Non-monotonic dependency of PPI on temporal parameters: differential alteration by ketamine and MK-801 as opposed to apomorphine and DOI

Abstract.

Rationale: Prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating, is a time-linked phenomenon which depends on prepulse duration (PD) and prepulse-pulse interval (PP). Rats treated with dopaminergic agonists, serotoninergic agonists or glutamatergic antagonists are commonly used as models for the deficit in PPI observed in schizophrenic patients. An important question was whether there is a parametric specificity for the effects of such pharmacological agents. Objective: We investigated the contribution of PD, PP, and then of ratio R (PD:PP) to the expression of PPI and we looked for a modification of the temporal dependency of PPI by either apomorphine, DOI, ketamine and/or MK-801. Methods: Male Sprague-Dawley rats were used. The values used to test PD varied from 5 to 1280 ms, with PP being fixed at 20 ms and vice versa to test PP. Different ratios were used to test R. The effect of either apomorphine (0.5 mg/kg), DOI (1 mg/kg), ketamine (1.5–6 mg/kg) or MK-801 (0.1–0.5 mg/kg) was compared to their vehicle. Results: PPI was a non-monotonic function of each parameter tested. The functions of PD and PP differed. All drugs reduced PPI in each parameter. The shape of the function obtained by varying PD was modified by ketamine and MK-801, but not by apomorphine or DOI. Conclusions: The specific effect of ketamine and MK-801 was discussed in relation to the hypotheses about the mechanism underlying the modulation of PPI by temporal parameters. These findings stress the importance of non-competitive NMDA antagonist-induced disruption of PPI as a model of the sensorimotor gating deficit observed in schizophrenic patients.