Prefrontal D1 and ventral hippocampal N-methyl-D-aspartate regulation of startle gating in rats

Background: Sensorimotor gating, as measured by prepulse inhibition of the startle reflex, is deficient in schizophrenia patients, and in rats after specific manipulations of limbic cortico-striato-pallido-thalamic circuitry. For example, prepulse inhibition in rats is disrupted after D1 blockade in the medial prefrontal cortex, and after N-methyl-D-aspartate infusion into the ventral hippocampus. In the present study, we examined whether these two substrates form part of an integrated circuit regulating sensorimotor gating, which might contribute to the loss of prepulse inhibition in patient populations. Methods: Prepulse inhibition was assessed in male Sprague-Dawley rats after systemic or intra-medial prefrontal cortex administration of the D1 antagonist, SCH 23390. Separate rats received intra-medial prefrontal cortex infusion of the retrograde transported label Fluoro-Gold. In rats with sham or electrolytic lesions of the medial prefrontal cortex, prepulse inhibition was tested after infusion of N-methyl-D-aspartate or vehicle into ventral hippocampus regions that were determined to send projections to the medial prefrontal cortex. Results: Prepulse inhibition was disrupted after systemic SCH 23390 treatment and after infusion of SCH 23390 into medial prefrontal cortex sites within the prelimbic and cingulate cortices. Fluoro-Gold infusion into these medial prefrontal cortex sites labeled cells in the ventral hippocampus complex, including regions CA1 and entorhinal cortex. N-methyl-D-aspartate infusions into these ventral hippocampus regions disrupted prepulse inhibition in rats after sham but not electrolytic lesions of the medial prefrontal cortex. Conclusions: Prepulse inhibition appears to be regulated by interacting substrates within the ventral hippocampus and MPFC. Specifically, NMDA activation of the ventral hippocampus appears to disrupt prepulse inhibition in a manner that is dependent on the integrity of infralimbic or cingulate cortical regions that also support a D1-mediated regulation of prepulse inhibition. Conceivably, dysfunction within these hippocampal-frontal circuits may contribute to sensorimotor gating deficits in schizophrenia. (c) 2005 IBRO. Published by Elsevier Ltd. All rights reserved.