Sex differences in schizophrenia may originate early in life. Mice given phencyclidine (PCP) on postnatal days 7, 9, and 11 showed dose-dependent deficits in open field, social interaction, and prepulse inhibition tests during late adolescence (PN48-50). Males were more susceptible to these behavioral deficits and had reduced GluN1 subunit expression in the frontal cortex at early adolescence (PN30). By late adolescence (PN50), cortical GluN1 was increased in both sexes, while PCP increased cortical and decreased hippocampal PSD-95 in females. The antipsychotic olanzapine failed to mitigate most PCP-evoked alterations and sometimes worsened deficits, suggesting its use during adolescence needs further evaluation.
In adolescent mice, nicotine exposure did not worsen and may have even ameliorated psychotic-like behavior induced by phencyclidine, a model of psychosis. The antipsychotic drug raclopride prevented the development of this behavior, and nicotine temporarily boosted raclopride's inhibitory effect. Nicotine history shortened the expression of sensitized behavior after withdrawal. The findings suggest that nicotine may transiently improve the efficacy of antipsychotic medication through mechanisms involving dopamine D2 receptors.