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

Abstract

Background: 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. Aims: To determine sensitivity of Nrg1 III tg mice to the psychostimulant methamphetamine (METH) in schizophrenia and addiction-relevant behavioural tests. Methods: 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). Results: 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. Conclusions: 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.

Epigenetic Regulatory Dynamics in Models of Methamphetamine-Use Disorder

“…These miRNAs are known to play a crucial role in cell communication in the CNS and peripheral system [140]. These investigators also showed decreased hippocampal protein levels of ErbB4 and NRG1, that might serve as markers of METH-induced psychosis [141,142].…”

Sex differences in methamphetamine use disorder perused from pre-clinical and clinical studies: Potential therapeutic impacts

“…In addition, females exhibited enhanced drug-induced locomotor activity for a longer period of time of drug withdrawal than male rats ( Ramos et al, 2020 ). Similarly, female mice showed greater locomotor activity after an acute injection of METH (0.1 mg/kg, 1.0 mg/kg and 4.0 mg/kg) ( Chesworth et al, 2021 ; Cullity et al, 2021 ; Ohia-Nwoko et al, 2017 ). In contrast to observations made in rats and mice, prairie voles injected with 0.2 mg/kg METH showed greater locomotor activity in males in comparison to female voles ( Perry et al, 2019 ).…”

Extracellular Vesicle-Encapsulated miR-183-5p from Rhynchophylline-Treated H9c2 Cells Protect against Methamphetamine-Induced Dependence in Mouse Brain by Targeting NRG1

“…NRG1 is not only an EGF-like protein implicated in neural development and brain activity homeostasis [35] but also an important factor for memory formation and an indicator of Meth dependence [36], which regulates nerve cell differentiation, neuron migration, neurotransmission, neurite outgrowth, and synaptic activity and protects neurons under various pathological conditions [37]. Furthermore, recent evidence also suggested that NRG1 is an appropriate candidate gene for Meth-induced psychosis and overexpression of NRG1 type III modulated the behavioral tests induced by Meth [38,39]. In particular, neuregulins (NRGs) are cell-cell signaling proteins that act as ligands for receptor tyrosine kinases of the ErbB family.…”