Influence of strain, sex and ovarian hormones on cannabinoid self-administration in rats

Liana Fattore1, Maria Sabrina Spano2, Silvia Altea2, Paola Fadda2, Walter Fratta2. 1Institute of Neuroscience CNR, Cagliari, Italy, 2Department of Neuroscience, Univ Cagliari, Cagliari, Italy.

Numerous evidence indicate that Cannabis derivatives may serve as positive reinforcers in rodents, yet the hypothesis whereby genetic or gender related factors may influence drug taking behaviour has not been tested in laboratory animals. In this study we verified whether rat strain, sex and ovariectomy might be critical in the initiation, retention and extinction of the self-administration (SA) of the cannabinoid CB1 receptor agonist WIN 55,212-2 (WIN).

To this purpose, Long Evans (LE), Lister Hooded (LH) and Sprague-Dawley (SD) male and female rats (n=10-12), these latter either intact or bilaterally ovariectomized (OVX), were trained to self-administer WIN as previously described (Fattore et al. 2001), i.e. at the unit dose of 12.5 μg/kg/inf under a continuous (FR1) reinforcement schedule and lever-pressing as operandum.

In line with our recent observations (Deiana et al. 2007), ANOVA analysis revealed that LE and LH, but not SD, male and female rats were able to acquire and retain stable cannabinoid SA, as defined by significant (p<0.01) differences between responding in the active versus the inactive lever. In rats developing firm WIN intake, significant differences (p<0.05) in the length of acquisition, amount of the daily drug intake during maintenance but not timing of extinction, were found between males and intact females. Indeed, responding was lower in males than females during both acquisition and extinction, with females showing higher intake during maintenance (-22.25% and -33.63% for LE and LH strains, respectively). Moreover, OVX females of both strains acquired SA behaviour at lower percentage, showing slower acquisition, lower WIN intake (-30.85% and -53.66% for LE and LH strains, respectively) and longer extinction than corresponding intact females. Finally, only one out of ten intact SD females, but not OVX or males, acquired stable SA behaviour.

Altogether, these findings revealed that cannabinoid SA is significantly influenced by strain, as LE and LH but not SD male and female rats developed and maintained stable WIN intake, and by sex, as intact females developed cannabinoid SA faster (i.e. LH strain) or at higher percentage (i.e. LE strain) than males. Moreover, when compared to intact females, OVX LE and LH rats displayed decreased ability to develop cannabinoid SA and lower intake after acquisition, suggesting that ovarian hormones might play a critical role in modulating the reinforcing effect of cannabinoids, as previously reported for other drugs of abuse (Lynch et al 2006)

Deiana S, Fattore L, Spano MC, Cossu G, Porcu E, Fadda P, Fratta W (2007) Strain and schedule-dependent differences in the acquisition, maintenance and extinction of intravenous cannabinoid self-administration in rats. Neuropharmacology 52(2):646-54.

Fattore L, Cossu G, Martellotta CM, Fratta W (2001) Intravenous self-administration of the cannabinoid CB1 receptor agonist WIN 55,212-2 in rats. Psychopharmacology 156(4):410-6.

Lynch WJ (2006) Sex differences in vulnerability to drug self-administration. Exp Clin Psychopharmacol 14(1):34-41.