Adolescent Cannabinoid Exposure in a Rodent Model of Schizophrenia Susceptibility

This project aims to explore the interaction of genetic and environmental factors in the development of psychotic symptoms. Cannabinoid exposure during adolescence is associated with an increased risk of developing schizophrenia, but this correlation is not causative. Thus, it is likely that people with a genetic predisposition to psychotic symptoms are more strongly affected by environmental risk factors. We have developed an animal model with increased susceptibility to schizophrenia-like symptoms by using the second filial (F2) generation of rats that were developmentally disrupted with methylazoxymethanol acetate (MAM). We hypothesize cannabinoid exposure during adolescence will increase the proportion of these 'F2 MAM' rats displaying a schizophrenia-like phenotype. This phenotype will be evaluated at the behavioral level (with stimulant-induced hyperlocomotion, social interaction, and attentional set-shifting), the cellular level (spontaneousdopamine neuron activity and hippocampal pyramidal activity), and the molecular level (expression of inhibitory markers). Understanding additive or interactive effects of risk factors could allow us to make more accurate predictions of developing psychotic symptoms, as well as personalize warnings for those already at risk. Furthermore, a model of susceptibility would be extremely useful for preventative experimental therapies. This proposal will provide important training in experimental design, laboratory and analytical techniques, ethics, and other essential skills for a future independent investigator. PUBLIC HEALTH RELEVANCE: The causes behind schizophrenia, a mental disorder affecting over 1% of the population, are not well understood. Most animal models of the disease consistently express psychotic symptoms, but few models emulate the human susceptibility to develop schizophrenia. We have developed a rodent model of psychotic susceptibility and will utilize it to explore the interaction between genetic and environmental risks.