Research articleΔ9-tetrahydrocannabinol (Δ9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice

•Neonatal PCP (P7) administration induces schizophrenia-like phenotypes.•In this model, Δ9-THC administration in young adults potentiates these phenotypes.•Δ9-THC or combined PCP + Δ9-THC decreases cortical CB1 receptor expression.•PCP or combined PCP + Δ9-THC decreases cortical NR1 receptor expression.

The clinical onset of schizophrenia often coincides with cannabis use in adolescents and young adults. However, the neurobiological consequences of this co-morbidity are not well understood. In this study, we examined the effects of Δ9-THC exposure during early adulthood on schizophrenia-related behaviors using a developmental mouse model of schizophrenia.Phencyclidine (PCP) or saline was administered once in neonatal mice (at P7; 10 mg/kg). In turn, Δ9-THC or saline was administered sub-acutely later in life to cohorts of animals who had received either PCP or saline (P55-80, 5 mg/kg). Mice who were administered PCP alone displayed behavioral changes in the Morris water waze (MWM) and pre-pulse inhibition (PPI) task paradigm that were consistent with schizophrenia-related phenotypes, but not in the locomotor activity or novel object recognition (NOR) task paradigms. Mice who were administered PCP and then received Δ9-THC later in life displayed behavioral changes in the locomotor activity paradigm (p < 0.001) that was consistent with a schizophrenia-related phenotype, as well as potentiated changes in the NOR (p < 0.01) and MWM (p < 0.05) paradigms as compared to mice that received PCP alone. Decreased cortical receptor expression of NMDA receptor 1 subunit (NR1) was observed in mice that received PCP and PCP + Δ9-THC, while mice that received Δ9-THC and PCP + Δ9-THC displayed decreases in CB1 receptor expression. These findings suggest that administration of Δ9-THC during the early adulthood can potentiate the development of schizophrenia-related behavioral phenotypes induced by neonatal exposure to PCP in mice.