Inhibition of NAALADase by 2‐PMPA attenuates cocaine‐induced relapse in rats: a NAAG‐mGluR2/3‐mediated mechanism

Abstract

Pharmacological activation of group II metabotropic glutamate receptors (mGluR2/3) inhibits cocaine self‐administration and reinstatement of drug‐seeking behavior, suggesting a possible use of mGluR2/3 agonists in the treatment of cocaine dependence. In this study, we investigated whether elevation of the endogenous mGluR2/3 ligand N‐acetyl‐aspartatylglutamate (NAAG) levels by the N‐acetylated‐alpha‐linked‐acidic dipeptidase inhibitor 2‐(phosphonomethyl)pentanedioic acid (2‐PMPA) attenuates cocaine self‐administration and cocaine‐induced reinstatement of drug seeking. N‐acetylated‐alpha‐linked‐acidic dipeptidase is a NAAG degradation enzyme that hydrolyzes NAAG to N‐acetylaspartate and glutamate. Systemic administration of 2‐PMPA (10‐100 mg/kg, i.p.) inhibited intravenous self‐administration maintained by low unit doses of cocaine and cocaine (but not sucrose)‐induced reinstatement of drug‐seeking behavior. Microinjections of 2‐PMPA (3–5 μg/side) or NAAG (3–5 μg/side) into the nucleus accumbens (NAc), but not into the dorsal striatum, also inhibited cocaine‐induced reinstatement, an effect that was blocked by intra‐NAc injection of LY341495, a selective mGluR2/3 antagonist. In vivo microdialysis demonstrated that 2‐PMPA (10‐100 mg/kg, i.p.) produced a dose‐dependent reduction in both extracellular dopamine (DA) and glutamate, an effect that was also blocked by LY341495. Finally, pre‐treatment with 2‐PMPA partially attenuated cocaine‐enhanced extracellular NAc DA, while completely blocking cocaine‐enhanced extracellular NAc glutamate in rats during reinstatement testing. Intra‐NAc perfusion of LY341495 blocked 2‐PMPA‐induced reductions in cocaine‐enhanced extracellular NAc glutamate, but not DA. These findings suggest that 2‐PMPA is effective in attenuating cocaine‐induced reinstatement of drug‐seeking behavior, likely by attenuating cocaine‐induced increases in NAc DA and glutamate via pre‐synaptic mGluR2/3s.

Glutamate in CNS Neurodegeneration and Cognition and its Regulation by GCPII Inhibition

“…Many preclinical and clinical studies have been conducted with the purpose of exploring GCPII regulation strategies for pathological CNS disorders. Inhibition of GCPII has demonstrated beneficial and dose-dependent neuroprotective properties in models of inflammatory and neuropathic pain [152][153][154][155][156][157][158][159][160][161][162][163][164][165][166] brain ischemia [167][168][169][170][171] motor neuron disease [172] spinal cord and traumatic brain injury [173][174][175], peripheral neuropathy [156,161,176,177], epilepsy [178] and drug abuse [179][180][181][182][183][184][185]. Inhibition of GCPII in in vitro and in vivo models of injury cause an increase in extracellular NAAG concentration and a decrease in extracellular glutamate concentration [108].…”

Addiction and Brain Reward and Antireward Pathways

“…The facts that glutamate circuits innervate and modulate brain reward mechanisms [253–260], and that glutamatergic circuits mediate at least some forms of relapse to drug-seeking behavior [164,165], make the development of drugs acting on the glutamate circuitry of the brain attractive as potential anti-addiction medications [41,261–265]. …”

Distinct Neurochemical Adaptations Within the Nucleus Accumbens Produced by a History of Self-Administered vs Non-Contingently Administered Intravenous Methamphetamine

“…However, in the majority of studies of rats with a history of self-administered cocaine, the cocaine-induced rise in NAC glutamate is very rapid in onset whether micordialysis is performed during subsequent IV self-administration (Miguens et al, 2008;Suto et al, 2010) or before an IP cocaine challenge, following some form of extinction training regardless of testing environment (in the self-administration context: Baker et al, 2003;Li et al, 2010Madayag et al, 2010;Miguens et al, 2008;Xi et al, 2010; or in a neutral context: Kippin et al, 2008;Xi et al, 2006). In studies where the cocaine is self-administered (Miguens et al, 2008;Suto et al, 2010), the cocaine-induced rise in NAC glutamate is maintained, whereas in studies where the cocaine challenge was administered IP to animals with a cocaine self-administration and extinction history, the glutamate rise is transient (Baker et al, 2003;Kippin et al, 2008;Li et al, 2010;McFarland et al, 2003;Xi et al, 2006Xi et al, , 2010; but see also Madayag et al, 2010) and can be blocked completely by N-acetyl-cystine pretreatment (Baker et al, 2003), suggesting a critical role for non-neuronal glutamate sources in this regard (Baker et al, 2002). Although the source of glutamate undergoing methamphetamine-induced plasticity on self-administration remains to be determined, it is clear from the present data that this source is heavily influenced by factors related to the act of drug-taking.…”