Ketamine-induced deficit of auditory gating in the hippocampus of rats is alleviated by medial septal inactivation and antipsychotic drugs.

RATIONALE: Gating of sensory responses is impaired in schizophrenic patients and animal models of schizophrenia. Ketamine, an N-methyl-D-aspartate receptor antagonist, is known to induce schizophrenic-like symptoms including sensory gating deficits in humans.
OBJECTIVE: This study aims to investigate the mechanisms underlying ketamine's effect on gating of auditory evoked potentials in the hippocampus of freely moving rats.
METHODS: Gating was measured by the ratio of the test-click response (T) to the conditioning-click response (C), or T/C, with T and C measured as peak amplitudes.
RESULTS: Ketamine (1, 3, or 6 mg/kg s.c.) injection dose-dependently increased T/C ratio as compared to saline injection (s.c.). T/C ratio was 0.48 +/- 0.05 after saline injection and 0.73 +/- 0.17 after ketamine (3 mg/kg s.c.) injection. The increase in T/C ratio after ketamine was blocked by prior inactivation of the medial septum with GABA(A) receptor agonist muscimol or by systemic administration of antipsychotic drugs, including chlorpromazine (5 mg/kg i.p.), haloperidol (1 mg/kg i.p.), or clozapine (7.5 mg/kg i.p.). Infusion of muscimol into the medial septum or injection of an antipsychotic drug alone did not affect the T/C ratio. However, rats with selective lesion of the septohippocampal cholinergic neurons by 192 IgG-saporin showed a significantly higher T/C ratio (0.86 +/- 0.10) than sham lesion rats (0.26 +/- 0.07), and ketamine did not further increase T/C ratio in rats with septohippocampal cholinergic neuron lesion.
CONCLUSIONS: Ketamine's disruption of hippocampal auditory gating was normalized by inactivation of the medial septum; in addition, septal cholinergic neurons participate in normal auditory gating.