1. ¹Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
2. ²Department of Psychiatry, Yale University, New Haven, CT, USA

Correspondence: B Moghaddam, Department of Neuroscience, 446 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260, USA. Tel: +1 412 624 2653; Fax: +1 412 624 9198; E-mail: bita@pitt.edu

Received 22 October 2003; Revised 17 December 2003; Accepted 13 January 2004; Published online 10 March 2004.

Abstract

Pharmacological manipulation of N-methyl-D-aspartate (NMDA) receptors may be critical for the treatment of many neurological and psychiatric disorders. Metabotropic glutamate (mGlu5) receptors are abundant in corticolimbic circuitry, where they modulate NMDA receptor-mediated signal transduction. Therefore, pharmacological manipulation of mGlu5 receptor may provide a treatment strategy for cognitive disorders that are associated with NMDA receptor dysfunction. We sought to determine whether the recently described molecular and cellular interactions between NMDA and mGlu5 receptors coregulate higher order behaviors. We examined the interaction of the selective mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and the use-dependent NMDA antagonist MK-801, on locomotion, stereotypy, working memory, instrumental learning, and corticolimbic dopamine release. MPEP, at 10 mg/kg, but not 3 mg/kg, impaired working memory and instrumental learning, transiently increased dopamine release in prefrontal cortex and nucleus accumbens, and augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with 3 mg/kg of MPEP enhanced the detrimental effects of MK-801 on cognition. These results demonstrate that an mGlu5 receptor antagonist can potentiate the motoric, cognitive, and dopaminergic effects of an NMDA receptor antagonist. Thus, mGlu5 receptors appear to play a major role in regulating NMDA receptor-dependent cognitive functions such as learning and working memory. By extension, these results suggest that pharmacological potentiation of mGlu5 receptors may ameliorate the cognitive and other behavioral abnormalities associated with NMDA receptor deficiency.