Sex-specific sensitivity to methamphetamine-induced schizophrenia-relevant behaviours in neuregulin 1 type III overexpressing mice.

Abstract

Gene-environment interactions contribute to schizophrenia aetiology. Neuregulin 1 is a well-established genetic risk factor for schizophrenia, and elevated expression of type III neuregulin 1 mRNA in the dorsolateral prefrontal cortex is observed in patients with a core risk haplotype. A mouse model of type III Nrg1 overexpression (Nrg1 III tg) possesses face and construct validity for schizophrenia; however, the sensitivity of these transgenic mice to environmental risk factors relevant to schizophrenia is unknown. To determine sensitivity of Nrg1 III tg mice to the psychostimulant methamphetamine (METH) in schizophrenia and addiction-relevant behavioural tests. We examined behavioural responses of adult male and female Nrg1 III tg mice METH (1-3 mg/kg) in schizophrenia-relevant paradigms (drug-induced locomotion, sensorimotor gating) and drug reward (conditioned place preference). Male Nrg1 III tg mice were less sensitive to METH-induced stereotypies, yet showed a greater negative impact of METH on prepulse inhibition compared with wild type-like males. In contrast, female Nrg1 III tg mice were less sensitive to METH-induced locomotion than wild type-like females, while sensorimotor gating was similarly impaired by METH between the genotypes. There were no genotype differences for METH reward, or anxiety-like and exploratory behaviours. These results indicate that overexpression of Nrg1 type III modulates schizophrenia-relevant behaviours, and may help to explain increased sensitivity to the psychoactive effects of METH in patients with schizophrenia.