N-acetylaspartylglutamate (NAAG) inhibits intravenous cocaine self-administration and cocaine-enhanced brain-stimulation reward in rats

doi:10.1016/j.neuropharm.2009.06.016

Neuropharmacology

Volume 58, Issue 1, January 2010, Pages 304-313

https://doi.org/10.1016/j.neuropharm.2009.06.016 Get rights and content

Abstract

Pharmacological activation of group II metabotropic glutamate (mGlu2 and mGlu3) receptors inhibits reward-seeking behavior and/or rewarding efficacy induced by drugs (cocaine, nicotine) or natural rewards (food, sucrose). In the present study, we investigated whether elevation of brain N-acetylaspartylglutamate (NAAG), an endogenous group II mGlu receptor agonist, by the NAAG peptidase inhibitor 2-PMPA attenuates cocaine's rewarding effects, as assessed by intravenous cocaine self-administration and intracranial electrical brain-stimulation reward (BSR) in rats. Systemic administration of 2-PMPA (10, 30, 100 mg/kg, i.p.) or intranasal administration of NAAG (100, 300 μg/10 μl/nostril) significantly inhibited intravenous cocaine self-administration under progressive-ratio (PR), but not under fixed-ratio 2 (FR2), reinforcement conditions. In addition, 2-PMPA (1, 10, 30 mg/kg, i.p) or NAAG (50, 100 μg/10 μl/nostril) significantly inhibited cocaine-enhanced BSR, but not basal BSR. Pretreatment with LY341495 (1 mg/kg, i.p.), a selective mGlu2/3 receptor antagonist, prevented the inhibitory effects produced by 2-PMPA or NAAG in both the self-administration and BSR paradigms. In vivo microdialysis demonstrated that 2-PMPA (10, 30, 100 mg/kg) dose-dependently attenuated cocaine-enhanced extracellular dopamine (DA) in the nucleus accumbens (NAc). 2-PMPA alone inhibited basal NAc DA release, an effect that was prevented by LY341495. These findings suggest that systemic administration of 2-PMPA or intranasal administration of NAAG inhibits cocaine's rewarding efficacy and cocaine-enhanced NAc DA – likely by activation of presynaptic mGlu2/3 receptors in the NAc. These data suggest a potential utility for 2-PMPA or NAAG in the treatment of cocaine addiction.

Section snippets

Animals

Experimentally naïve male Long-Evans rats (Charles River Laboratories, Raleigh, NC, USA) weighing 250–300 g were used. They were housed individually in a climate-controlled room on a reversed light–dark cycle (lights on at 7:00 PM, lights off at 7:00 AM) with free access to food and water. The animal facility was fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International. All experimental procedures were conducted in accordance with the Guide

2-PMPA has no effect on cocaine self-administration under FR2 reinforcement

Fig. 1A illustrates representative cocaine self-administration patterns before and after 2-PMPA administration. Fig. 1B shows the total number of cocaine infusions within a 3-h session of cocaine self-administration. Pretreatment with 2-PMPA (10, 30, 100 mg/kg, i.p.) did not significantly alter i.v. cocaine self-administration (F_3,18 = 0.92, p = NS).

2-PMPA inhibits cocaine self-administration under PR reinforcement

Fig. 2A and B illustrate representative records of cocaine self-administration under PR reinforcement, indicating that 100 mg/kg 2-PMPA

Discussion

The major findings of the present study include: 1) systemic administration of 2-PMPA or intranasal administration of NAAG inhibited cocaine self-administration under PR (but not FR2) reinforcement and cocaine-enhanced BSR. Neither 2-PMPA nor NAAG alone altered BSR itself; 2) pretreatment with LY341495, a selective mGlu2/3 receptor antagonist, attenuated the action of 2-PMPA or NAAG on cocaine self-administration and cocaine-enhanced BSR; 3) 2-PMPA produced a dose-dependent reduction in both

Disclosure/Conflict of interest

All authors hereby declare that, except for income received from their respective primary employers, no financial support or compensation has been received from any individual or corporate entity over the past three years for research or professional services. There are no personal financial holdings that could be perceived as constituting a potential conflict of interest.

Acknowledgement

This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services.

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N-acetylaspartylglutamate (NAAG) inhibits intravenous cocaine self-administration and cocaine-enhanced brain-stimulation reward in rats

Abstract

Section snippets

Animals

2-PMPA has no effect on cocaine self-administration under FR2 reinforcement

2-PMPA inhibits cocaine self-administration under PR reinforcement

Discussion

Disclosure/Conflict of interest

Acknowledgement

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Int. J. Pharm.

Behav. Brain Res.

Neuropharmacology

Behav. Brain Res.

Drug Discov. Today

J. Control Release

Curr. Opin. Pharmacol.

Neuropharmacology

J. Neurosci. Methods

Biochem. Pharmacol.

Neuropharmacology

Biol. Psychiatry

Behav. Brain Res.

Neurosci. Biobehav. Rev.

Neuropharmacology

Brain Res.

Trends Pharmacol. Sci.

Pharmacol. Ther.

J. Neurosci. Methods

Drug Discov. Today

Behav. Brain Res.

Neuropharmacology

Neuropharmacology.

Brain Res.

Pharmacological stimulation of group II metabotropic glutamate receptors reduces cocaine self-administration and cocaine-induced reinstatement of drug seeking in squirrel monkeys

J. Pharmacol. Exp. Ther.

Preferential enhancement of dopamine transmission within the nucleus accumbens shell by cocaine is attributable to a direct increase in phasic dopamine release events

J. Neurosci.

Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: comparison between cocaine and a potent conventional reinforcer

J. Neurosci.

Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene

J. Neurosci.

Characterization of [3H]-(2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl)glycine ([3H]-DCG IV) binding to metabotropic mGlu2 receptor-transfected cell membranes

Br. J. Pharmacol.

Tolerance to the motor impairment, but not to the reversal of PCP-induced motor activities by oral administration of the mGlu2/3 receptor agonist, LY379268

Naunyn Schmiedebergs Arch. Pharmacol.

The neuroactive peptide N-acetylaspartylglutamate (NAAG) is not an agonist at the mGluR3 subtype of metabotropic glutamate receptor

J. Pharmacol. Exp. Ther.