Adolescent WIN 55,212-2 pre-exposure affects rat behavioral and neurochemical response to cocaine

THESIS ABSTRACT Introduction and objectives: Recently, the effects of cannabis use on the brain received increasing attention in relationship with the implications for public health (Hall and Linskey, 2016). Noteworthy, cannabis consumption is also associated with later use of cocaine. The epidemiological studies describing such progressive pattern of different substance use, refers to the Gateway Hypothesis (Kandel, 1975). In this context, since the endocannabinoid system plays a central role in the development and in the reward circuits of the adolescent brain (Diaz Alonso et al., 2012), it is relevant to understand if and how early exposure to cannabinoids could cause neurobiological changes that increase the risk of vulnerability to abuse other drugs. For this purpose, we investigated the prospective gateway effect of WIN55,212-2 (WIN), a synthetic cannabinoid and full agonist of the CB1 receptors, evaluating drug’s cross-sensitizing behavioral and neurobiological effects to cocaine in both adolescence and adulthood. Results: Adolescent and adult male rats received administration of increasing doses of WIN, or its vehicle, twice-daily for 11 consecutive days. After 7 days of abstinence, rats were treated with cocaine, and tested with voltammetry in the nucleus accumbens (NAcc), or with locomotor activity 24 hours after the last day of abstinence. Adolescent, but not adult WIN-pre-treated rats later exposed to cocaine, showed an increase in the amplitude of dopamine release in the NAcc, and in the motor-activating effects of cocaine compared to vehicle-pre-treated animals. Furthermore, using a multi-omics approach, we found that the cocaine-induced behavioral cross-sensitization of WIN- pre-treated rats correlates with a variety of molecular and epigenetic modifications at the level of the pre-frontal cortex. Moreover, since substance use disorders are triggered by repeated exposures that involve drastic epigenetic and synaptic alterations, we also evaluated the long-term persistence of motor cross- sensitization and the possible positive reinforcement after repetitive cocaine administrations. We found a close-to-significant persistence of motor cross-sensitization between WIN and cocaine and a conditioned place preference for cocaine in adolescent WIN pre-treated animals. Conclusions: The findings of the present thesis aim to provide a contribution to the literature to better understand the effects of cannabis use on the brain, and to provide a significant piece of knowledge for decision makers to address more effectively the subtle issue of cannabis legalization.