Details

Autor(en) / Beteiligte

• Hicks, Callum
• Gregg, Ryan A.
• Nayak, Sunil U.
• Cannella, Lee Anne
• Schena, Giana J.
• Tallarida, Christopher S.
• Reitz, Allen B.
• Smith, Garry R.
• Rawls, Scott M.

Titel

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

Ist Teil von

• Psychopharmacology, 2017-06, Vol.234 (11), p.1671-1681

Ort / Verlag

Berlin/Heidelberg: Springer Berlin Heidelberg

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Psychology and Behavioral Sciences Collection

Beschreibungen/Notizen

• 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.