MULTIPLE LIMBIC REGIONS MEDIATE THE DISRUPTION OF PREPULSE INHIBITIONPRODUCED IN RATS BY THE NONCOMPETITIVE NMDA ANTAGONIST DIZOCILPINE

Prepulse inhibition (PPI), a phenomenon in which a weak prestimulus de creases the startle response to an intense stimulus, provides an opera tional measure of sensorimotor gating (a process by which an organism filters sensory information) and is diminished in schizophrenia and sc hizotypal patients. The psychotomimetic phencyclidine and its potent c ongener dizocilpine are noncompetitive antagonists of the NMDA recepto r complex, and they disrupt PPI in rodents, mimicking the clinically o bserved PPI deficit. The neuroanatomical substrates mediating the PPI- disruptive effects of noncompetitive NMDA antagonists are unknown. The present study sought to identify brain regions subserving the disrupt ion of PPI produced by noncompetitive NMDA antagonists in rats. PPI wa s measured in startle chambers immediately after bilateral infusion of dizocilpine (0, 0.25, 1.25, and 6.25 mu g/0.5 mu l/side) into one of six brain regions: amygdala, dorsal hippocampus, medial prefrontal cor tex, nucleus accumbens, ventral hippocampus, and dorsomedial thalamus. Dizocilpine significantly decreased PPI after infusion into the amygd ala or dorsal hippocampus. A trend toward PPI disruption was observed with administration into medial prefrontal cortex. In contrast, no cha nge in PPI was produced by dizocilpine infusion into nucleus accumbens , ventral hippocampus, or dorsomedial thalamus. Startle reactivity was increased by dizocilpine infusion into amygdala, dorsal hippocampus, nucleus accumbens, and dorsomedial thalamus, but not medial prefrontal cortex. These findings indicate that multiple limbic forebrain region s mediate the ability of noncompetitive NMDA antagonists to disrupt PP I and that the PPI-disruptive and the startle-increasing effects of di zocilpine are mediated by different central sites.