Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine

Abstract

Prepulse inhibition (PPI), a phenomenon in which a weak prestimulus decreases the startle response to an intense stimulus, provides an operational measure of sensorimotor gating (a process by which an organism filters sensory information) and is diminished in schizophrenia and schizotypal patients. The psychotomimetic phencyclidine and its potent congener dizocilpine are noncompetitive antagonists of the NMDA receptor complex, and they disrupt PPI in rodents, mimicking the clinically observed 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 disruption of PPI produced by noncompetitive NMDA antagonists in rats. PPI was measured in startle chambers immediately after bilateral infusion of dizocilpine (0, 0.25, 1.25, and 6.25 microgram/0.5 microliter/side) into one of six brain regions: amygdala, dorsal hippocampus, medial prefrontal cortex, nucleus accumbens, ventral hippocampus, and dorsomedial thalamus. Dizocilpine significantly decreased PPI after infusion into the amygdala or dorsal hippocampus. A trend toward PPI disruption was observed with administration into medial prefrontal cortex. In contrast, no change 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 regions mediate the ability of noncompetitive NMDA antagonists to disrupt PPI and that the PPI-disruptive and the startle-increasing effects of dizocilpine are mediated by different central sites.

Fig. 1.

Effects on prepulse inhibition of dizocilpine microinfusion into AM (A), DH (B), MPFC (C), VH (D), NAcc (E), and DMT (F). Error bars represent SE for each experiment. Doses are in μg/0.5 μl/side. *p < 0.05, compared with saline vehicle.

Fig. 2.

Effects on startle magnitude of dizocilpine microinfusion into AM (A), DH (B), MPFC (C), VH (D), NAcc (E), and DMT (F). Error bars represent SE for each experiment. Doses are in μg/0.5 μl/side. *p < 0.05, compared with saline vehicle.

Fig. 3.

Reconstructions of coronal cross sections depicting the location of injector tips in AM (A), DH (B), MPFC (C), VH (D), NAcc (E), and DMT (F). Eachfilled circle represents injector tip placement for a different animal. Sketches were adapted from either the atlas ofPellegrino et al. (1979) or the atlas of Paxinos and Watson (1986).

Fig. 4.

Photomicrograph of a Nissl-stained coronal section through the AM. Note the lack of necrosis or lesioning at the injection sites after dizocilpine infusion. The tissue integrity of this section is representative of that in all the other brain regions studied.