Neuropeptide Y Y5 Receptor Antagonism Causes Faster Extinction and Attenuates Reinstatement in Cocaine-Induced Place Preference.

Neuropeptide Y Y5 receptor antagonism causes faster extinction and attenuates reinstatement in cocaine-induced place preference.

Pharmacol Biochem Behav. 2013 Feb 26;
Sørensen G, Wörtwein G, Fink-Jensen A, Woldbye DP

Several studies have suggested a role for neuropeptide Y (NPY) in addiction to drugs of abuse, including cocaine. Recently, our group showed a role for the NPY Y5 receptor in the modulation of acute reinforcing effects of cocaine using self-stimulation and hyperlocomotion paradigms. In the present study, we further explored potential anti-addiction-related effects of Y5 antagonism in another murine model of cocaine addiction-related behavior: conditioned place-preference (CPP). Using this model, it was tested whether blockade or deficiency of the NPY Y5 receptor could influence the induction, extinction or reinstatement of a conditioned cocaine response. We found that the Y5 antagonist L-152,804 causes faster extinction and reduced reinstatement of cocaine-induced CPP but did not reduce the ability of cocaine to induce CPP. Similarly, Y5-KO mice displayed faster extinction, and reinstatement of cocaine-induced CPP was absent. The development of CPP for cocaine was similar between Y5-KO and WT mice. Taken together, the present data confirm that Y5 antagonism attenuates relapse to cocaine addiction-related behavior. Prevention of relapse is considered to be of pivotal importance for the development of an effective treatment against cocaine addiction and therefore Y5 receptors could be a potential future therapeutic target in cocaine addiction. HubMed – addiction


Design and Functional Evaluation of an Optically Active ?-Opioid Receptor.

Eur J Pharmacol. 2013 Feb 26;
Barish PA, Xu Y, Li J, Sun J, Jarajapu YP, Ogle WO

The use of opioids, which achieve therapeutic analgesia through activation of ?-opioid receptors, are limited in the management of chronic pain by adverse effects including tolerance and addiction. Optogenetics is an emerging approach of designing molecular targets that can produce cell-specific receptor-mediated analgesia with minimal side effects. Here we report the design and functional characterization of a chimeric ?-opioid receptor that could be photoactivated to trigger intracellular signaling. A prototype optoactive ?-opioid receptor (optoMOR) was designed by replacing the intracellular domains from rhodopsin with those of the native ?-opioid receptor and was transiently expressed in human embryonic kidney (HEK293) cells. Expression and distribution of the protein were confirmed by immunocytochemistry. The signal-transduction mechanisms induced by photoactivation of the optoMOR were evaluated and compared with the native ?-opioid receptor stimulation by an agonist, D-Ala2, N-MePhe4, Gly-ol-enkephalin (DAMGO). Cells were depolarized by extracellular potassium and the depolarization-induced calcium (Ca2+) influx was quantified by using Fura-2 imaging. The forskolin-stimulated adenylate cyclase/cAMP cascade was evaluated by ELISA or western blotting of brain-derived neurotrophic factor (BDNF) and the phosphorylation of cAMP response element binding protein (CREB). The optoMOR protein distribution was observed intracellularly and on the plasma membrane similar to the native ?-opioid receptor in HEK293 cells. Photoactivation of optoMOR decreased the Ca2+ influx and inhibited the forskolin-induced cAMP generation, activation of CREB, and BDNF levels in optoMOR-expressing cells similar to the activation of native ?-opioid receptor by DAMGO. Thus the current study has accomplished the design of a prototype optoMOR and characterized the cellular signaling mechanisms activated by light stimulation of this receptor. HubMed – addiction


Low frequency genetic variants in the mu-opioid receptor (OPRM1) affect risk for addiction to heroin and cocaine.

Neurosci Lett. 2013 Feb 20;
Clarke TK, Crist RC, Kampman KM, Dackis CA, Pettinati HM, O’Brien CP, Oslin DW, Ferraro TN, Lohoff FW, Berrettini WH

The ?-opioid receptor (MOR) binds exogenous and endogenous opioids and is known to mediate the rewarding effects of drugs of abuse. Numerous genetic studies have sought to identify common genetic variation in the gene encoding MOR (OPRM1) that affects risk for drug addiction. The purpose of this study was to examine the contribution of rare coding variants in OPRM1 to the risk for addiction. Rare and low frequency variants were selected using the National Heart Lung and Blood Institute-Exome Sequencing Project (NHLBI-ESP) database, which has screened the exomes of over 6500 individuals. Two SNPs (rs62638690 and rs17174794) were selected for genotyping in 1377 European American individuals addicted to heroin and/or cocaine. Two different SNPs (rs1799971 and rs17174801) were genotyped in 1238 African American individuals addicted to heroin and/or cocaine. Using the minor allele frequencies from the NHLBI-ESP dataset as a comparison group, case-control association analyses were performed. Results revealed an association between rs62638690 and cocaine and heroin addiction in European Americans (p=0.02; 95% C.I. 0.47 [0.24-0.92]). This study suggests a potential role for rare OPRM1 variants in addiction disorders and highlights an area worthy of future study. HubMed – addiction



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