Adolescent neuregulin 1 heterozygous mice display enhanced behavioural sensitivity to methamphetamine

Methamphetamine use triggers psychosis in genetically vulnerable individuals, however the exact nature of this genetic predisposition requires elucidation. In addition, adolescence may be a particular period of neurodevelopmental vulnerability to the actions of methamphetamine; interestingly, this period coincides with a higher likelihood of onset of schizophrenia and drug experimentation. In the current study we investigated whether adolescent mice heterozygous for the schizophrenia susceptibility gene neuregulin 1 (Nrg1 HET mice) exhibit altered behavioural responses to methamphetamine (0.6 or 2.4 mg/kg) in schizophrenia-relevant paradigms. The responses measured were locomotor activity in the open field test and sensorimotor gating function in the prepulse inhibition of startle paradigm (PPI). Adolescent Nrg1 HET mice displayed a subtle, transient, novelty-induced baseline locomotor hyperactivity over days, and a selective PPI deficit at the prepulse intensity-interstimulus interval (ISI) combination of 82 dB-64 ms. Adolescent Nrg1 HET mice were more sensitive to the locomotor stimulatory effects of an acute, low-dose of methamphetamine (0.6 mg/kg) relative to wild-type (WT) controls. The augmented response to acute methamphetamine observed in Nrg1 HET mice disappeared with repeated, daily dosing over 7 days. Methamphetamine did not affect average PPI (total or across different prepulse intensities), however 0.6 mg/kg methamphetamine triggered a PPI deficit selectively in Nrg1 HET mice but not WT mice at 82 dB-256 ms. Our results show that locomotor hyperactivity in Nrg1 HET mice, albeit subtle, can manifest much earlier than previously reported and that Nrg1 may confer vulnerability to the acute actions of methamphetamine, a drug known to trigger psychotic reactions in humans.

► We studied the behavioural response of adolescent Nrg1 HET mice to methamphetamine. ► Nrg1 HET mice displayed subtle baseline locomotor hyperactivity and PPI deficits. ► Nrg1 HET mice showed increased locomotor response to a low dose of methamphetamine. ► Nrg1 HET mice showed selective PPI deficits in response to methamphetamine.