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

Rationale: Prepulse inhibition (PPI) of the startle reflex, a measure of se nsorimotor gating, is a time-linked phenomenon which depends on prepulse du ration (PD) and prepulse-pulse interval (PP). Rats treated with dopaminergi c agonists, serotoninergic agonists or glutamatergic antagonists are common ly used as models for the deficit in PPI observed in schizophrenic patients . An important question was whether there is a parametric specificity for t he effects of such pharmacological agents. Objective: We investigated the c ontribution 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 eith er apomorphine. DOI, ketamine and/or MK-801. Methods: Male Sprague-Dawley r ats 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), ke tamine (1.5-6 mg/kg) or MK-801 (0.1-0.5 mg/kg) was compared to their vehicl e. 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. T he shape of the function obtained by varying PD was modified by ketamine an d MK-801, but not by apomorphine or DOI. Conclusions: The specific effect o f ketamine and MK-801 was discussed in relation to the hypotheses about the mechanism underlying the modulation of PPI by temporal parameters. These f indings stress the importance of non-competitive NMDA antagonist-induced di sruption of PPI as a model of the sensorimotor gating deficit observed in s chizophrenic patients.