TOWARDS A CROSS-SPECIES PHARMACOLOGY OF SENSORIMOTOR GATING - EFFECTSOF AMANTADINE, BROMOCRIPTINE, PERGOLIDE AND ROPINIROLE ON PREPULSE INHIBITION OF ACOUSTIC STARTLE IN RATS

Animal models in behavioral pharmacology can be evaluated based on the ir face, predictive and construct validity. A further level of validit y may be achieved if a model is reproduced precisely across species - from laboratory animal to human - using identical conditions and manip ulations to elicit identical behavioral changes. Under circumstances i n which a model achieves 'homologous' validity, it should be possible to demonstrate that the same pharmacological agents produce parallel c hanges in the same behavior (as distinct from the clinical condition t hat the animal behaviors are hypothesized to model), when studied in l aboratory animals and in humans. Studies have demonstrated that the di sruption of sensorimotor gating of the startle reflex, measured by pre pulse inhibition (PPI), in rats by dopamine agonists exhibits face, pr edictive and construct validity for the relative loss of PPI in schizo phrenia patients. To assess the homologous validity of this model, and to expand its utility in understanding the pathophysiology of sensori motor gating deficits and in developing novel antipsychotic agents to reverse these deficits, it will be important to study PPI across speci es, comparing response profiles to identical pharmacological manipulat ions. In the present studies, we report that PPI in rats is reduced in a dose-dependent manner by four dopamine agonists that can be adminis tered with relative ease to humans. We also report that the PPI-disrup tive effects of the clinically useful dopamine agonist pergolide are r eversed by both typical and atypical antipsychotics. These studies est ablish a foundation for pursuing human pharmacological studies of PPI, and for extrapolating the substantial neurochemical and neurophysiolo gical information from animal studies of PPI, towards understanding th e neural basis for deficient sensorimotor gating in specific neuropsyc hiatric disorders. Behav Pharmacol 1998; 9:389-396 (C) 1998 Lippincott Williams & Wilkins.