Studio degli effetti della pre-esposizione adolescenziale al Δ9-THC nell’autosomministrazione di eroina, in età adulta, in un modello animale di maggiore (ratti Lewis) e minore (ratti Fischer 344) predisposizione all’abuso.

Introduction: The progression from adolescence strong use of Cannabis to heroin abuse in adulthood, theorized by Kandel as Gateway Hypothesis (GH) doesn't adequately account the importance of phenotype vulnerability as predisposing factor involved in the development of a drug abuse-related behavioral disorder. Addiction prone Lewis (LEW) and addiction resistant Fischer (F344) inbred rat strains represents a useful animal model of different drug vulnerability in light of the different susceptibility to opiates and psychostimulants reinforcing properties. Aim: Thus, the purpose of this study was to investigate the influence of Δ9-THC adolescence exposure on the addictive properties of heroin in LEW and F344 strain, during heroin self-administration (SA) in adulthood. Methods: On the 6th postnatal (PN) week rats were administered twice a day with increasing doses of Δ9-THC (2, 4, 8 mg/kg, i.p.) for three consecutive days. In adulthood (12th PN), LEW and F344 rats were trained to acquire heroin SA behavior (0.025 mg/kg/48 μl, 1-h daily session), under Fixed Ratio-1 (FR-1) (1NP = 1 infusion) schedule of responding. When criterion of acquisition was met, LEW and F344 rats were subjected to self administer heroin: i) under Fixed Ratio (FR-3 and FR-5) schedule of responding (Exp I), to better understand how Δ9-THC could influence heroin reinforcing properties; ii) under Progressive Ratio (PR3-4) schedule of reinforcement (Exp II) in order to evaluate if Δ9-THC adolescent exposure affect the motivational value of heroin; iii) during daily 4-h SA (long access, LA), with increasing doses of heroin (0.025, 0.050 and 0.100 mg/kg), under FR-1 schedule (Exp. III) to determine the role of Δ9-THC as predisposing factor in the vulnerability of opiate abuse by escalation of heroin intake. Results: In each experiments, adolescent pre-exposure to Δ9-THC induced higher operant responding activity and greater adaptation to all experimental conditions (Exp I, II, III) of opiate-reinforced SA behavior in adult LEW rats as well as progressive escalation of heroin intake when exposed to higher doses of heroin, compared to LEW vehicle as well as to F344 strain (Exp III). Furthermore, LEW Δ9-THC pretreated rats readily acquire PR schedule, showing greater nose poking behavior and higher breaking point values compared to their controls as well as to the counterpart F344 groups. No such differences were observed in the F344 rats strain. Conclusion: Genetic vulnerability plays a critical role as a predisposing factor in the progression to opiate abuse and related behavioral disease. The results of my research strongly demonstrate that Δ9-THC pre-treatment in adolescence differentially affects both heroin rewarding properties and motivational value, in adulthood, in a strain-related way, and for the first time clearly indicate that heavy Cannabis use during adolescence could have a gateway effect in the adulthood only on individuals provided by an addiction prone genetic and/or phenotype background.