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J Neurophysiol (December 8, 2004). doi:10.1152/jn.00875.2004
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Submitted on August 24, 2004
Accepted on December 4, 2004

Activation of metabotropic glutamate 2/3 (mGlu2/3) receptors reverses the effects of NMDA receptor hypofunction on prefrontal cortex unit activity in awake rats

Houman Homayoun1, Mark E. Jackson1, and Bita Moghaddam1*

1 Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA

* To whom correspondence should be addressed. E-mail: moghaddam{at}bns.pitt.edu.

Systemic exposure to NMDA receptor antagonists can lead to psychosis and prefrontal cortex (PFC)-dependent behavioral impairments. Agonists of metabotropic glutamate 2/3 (mGlu2/3) receptors ameliorate the adverse behavioral effects of NMDA antagonists in humans and laboratory animals, and are being considered as a novel treatment for some symptoms of schizophrenia. Despite the compelling behavioral data, the cellular mechanisms by which potentiation of mGlu2/3 receptor function attenuates the effects of NMDA receptor hypofunction remains unclear. In freely moving rats, we recorded the response of PFC single units to treatment with the NMDA antagonist MK801 and assessed the dose-dependent effect of pre- or post-treatment with the mGlu2/3 receptor agonist LY354740 on this response. NMDA receptor antagonist-induced behavioral stereotypy was measured during recording because it may relate to the psychotomimetic properties of this treatment and is dependent on the functional integrity of the PFC. In most PFC neurons, systemic administration of MK801 increased the spontaneous firing rate, decreased the variability of spike trains, and disrupted patterns of spontaneous bursts. Given alone, LY354740 (1, 3 and 10 mg/kg) decreased spontaneous activity of PFC neurons at the highest dose. Pre- or post-treatment with LY354740 blocked MK801-induced changes on firing rate, burst activity, and variability of spike activity. These physiological changes coincided with a reduction in MK801-induced behavioral stereotypy by LY354740. These data indicate that activation of mGlu2/3 receptors reduces the disruptive effects of NMDA receptor hypofunction on the spontaneous spike activity and bursting of PFC neurons. This mechanism may provide a physiological basis for reversal of NMDA antagonist-induced behaviors by mGlu2/3 agonists.




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