Adolescent cannabinoid exposure interacts with other risk factors in schizophrenia: A review of the evidence from animal models

Many factors and their interaction are linked to the aetiology of schizophrenia, leading to the development of animal models of multiple risk factors and adverse exposures. Differentiating between separate and combined effects for each factor could better elucidate schizophrenia pathology, and drive development of preventative strategies for high-load risk factors. An epidemiologically valid risk factor commonly associated with schizophrenia is adolescent cannabis use. The aim of this review is to evaluate how early-life adversity from various origins, in combination with adolescent cannabinoid exposure interact, and whether these interactions confer main, synergistic or protective effects in animal models of schizophrenia-like behavioural, cognitive and morphological alterations. Patterns emerge regarding which models show consistent synergistic or protective effects, particularly those models incorporating early-life exposure to maternal deprivation and maternal immune activation, and sex-specific effects are observed. It is evident that more research needs to be conducted to better understand the risks and alterations of interacting factors, with particular interest in sex differences, to better understand the translatability of these preclinical models to humans.