Modification of anxiety‐like behaviors by nociceptin/orphanin FQ (N/OFQ) and time‐dependent changes in N/OFQ‐NOP gene expression following ethanol withdrawal

Abstract

Anxiety is a key consequence of ethanol withdrawal and important risk factor for relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ), or agonists at this peptide’s receptor (NOP), exert anxiolytic-like and anti-stress actions. N/OFQ dysfunction has been linked to both a high-anxiety behavioral phenotype and excessive ethanol intake. Recent studies suggest a possible link between genetic polymorphisms of the NOP transcript and alcoholism. Thus, in the present study, the effects of intracerebroventricularly (ICV) administered N/OFQ were tested for modification of anxiety-like behaviors, using the shock-probe defensive burying and elevated plus maze tests, in ethanol-dependent vs. nondependent rats, one and three weeks following termination of ethanol exposure. Additionally, Prepro-N/OFQ (ppN/OFQ) and NOP receptor gene expression was measured in the central nucleus of the amygdala, in the bed nucleus of the stria terminalis, and in the lateral hypothalamus at the same time points in separate subjects. One week post-ethanol, N/OFQ dose-dependently attenuated elevated anxiety-like behavior in ethanol-dependent rats and produced anxiolytic-like effects in nondependent controls in both behavioral tests. However, three weeks post-ethanol, N/OFQ altered behavior consistent with anxiogenic-like actions in ethanol-dependent rats, but continued to exert anxiolytic-like actions in nondependent controls. These findings were paralleled by ethanol history-dependent changes of ppN/OFQ and NOP gene expression that showed a distinctive time-course in the examined brain structures. The results demonstrate that ethanol dependence and withdrawal are associated with neuroadaptive changes in the N/OFQ-NOP system suggesting a role of this neuropeptidergic pathway as a therapeutic target for the treatment of alcohol abuse.

Low-dose Nociceptin/Orphanin FQ reduces anxiety-like performance in alcohol-withdrawn, but not alcohol-naïve, Male Wistar rats

“…Furthermore, no effect was observed in either behavioral test for either alcohol-history group at 0, 0.125, or 0.5 mg of N/OFQ. The lack of effect at 0 and 0.5 mg replicates results from a previous study in which animals were tested under similar conditions on the elevated plus-maze and defensive burying tests (Aujla et al, 2013).…”

“…In a previous study, we demonstrated a divergence in the actions of N/OFQ on open arm exploration in the elevated plus maze and duration of burying of an electrified probe in animals with or without a history of alcohol administration. Our results revealed the same dose that produced anxiolytic-like effects in controls also increased anxietylike performance in alcohol-withdrawn rats (Aujla et al, 2013).…”

“…Thus, subthreshold doses in control animals may be effective in producing anxiolytic actions in alcohol-withdrawn rats if there were increased sensitivity to the actions of N/OFQ. In the present experiment we assessed this hypothesis by examining the actions of low doses of N/OFQ in controls vs. alcohol-withdrawn rats following otherwise similar parameters to those of Aujla et al (2013). Thus, animals receiving alcohol via intragastric intubation were tested on the elevated plus maze and shock-probe defensive burying tests three weeks following the last alcohol administration after receiving 0, 0.125, 0.25 or 0.5 mg of N/OFQ.…”

Genetic Deletion of the Nociceptin/Orphanin FQ Receptor in the Rat Confers Resilience to the Development of Drug Addiction

“…Most importantly, in a series of studies carried out in our laboratories, we have found that genetically selected msP rats, that are characterized by innate predisposition to excessive drinking, have an elevated expression of N/OFQ and NOP receptor transcripts in several brain areas (Economidou et al, 2008;Hansson et al, 2006). We also observed that N/OFQ signaling is heavily affected by chronic ethanol, as evidenced by the upregulation of NOP receptor transcript in the CeA and BNST, and of the N/OFQ transcript in the BNST, in rats with a history of ethanol dependence (Aujla et al, 2013). These findings provide a link between upregulation of the NOP system and increased propensity to excessive drinking and possibly transition to a later stage of addiction.…”

Investigation of allyphenyline efficacy in the treatment of alcohol withdrawal symptoms

“…The procedure of binge alcohol exposure used in this study elicits anxiety symptoms about 6 days into withdrawal as showed by defensive burying and elevated plus maze tests (Ruggeri et al, 2010;Economidou et al, 2011;Lal et al, 1993Prather et al, 1991Aujla et al, 2013).…”