Chronic Treatment with Novel Brain-Penetrating Selective NOP Receptor Agonist MT-7716 Reduces Alcohol Drinking and Seeking in the Rat
| Autor: | Marisa Roberto, Serena Stopponi, Hiroshi Kinoshita, Koji Teshima, Daina Economidou, Makoto Kuriyama, Markus Heilig, Friedbert Weiss, Roberto Ciccocioppo |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Agonist
Male Liquid diet Alcohol Drinking medicine.drug_class Narcotic Antagonists NOP Drug-Seeking Behavior Pharmacology Choice Behavior Naltrexone Nociceptin Receptor medicine Animals Humans Rats Wistar Receptor Opioid peptide Dose-Response Relationship Drug business.industry Acenaphthenes Rats Substance Withdrawal Syndrome Psychiatry and Mental health Nociceptin receptor HEK293 Cells Opioid Peptides Alcohol Deterrents Receptors Opioid Original Article Benzimidazoles business Stress Psychological medicine.drug |
| Popis: | Since its discovery, the nociceptin/orphanin FQ (N/OFQ)-NOP receptor system has been extensively investigated as a promising target to treat alcoholism. Encouraging results obtained with the endogenous ligand N/OFQ stimulated research towards the development of novel brain-penetrating NOP receptor agonists with a pharmacological and toxicological profile compatible with clinical development. Here we describe the biochemical and alcohol-related behavioral effects of the novel NOP receptor agonist MT-7716. MT-7716 has high affinity for human NOP receptors expressed in HEK293 cells with a Ki value of 0.21 nM. MT-7716 concentration-dependently stimulated GTPγ(35)S binding with an EC50 value of 0.30 nM and its efficacy was similar to N/OFQ, suggesting that MT7716 is a full agonist at NOP receptors. In the two bottle choice test MT-7716 (0, 0.3, 1, and 3 mg/kg, bid) given orally for 14 days dose-dependently decreased voluntary alcohol intake in Marchigian Sardinian rats. The effect became gradually stronger following repeated administration, and was still significant 1 week after discontinuation of the drug. Oral naltrexone (30 mg/kg, bid) for 14 days also reduced ethanol intake; however, the effect decreased over the treatment period and rapidly disappeared when drug treatment was discontinued. MT-7716 is also effective for preventing reinstatement caused by both ethanol-associated environmental stimuli and stress. Finally, to investigate the effect of MT-7716 on alcohol withdrawal symptoms, Wistar rats were withdrawn from a 7-day alcohol liquid diet. MT-7716 significantly attenuated somatic alcohol withdrawal symptoms. Together these findings indicate that MT-7716 is a promising candidate for alcoholism treatment remaining effective with chronic administration. |
| Databáze: | OpenAIRE |
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