Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats. Export

@article{citeulike:6080973, abstract = {We have recently reported that the endogenous mGlu2/3 agonist N-acetylaspartylglutamate (NAAG) and the N-acetylated-alpha-linked-acidic dipepetidase (NAALADase, a NAAG degradation enzyme) inhibitor 2-PMPA significantly inhibit cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior by attenuating cocaine-enhanced extracellular dopamine and glutamate in the nucleus accumbens. However, the poor oral bioavailability of NAAG and 2-PMPA limits their practical use in humans. In the present study, we investigated the effects of the orally active NAALADase inhibitor GPI-5693 and its enantiomers on cocaine-taking and cocaine-seeking behaviors. We found that oral administration of GPI-5693 (15, 30, 60mg/kg, p.o.) did not significantly alter intravenous cocaine self-administration under fixed-ratio (FR2) reinforcement, but significantly inhibited cocaine-induced reinstatement of the extinguished drug-seeking behavior. This inhibition was blocked by pretreatment with LY341495, a selective mGlu2/3 receptor antagonist. Pretreatment with the same doses (15, 30, 60mg/kg, p.o.) of GPI-16476 or GPI-16477, two enantiomers of GPI-5693, also inhibited cocaine-induced reinstatement similar to GPI-5693. In contrast, GPI-5693 altered neither oral sucrose self-administration nor sucrose-triggered reinstatement of sucrose-seeking behavior. These data suggest that orally effective NAAG peptidase inhibitors deserve further study as potential agents for the treatment of cocaine addiction.}, author = {Peng, Xiao-Qing Q. and Li, Jie and Gardner, Eliot L. and Ashby, Charles R. and Xi, Zheng-Xiong X.}, citeulike-article-id = {6080973}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.ejphar.2009.10.062}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/19887067}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=19887067}, day = {31}, doi = {10.1016/j.ejphar.2009.10.062}, issn = {1879-0712}, journal = {European journal of pharmacology}, month = {October}, posted-at = {2009-11-06 14:22:11}, priority = {2}, title = {Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats.}, url = {http://dx.doi.org/10.1016/j.ejphar.2009.10.062}, year = {2009} }

TY - JOUR ID - citeulike:6080973 L3 - citeulike-article-id:6080973 N2 - We have recently reported that the endogenous mGlu2/3 agonist N-acetylaspartylglutamate (NAAG) and the N-acetylated-alpha-linked-acidic dipepetidase (NAALADase, a NAAG degradation enzyme) inhibitor 2-PMPA significantly inhibit cocaine self-administration and cocaine-induced reinstatement of drug-seeking behavior by attenuating cocaine-enhanced extracellular dopamine and glutamate in the nucleus accumbens. However, the poor oral bioavailability of NAAG and 2-PMPA limits their practical use in humans. In the present study, we investigated the effects of the orally active NAALADase inhibitor GPI-5693 and its enantiomers on cocaine-taking and cocaine-seeking behaviors. We found that oral administration of GPI-5693 (15, 30, 60mg/kg, p.o.) did not significantly alter intravenous cocaine self-administration under fixed-ratio (FR2) reinforcement, but significantly inhibited cocaine-induced reinstatement of the extinguished drug-seeking behavior. This inhibition was blocked by pretreatment with LY341495, a selective mGlu2/3 receptor antagonist. Pretreatment with the same doses (15, 30, 60mg/kg, p.o.) of GPI-16476 or GPI-16477, two enantiomers of GPI-5693, also inhibited cocaine-induced reinstatement similar to GPI-5693. In contrast, GPI-5693 altered neither oral sucrose self-administration nor sucrose-triggered reinstatement of sucrose-seeking behavior. These data suggest that orally effective NAAG peptidase inhibitors deserve further study as potential agents for the treatment of cocaine addiction. JF - European journal of pharmacology SN - 1879-0712 TI - Oral administration of the NAALADase inhibitor GPI-5693 attenuates cocaine-induced reinstatement of drug-seeking behavior in rats. AU - Peng, Xiao-Qing AU - Li, Jie AU - Gardner, Eliot AU - Ashby, Charles AU - Xi, Zheng-Xiong PY - 2009/10/31/ UR - http://dx.doi.org/10.1016/j.ejphar.2009.10.062 ER -