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Effects of GABA-B receptor positive modulator on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in freely moving rats

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Abstract

Rationale

Decreased GABAB receptor function is proposed to mediate some symptoms of schizophrenia.

Objectives

In this study, we tested the effect of CGP7930, a GABAB receptor positive allosteric modulator, on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in behaving rats.

Methods

Electrodes were bilaterally implanted into the hippocampus, and cannulae were placed into the lateral ventricles of Long-Evans rats. CGP7930 or vehicle was injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.), alone or 15 min prior to ketamine (3 mg/kg, subcutaneous) injection. Paired click auditory evoked potentials in the hippocampus (AEP), prepulse inhibition (PPI), and locomotor activity were recorded before and after drug injection.

Results

CGP7930 at doses of 1 mg/kg (i.p.) prevented ketamine-induced deficit of PPI. CGP7930 (1 mg/kg i.p.) also prevented the decrease in gating of hippocampal AEP and the increase in hippocampal gamma (65–100 Hz) waves induced by ketamine. Unilateral i.c.v. infusion of CGP7930 (0.3 mM/1 μL) also prevented the decrease in gating of hippocampal AEP induced by ketamine. Ketamine-induced behavioral hyperlocomotion was suppressed by 5 mg/kg i.p. CGP7930. CGP7930 alone, without ketamine, did not significantly affect integrated PPI, locomotion, gating of hippocampal AEP, or gamma waves. CGP7930 (1 mg/kg i.p.) increased heterosynaptically mediated paired pulse depression in the hippocampus, a measure of GABAB receptor function in vivo.

Conclusions

CGP7930 reduces the behavioral and electrophysiological disruptions induced by ketamine in animals, and the hippocampus may be one of the neural targets where CGP7930 exerts its actions.

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Acknowledgements

The research was financially supported by operating grants from the Natural Sciences and Engineering Research Council of Canada (1037-2013), the Canadian Institutes of Health Research (MOP-15685), and EpLink, the Epilepsy Research Program of the Ontario Brain Institute.

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  1. Department of Physiology and Pharmacology, The University of Western Ontario, Medical Sciences Building, London, ON, N6A 5C1, Canada

    Jingyi Ma & L. Stan Leung

  2. Graduate Program in Neuroscience, The University of Western Ontario, London, N6A 5C1, Canada

    L. Stan Leung

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Ma, J., Stan Leung, L. Effects of GABA-B receptor positive modulator on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in freely moving rats. Psychopharmacology 234, 3129–3142 (2017). https://doi.org/10.1007/s00213-017-4705-7

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