Possibili differenze sesso-specifiche nella vulnerabilità alle sostanze d’abuso in età adulta dopo esposizione al Δ9-tetraidrocannabinolo durante l’adolescenza

It is well established that early cannabis use during adolescence leads to neurobiological changes that can affect adult brain functions which in turn might lead to an increased vulnerability to drug abuse (Realini et al., 2009). Epidemiological evidence of cannabis use before other drugs has reinforced the idea of the "Cannabis gateway hypothesis" according to which early exposure to cannabis increases the risk of starting the use of harder drugs, such as heroin, cocaine and amphetamine (Kandel, 1975). Indeed, several studies have suggested the presence of significant functional interactions between the endocannabinoid and dopamine systems (Cheer et al., 2007; González et al., 2002) in the mesolimbic pathways, but also between endocannabinoid and opioid systems (Fattore et al., 2005) and between endocannabinoid and the cholinergic-nicotinic systems (Scherma et al., 2008) necessary for the expression of heroin and nicotine reward-related behaviours. Moreover, sex-dependent differences are frequently observed in the biological and behavioral effects of drugs of abuse (Becker and Hu, 2008) and in keeping with epidemiological data in humans, differences in drug-intake and seeking have been well-documented in animal studies, and the most recent findings have implicated cannabinoid abuse as well. (Fattore et al., 2010). Clinical and preclinical findings indicate that sex and gonadal hormones may account for individual differences in susceptibility to the reinforcing effects of addictive substances, and that differences in vulnerability to drug abuse may be mediated by the same biological mechanisms (Fattore et al., 2009). The aim of this study was to evaluate whether exposure to THC, primary psychoactive substituent of cannabis, during adolescence is able to increase the reinforcing effects of drugs of abuse such as nicotine, heroin and cannabinoids in adult male and female rats, and to compare the results obtained in order to identify possible sex-specific differences. To this end, behavioral studies have been conducted on both male and female rats using a validated experimental model to study dependence (O’Brien et al., 2005): the chronic intravenous self-administration (IVSA). Male, at 45 postnatal day (PND) and female adolescent, at 35 PND, Sprague-Dawley (for nicotine and heroin studies) and Lister Hooded rats (for WIN55,212-2 studies) (Deiana et al., 2007), were treated intraperitoneally (i.p) with increasing doses of THC (2.5, 5 and 10 mg/kg) or with vehicle twice/day for 11 consecutive days. Once animals reached the adulthood (85 or 75 PND), we studied the effects of THC exposure on acquisition and maintenance of nicotine (30 μg/kg/infusion), heroin (30 μg/kg/infusion) and cannabinoid agonist WIN55,212-2 (12.5 μg/kg/infusion) IVSA using continuous fixed-ratio (FR-1) schedule of reinforcement with lever-pressing as operandum. Faster acquisition and higher rate of drug intake was considered as index of vulnerability to drug abuse. Behavioral data obtained with male rats showed that exposure to THC during adolescence produces an increased vulnerability to CB1 receptor agonist WIN55,212-2 and heroin but not to nicotine intake in adulthood with respect to each control group. Data from nicotine self-administration in adult female rats showed no differences in intake between animal exposed to THC in adolescence and vehicle-treated rats. On the other hand, THC adolescence exposure increased both heroin and WIN55,212-2 intake as compared to corresponding control groups. Comparison of results obtained in females and male rats of heroin and WIN55,212-2 IVSA experiments shows that average intake of drugs during the maintenance phase of self-administration training is significantly higher in females than in males. This increased vulnerability of female rats to drug taking as compared to males is in line with previous studies on sex-dependent differences showing that females are more sensitive than males to cannabinoid-induced behavioral effects. In summary, these studies seem to support the hypothesis that a previous exposure to THC during adolescence increases the vulnerability to heroin and cannabinoids, but not to nicotine abuse in adult rats with sex-specific differences.