Ketamine-induced deficit of auditory gating in the hippocampus of rats is alleviated by medial septal inactivation and antipsychotic drugs.
BACKGROUND
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.
Ma
Jingyi
J
Department of Physiology and Pharmacology, Medical Sciences Building, The University of Western Ontario, London, ON, Canada N6A 5C1. jma2@uwo.ca
Tai
Siew Kian
SK
Leung
L Stan
LS
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005072:Evoked Potentials, Auditory / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D018755:GABA Agonists / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007279:Injections, Subcutaneous; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D020665:Septum of Brain / Q000378:metabolism
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D009118:Muscimol; D007649:Ketamine