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Glutamate carboxypeptidase II (GCPII) inhibitor 2-PMPA reduces rewarding effects of the synthetic cathinone MDPV in rats: a role for N-acetylaspartylglutamate (NAAG)

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Abstract

Rationale

Metabotropic glutamate 2 and 3 (mGluR2/3) receptors are implicated in drug addiction as they limit excessive glutamate release during relapse. N-acetylaspartylglutamate (NAAG) is an endogenous mGluR2/3 agonist that is inactivated by the glutamate carboxypeptidase II (GCPII) enzyme. GCPII inhibitors, and NAAG itself, attenuate cocaine-seeking behaviors. However, their effects on the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) have not been examined.

Objectives

We determined whether withdrawal following repeated MDPV administration alters GCPII expression in corticolimbic regions. We also examined whether a GCPII inhibitor (2-(phosphonomethyl)-pentanedioic acid (2-PMPA)), and NAAG, reduce the rewarding and locomotor-stimulant effects of MDPV in rats.

Methods

GCPII was assessed following repeated MDPV exposure (7 days). The effects of 2-PMPA and NAAG on acute MDPV-induced hyperactivity were determined using a locomotor test. We also examined the inhibitory effects of 2-PMPA and NAAG on MDPV-induced place preference, and whether the mGluR2/3 antagonist LY341495 could prevent these effects.

Results

MDPV withdrawal reduced GCPII expression in the prefrontal cortex. Systemic injection of 2-PMPA (100 mg/kg) did not affect the hyperactivity produced by MDPV (0.5–3 mg/kg). However, nasal administration of NAAG did reduce MDPV-induced ambulation, but only at the highest dose (500 μg/10 μl). We also showed that 2-PMPA (10–30 mg/kg) and NAAG (10–500 μg/10 μl) dose-dependently attenuated MDPV place preference, and that the effect of NAAG was blocked by LY341495 (3 mg/kg).

Conclusions

These findings demonstrate that MDPV withdrawal produces dysregulation in the endogenous NAAG-GCPII signaling pathway in corticolimbic circuitry. Systemic administration of the GCPII inhibitor 2-PMPA, or NAAG, attenuates MDPV reward.

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Acknowledgments

Research was funded by National Institute on Drug Abuse grants R01DA039139 and P30DA013429 to SMR, and T32DA007237 to CH.

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Authors and Affiliations

  1. Department of Pharmacology, Temple University School of Medicine, 3500 North Broad Street, Philadelphia, PA, 19140, USA

    Callum Hicks, Ryan A. Gregg, Sunil U. Nayak, Giana J. Schena, Christopher S. Tallarida & Scott M. Rawls

  2. Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA

    Callum Hicks, Ryan A. Gregg, Sunil U. Nayak, Giana J. Schena, Christopher S. Tallarida & Scott M. Rawls

  3. Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA, USA

    Lee Anne Cannella

  4. Fox Chase Chemical Diversity Center, Doylestown, PA, USA

    Allen B. Reitz & Garry R. Smith

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  1. Callum Hicks
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  2. Ryan A. Gregg
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  3. Sunil U. Nayak
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  4. Lee Anne Cannella
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  9. Scott M. Rawls
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Corresponding author

Correspondence to Scott M. Rawls.

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All experiments were conducted in accordance with the NIH Guide for the Care and Use of Laboratory Animals and Temple University’s Guidelines for the Care of Animals.

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The authors declare that they have no conflict of interest.

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Hicks, C., Gregg, R.A., Nayak, S.U. et al. Glutamate carboxypeptidase II (GCPII) inhibitor 2-PMPA reduces rewarding effects of the synthetic cathinone MDPV in rats: a role for N-acetylaspartylglutamate (NAAG). Psychopharmacology 234, 1671–1681 (2017). https://doi.org/10.1007/s00213-017-4568-y

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