PRESYNAPTIC DOPAMINE-GLUTAMATE INTERACTIONS IN THE NUCLEUS-ACCUMBENS REGULATE SENSORIMOTOR GATING

Prepulse inhibition (PPI) is the normal reduction in startle reflex th at occurs when a startling stimulus is preceded by a weak prepulse. PP I is reduced in patients with schizophrenia and in rats after central dopamine (DA) activation. The DA agonist-induced disruption of PPI in rats may thus model some features of impaired sensorimotor gating in s chizophrenia. Ascending DAergic and descending glutamatergic fibers co nverge within the nucleus accumbens (NAG), and interactions at this DA -glutamate interface have been implicated in the pathophysiology of sc hizophrenia. In this study, we examined the role of NAC DA-glutamate i nteractions in the regulation of PPI in rats. Intra-NAC infusion of th e non-NMDA antagonist, CNQX, attenuated the PPI-disruptive effects of d-amphetamine (AMPH), but CNQX did not affect PPI when injected alone, nor did it reverse the PPI-disruptive effects of the direct D-2/D-3 a gonist quinpirole. Intra-NAC infusion of the non-NMDA agonist AMPA sig nificantly reduced PPI. The PPI-disruptive effects of AMPA were blocke d by haloperidol and by 6-hydroxydopamine (60HDA) lesions of the NAG. These data suggest that the PPI-disruptive effects of AMPH are depende nt on tonic non-NMDA receptor activation in the NAG, and that non-NMDA receptor activation in the NAC results in a DA-dependent reduction in PPI. The parsimonious interpretation of these data is that non-NMDA g lutamate receptors in the NAC facilitate presynaptic DA function, and that this DA-glutamate interaction is a critical regulatory substrate of sensorimotor gating.