Abstract
Growing evidence suggests a role for metabotropic glutamate receptors (mGluRs) in the behavioral effects of cocaine related to its abuse. The mGluR5 subtype, in particular, has come under scrutiny due to its distribution in brain regions associated with drug addiction. This study investigated interactions between the selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) and cocaine in squirrel monkeys whose lever-pressing behavior was 1) maintained under a second-order schedule of cocaine self-administration, 2) extinguished and then reinstated by cocaine priming, and 3) controlled by the discriminative stimulus (DS) effects of cocaine. Additional studies determined the effects of MPEP on unconditioned behaviors, coordination, and muscle resistance. In each experiment, the effects of MPEP were compared with those of the N-methyl-d-aspartate antagonist dizocilpine. MPEP attenuated cocaine self-administration, cocaine-induced reinstatement of drug seeking, and the DS effects of cocaine at doses that did not markedly impair motor function or operant behavior in the context of drug discrimination. Dizocilpine also attenuated cocaine self-administration, but it did not significantly alter cocaine-induced reinstatement of drug seeking, and it enhanced rather than attenuated the DS effects of cocaine. The findings point to a significant contribution of mGluR5 mechanisms in the behavioral effects of cocaine related to its abuse and suggest that MPEP has properties of a functional cocaine antagonist, which are not secondary to antagonism at NMDA receptors. The contrasting interactions of MPEP and dizocilpine with cocaine imply that glutamate acting through different metabotropic and ionotropic receptors may modulate the behavioral effects of cocaine in qualitatively different ways.
Footnotes
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↵1 Current address: Laboratory of Molecular Neuroimaging, UCLA, Los Angeles, CA.
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This research was supported by National Institute on Drug Abuse Grants DA17700 and DA11054 and the National Institute for Research Resources Grant RR00168.
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doi:10.1124/jpet.104.078733.
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ABBREVIATIONS: iGluR, ionotropic glutamate receptor; NMDA, N-methyl-d-aspartate; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; mGluR, metabotropic glutamate receptor; MPEP, 2-methyl-6-(phenylethynyl)-pyridine; DS, discriminative stimulus; FI, fixed interval; FR, fixed ratio; NET, norepinephrine transport.
- Received October 1, 2004.
- Accepted November 16, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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