withdrawal in mice was evaluated using a protocol of conditioned place aversion adapted from a previous study (1). Mecamylamine precipitated several withdrawal signs in nicotine chronically treated mice: paw tremor (57.20 + 9.99), wet-dog shakes (5.30 + 0.83), genital licks (1.60 + 0.21) and scratches (11.80 + 4.10) compared to saline chronically treated mice: (2.89 + 1.06), (0.89 + 0.20), (0.22 + 0.15) and (2.00 + 0.62) respectively. Comparisons between saline and nicotine treated groups (one-way ANOVA) showed that paw tremor (p < 0.001), wet-dog shakes (p < 0.001), genital licks (p < 0.001) and scratches (p < 0.05) were significantly higher in mice receiving acute vehicle. Dunnett´s post-hoc test showed that the three doses of THC (0.3, 1 and 3 mg/kg, i.p) significantly decreased paw tremor (16.20 + 3.45, 11.0 + 2.36, 1.90 + 0.81, respectively) and wet-dog shakes (2.30 + 0.56, 1.89 + 0.43, 0.80 + 0.39, respectively) in nicotine treated mice (p < 0.001) compared to vehicle, and the highest dose of THC also significantly decreased genital licks (0.10 + 0.10, p < 0.001). THC (0.3 and 3 mg/kg) also significantly decreased scratches (0.80 + 0.36, 0.10 + 0.10, respectively) in nicotine treated mice compared to vehicle (p < 0.01). The analysis of the global withdrawal score confirmed that the three doses of THC significantly decreased the score in nicotine treated mice (18.80 + 2.10, 18.06 + 0.88, 11.25 + 1.19, respectively, p < 0.001, Dunnett´s post-hoc test) compared to vehicle (46.05 + 5.51). Then we have evaluated whether this effect of THC was due to possible adaptive changes induced by chronic nicotine on CB1 cannabinoid receptors. The stimulation of GTPgS-binding proteins by the cannabinoid agonist WIN 55,212-2 (2) and the density of CB1 cannabinoid receptor binding labelled with [3H] CP-55,940 (3) were not modified by chronic nicotine treatment in the different brain structures investigated. THC also reversed conditioned place aversion associated to naloxone-precipitated nicotine withdrawal. Thus, post hoc analysis (Fisher’s test) showed a significant difference in the place aversion score of vehicle treated nicotine-dependent animals conditioned to naloxone-precipitated withdrawal (-126.76 + 43.92) as compared to the same group of mice receiving THC (33.35 + 50.14, p < 0.05). Taken together, these results indicate that THC administration attenuated somatic signs and the aversive motivational consequences of nicotine withdrawal, and these effects were not associated to compensatory changes on CB1 cannabinoid receptors during chronic nicotine administration. References 1- Watkins, S.S., Stinus, L., Koob, G.F. & Markou, A., 2000. J. Pharmacol. Exp. Ther. 292, 1053-1064. 2- Sim, L.J., Selley, D.E. & Childers, S.R., 1995. Proc. Natl. Acad. Sci. USA. 92, 7242-7246.                     3- Herkenham, M., Lynn, A.B., Johnson, M.R., Melvin, L.S., de Costa, B.R. & Rice, K.C., 1991. J. Neurosci. 11, 563-583.