The Nociceptin/Orphanin FQ Receptor Agonist Ro 64-6198 Reduces Alcohol Self-Administration and Prevents Relapse-Like Alcohol Drinking

Abstract

Effects of the opioid receptor like-1 (ORL-1) receptor agonist Ro 64-6198 (0.1, 0.3, and 1.0 mg/kg intraperitoneally (i.p.)) on operant ethanol self-administration and activation of self-administration by ethanol deprivation were studied in male Wistar rats. Acute administration of Ro 64-6198 caused a dose-dependent reduction of ethanol self-administration. In comparison, the opioid antagonist naltrexone (0.1, 0.3, and 1.0 mg/kg i.p.) inhibited ethanol self-administration at all doses tested. Ethanol deprivation for 10 days significantly increased ethanol self-administration during the first 2 days after deprivation. Daily pretreatment with Ro 64-6198 (0.3 mg/kg) or naltrexone (0.3 mg/kg) during the last 3 days of ethanol deprivation abolished the deprivation-induced increase in ethanol intake. Thus, stimulation of the ORL-1 receptors by Ro 64-6198 reduced the acute reinforcing effects of ethanol and prevented relapse-like behavior in the ethanol-deprivation model in a similar manner as a blockade of opioid receptors by naltrexone. Ro 64-6198 at 0.1 and 0.3 mg/kg doses did not alter self-administration of 0.2% saccharin solution, indicating an apparent selectivity of this compound in modification of ethanol reward. These findings add further support to the idea that Ro 64-6198 and potentially other synthetic ORL-1 receptor agonists are as effective as naltrexone in blocking the actions of ethanol important for its addictive potential in animal experiments, and therefore may have therapeutic value in the treatment of alcoholism. Neuropsychopharmacology (2007) 32, 902-910.

Neuropeptide Receptors as Treatment Targets in Alcohol Use Disorders

“…Our findings are in agreement with previous studies showing that NOP receptors regulate the rewarding effects of various drugs of abuse (145,302,303). Specifically, previous studies have shown that activation of NOP receptors reduces anxiety (142), attenuates alcohol self-administration as well as cue-and stress-induced reinstatement of alcohol seeking (143). Cue-and stressinduced reinstatement to drug seeking are mediated by distinct brain pathways that ultimately converge, with cue-induced reinstatement primarily mediated by the mesolimbic DA system and stress-induced reinstatement primarily mediated by CRH and noradrenaline (304,305).…”

“…These results are supported by previous findings where activation of NOP receptors decreases alcohol self-administration (141,143,298). The operant self-administration model better reflects motivation to obtain alcohol compared to home cage drinking which further strengthens these results.…”

“…Our results are in parallel support and expand on previous findings by Kuzmin and colleagues that NOP agonism potently and selectively suppresses alcohol selfadministration, motivation to seek alcohol, as well as cue-and stress-induced reinstatement of alcohol seeking (143). …”

“…It has also been demonstrated that the NOP agonist Ro64-6198 significantly blocks acquisition, expression and reinstatement of alcohol-induced CPP, self-administration and prevents relapse-like alcohol drinking (143,155). The NOP antagonist J-113397 blocks the effects of the NOP receptor agonist Ro65-6570 on the acquisition of opiateand psychostimulant-induced conditioned place preference in rats.…”

“…For example ICV administration of NOP reduced voluntary alcohol-intake in the alcohol-preferring msP rat (139)(140)(141). In addition systemic (IP) administration of the NOP receptor agonist Ro64-6198 reduced anxiety (142) and alcohol selfadministration and prevented relapse-like behavior in an alcohol deprivation model in rats (143). It has also been reported that ICV administration of nociceptin reduces the rewarding effects of several drugs of abuse in the conditioned place preference (CPP) paradigm.…”