Long-term evaluation of isolation-rearing induced prepulse inhibition deficits in rats

Abstract.

Rationale: Rats reared in social isolation from weaning show prepulse inhibition (PPI) deficits which are thought to model the sensorimotor gating deficits seen in schizophrenia and other psychiatric disorders. However, recent studies have questioned the robustness of this paradigm. Objective: The existence of a substantial dataset generated over 4 years in our laboratory has allowed the investigation of the robustness and reliability of the procedure under a variety of environmental conditions. The effects of atypical antipsychotics (clozapine, olanzapine and risperidone) under different experimental conditions are also reported. Method: At weaning, Hooded Lister pups were singly (isolates) or group (n=5) housed (grouped). Eight weeks later, the startle and PPI response of isolates and grouped rats was investigated using conditions of fixed inter-stimulus interval (ISI) (pulse=110 dB/50 ms; prepulse=80 dB/30 ms; ISI=100 ms) or variable ISI conditions (same pulse and prepulse intensities/durations; ISI=30, 100, 300 ms). Locomotor activity (LMA) prior to and following PPI testing was also investigated. Results. Isolation-induced deficits in PPI were demonstrated in ten separate cohorts, reared in three different buildings. Only one cohort demonstrated weakening of the PPI-deficit which precluded further studies. In one cohort, the PPI response remained stable over the course of six PPI exposures. PPI was unaltered by daily handling, re-socialisation and LMA testing. Startle and PPI were not correlated, nor was LMA correlated to PPI or startle. Isolation-induced deficits were attenuated by clozapine (5 mg/kg SC), olanzapine (3 mg/kg SC) and risperidone (1 mg/kg IP) under variable ISI conditions but not by clozapine (2.5–7.5 mg/kg SC) or olanzapine (0.3–3 mg/kg SC) under fixed ISI conditions. Conclusion: Isolation-rearing produces robust and reliable PPI deficits which are reversed by atypical antipsychotics.