Atypical antipsychotics attenuate MK801-induced social withdrawal and hyperlocomotion in the RHA rat model of schizophrenia-relevant features

Abstract

Rationale: The administration of NMDA receptor (NMDAR) antagonists constitutes a widely used model that produce both positive (e.g., hyperactivity) and negative (e.g., social withdrawal) symptoms relevant for schizophrenia in rodents. These effects can be reversed with the administration of atypical (second and third generation) antipsychotics.

Objectives: In this study we combined the NMDAR-antagonist model with the Roman High-Avoidance (RHA) strain, a psychogenetically selected model of schizophrenia-relevant features. We also studied whether some atypical antipsychotic drugs (clozapine, ziprasidone, and aripiprazole) would be able to attenuate or reverse the behavioural alterations induced by MK801 and whether such effects might be dependent on the rat strain.

Methods: MK801 dose-response study was conducted in RHA and Roman Low-Avoidance (RLA) male rats. After that, the 0.15 mg/kg MK801 dose was selected to carry out pharmacological studies versus atypical antipsychotics.

Results: In the first experiment we establish that MK801 (dizocilpine), a NMDAR antagonist, produces dose-related hyperactivity and social withdrawal, which are more marked in RHA than RLA rats. The administration of the atypical antipsychotics clozapine (2.5 mg/kg) or ziprasidone (2.5 mg/kg) partially reversed or attenuated some of the social behaviour deficits and hyperactivity induced by the administration of MK801. Aripiprazole (3 mg/kg), a third-generation antipsychotic, reversed or attenuated the social preference deficit, the hyperactivity and the impairment of social latency induced by MK801.

Conclusions: These results seem to be in line with previous studies with the NMDAR-antagonist model and add face (MK801-induced social withdrawal and hyperactivity) and predictive (attenuation of MK801-induced effects by atypical antipsychotics) validity to the RHA rat strain as a model of schizophrenia-relevant features.

Keywords: Atypical antipsychotics; NMDAR antagonist; Negative symptoms; RHA and RLA rats; Schizophrenia; Social withdrawal.