Sensitivity to drug effects on prepulse inhibition in inbred and outbred rat strains

Genetic differences in the neurochemical regulation of PPI in rats may help clarify the neural basis of inherited PPI differences in neuropsychiatric disorders. We reported and characterized substantial heritable differences in sensitivity to PPI-disruptive effects of DA agonists in outbred Sprague Dawley (SDH) versus Long-Evans (LEH) rats. Other strains might yield large group separations and facilitate studies of the neural basis for these strain differences; inbred strains might also allow us to map genes associated with differential PPI sensitivity. Sensitivity to the PPI-disruptive effects of the DA agonist apomorphine (APO) and the NMDA antagonist phencyclidine (PCP) were compared across inbred and outbred strains. APO sensitivity was greatest in SDH and buffalo rats, but the effect in buffalo rats was complicated by significant APO-induced startle suppression. PPI APO sensitivity was least in ACI and LEH rats; F344s exhibited intermediate sensitivity and Lewis rats showed a nonlinear dose response (sensitivity at low but not higher doses). PPI APO insensitivity in ACI rats developed over time, with ACI pups exhibiting robust sensitivity. Substantial strain differences were observed in short-interval (10-30 ms) prepulse effects, and APO-induced increases in short-interval PPI occurred in SDH, LEH, and Lewis rats, but not in F344, ACI, or buffalo rats. Sensitivity to PPI-disruptive effects of PCP was generally greater in outbred than inbred rats. These findings identify strains suitable for comparisons of PPI neural circuitry and others for whom such comparisons would be complex and perhaps less informative.