Sex-specific critical periods determine the effects of cannabinoids on the mesocorticolimbic system

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Cannabis is the most frequently used illicit drug. Its widespread use in adolescents is associated with an increased risk for mental illness and is a major public health concern. For example, an increased rate of psychosis and an earlier onset of psychotic illness have been observed with heavy adolescent cannabis use. There is also a correlation between early cannabis use, the age at onset of psychotic disorders and the age at first hospitalization for 'pure' cannabis users. However, the pathophysiological mechanisms underlying the adverse effects of early cannabis use, such as perturbed social interactions, psychosis and addiction risk remain to be elucidated. A better understanding of these mechanisms is necessary to develop therapies & effective prevention programs, and to inform decisions on public policy, including cannabis legalization. Adolescence is a period of profound neurodevelopmental maturation, notably in the mesocortico-limbic system (MCS), an ensemble of interconnected structures involved in higher cognitive functions, emotions, reward and social behaviors. MCS development occurs at different rates in males and females. During adolescence, social play, an MCS-based behavior, guides the emergence and proper maturation of social interactions. Disruption of social play in the adolescent negatively affects adult behaviors. Impaired adolescent social play may also be a sign of emerging psychopathology. The main psychoactive ingredient of cannabis (i.e., THC) engages the abundant CB1 cannabinoid receptor (CB1R), competing with endogenous cannabinoids. CB1Rs are a core component of the endogenous cannabinoid system (ECS). The ECS is abundant throughout the MCS and modulates many neurodevelopmental, neuronal and synaptic processes, including adolescent social play. Recent discoveries from our laboratories fueled the concept that ECS dysfunction plays a key role in diverse neuropsychiatric diseases of environmental or genetic origin. Motivated by new, unpublished data, and using a rodent model, we propose a multi-disciplinary approach to establish the sex-specific development and distribution of ECS components in the MCS and how these affect the molecular, synaptic and behavioral consequences of adolescent cannabis (THC) exposure. Our 3 aims will: 1/ Characterize and compare the normal functional development of neuronal and synaptic responses in the MCS between male and female rats from pre-adolescence to adulthood. 2/ Establish the developmental patterns of expression and localization of key components of the ECS in the rat MCS in a sex and age-specific fashion. 3/ Determine the sex-specific functional (molecular, synaptic, and behavioral) consequences of THC exposure during critical periods of adolescence and adulthood. Together, the results of these studies will define new structural, molecular and functional synaptic substrates of the sex-specific effects of adolescent cannabis use on ECS function and behavior.