Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: a decade in review

Rationale: Patients with schizophrenia exhibit deficits in an operational m easure of sensorimotor gating: prepulse inhibition (PPI) of startle. Simila r deficits in PPI are produced in rats by pharmacological or developmental manipulations. These experimentally induced PPI deficits in rats are clearl y not animal models of schizophrenia per se, but appear to provide models o f sensorimotor gating deficits in schizophrenia patients that have face, pr edictive, and construct validity. In rodents, disruptions in PPI of startle are produced by: stimulation of D-2 dopamine (DA) receptors, produced by a mphetamine or apomorphine; activation of serotonergic systems, produced by serotonin (5-HT) releasers or direct agonists at multiple serotonin recepto rs; and blockade of N-methyl-D-aspartate (NMDA) receptors, produced by drug s such as phencyclidine (PCP). Accordingly, dopaminergic, serotonergic, and glutamatergic models of disrupted PPI have evolved and have been applied t o the identification of potential antipsychotic treatments. In addition, so me developmental manipulations, such as isolation rearing, have provided no n-pharmacological animal models of the PPI deficits seen in schizophrenia. Objective: This review summarizes and evaluates studies assessing the effec ts of systemic drug administrations on PPI in rats. Methods: Studies examin ing systemic drug effects on PPI in rats prior to January 15, 2001 were com piled and organized into six annotated appendices. Based on this catalog of studies, the specific advantages and disadvantages of each of the four mai n PPI models used in the study of antipsychotic drugs were critically evalu ated. Results: Despite some notable inconsistencies, the literature provide s strong support for significant disruptions in PPI in rats produced by DA agonists, 5-HT, agonists, NMDA antagonists, and isolation rearing. Each of these models exhibits sensitivity to at least some antipsychotic medication s. While the PPI model based on the effects of direct DA agonists is the mo st well-validated for the identification of known antipsychotics, the isola tion rearing model also appears to be sensitive to both typical and atypica l antipsychotics. The 5-HT PPI model is less generally sensitive to antipsy chotic medications, but can provide insight into the contribution of seroto nergic systems to the actions of newer antipsychotics that act upon multipl e receptors. The deficits in PPI produced by NMDA antagonists appear to be more sensitive to clozapine-like atypical antipsychotics than to typical an tipsychotics. Hence, despite some exceptions to this generalization, the NM DA PPI model might aid in the identification of novel or atypical antipsych otic medications. Conclusions: Studies of drug effects on PPI in rats have generated four distinctive models that have utility in the identification o f antipsychotic medications. Because each of these models has specific adva ntages and disadvantages, the choice of model to be used depends upon the q uestion being addressed. This review should help to guide such decisions.