title: MT-7716, a potent NOP receptor agonist, preferentially reduces ethanol seeking and reinforcement in post-dependent rats.
abstract: Dysregulation of the nociceptin (N/OFQ) system has been implicated in alcohol abuse and alcoholism, and growing evidence suggests that targeting this system may be beneficial for treating alcoholism. To further explore the treatment target potential of the N/OFQ system, the novel non-peptide, small-molecule N/OFQ (NOP) agonist MT-7716, (R)-2-{3-[1-(Acenaphthen-1-yl)piperidin-4-yl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-N-methylacetamide hydrochloride hydrate, was examined for its effects on ethanol self-administration and stress-induced reinstatement of alcohol seeking in non-dependent and post-dependent rats. Male Wistar rats were trained to self-administer ethanol and then made ethanol dependent via repeated intragastric ethanol intubation. The effects of MT-7716 (0.3 and 1 mg/kg; PO) on alcohol self-administration were determined 2 weeks following dependence induction, when baseline self-administration was restored. Effects of MT-7716 on stress-induced reinstatement were tested in separate cohorts of rats, 1 and 3 weeks post-withdrawal. MT-7716 reduced alcohol self-administration and stress-induced reinstatement of alcohol seeking in post-dependent rats, but was ineffective in non-dependent animals. Moreover, the prevention of stress-induced reinstatement by MT-7716 was more pronounced at 3 weeks post-dependence. The results further confirm treatment target potential for the NOP receptor and identify non-peptide NOP agonists as promising potential treatment drugs for alcohol abuse and relapse prevention. The findings also support dysregulation of the N/OFQ system as a factor in alcohol seeking and reinforcement.
authors.affiliation: Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA.|School of Pharmacy, Pharmacology Unit, University of Camerino, Italy.
authors.forename: Giordano
authors.initials: G
authors.lastname: de Guglielmo
authors.affiliation: Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Rémi
authors.initials: R
authors.lastname: Martin-Fardon
authors.affiliation: Department II (CNS), Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Teshima
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
authors.affiliation: Molecular and Cellular Neuroscience Department, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Friedbert
authors.initials: F
authors.lastname: Weiss
mesh_terms: D000073:Acenaphthenes / Q000494:pharmacology*; D000437:Alcoholism / Q000097:blood / Q000517:prevention & control*; D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D003216:Conditioning, Operant; D058999:Drug-Seeking Behavior / Q000187:drug effects; D000431:Ethanol / Q000378:metabolism; D008297:Male; D009292:Narcotic Antagonists / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects; D018847:Opioid Peptides / Q000037:antagonists & inhibitors*; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000187:drug effects; D012054:Reinforcement, Psychology; D012646:Self Administration; D013315:Stress, Psychological / Q000523:psychology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000073:Acenaphthenes; D001562:Benzimidazoles; D000431:Ethanol; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C000598520:2-(3-(1-(acenaphthen-1-yl)piperidin-4-yl)-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-N-methylacetamide; C000722285:Oprl1 protein, rat
keywords: Addiction; MT-7716; alcohol; nociceptin/orphanin FQ; reinstatement; self-administration; stress