Low-dose Nociceptin/Orphanin FQ reduces anxiety-like performance in alcohol-withdrawn, but not alcohol-naïve, Male Wistar rats.

Alcohol withdrawal is associated with neuroadaptation of stress-regulatory systems, including transmission of neuropeptides that have been implicated in anxiety-like performance. Nociceptin/Orphanin FQ (N/OFQ), an endogenous neuropeptide ligand at the NOP receptor, has been implicated in stress and has previously been shown to attenuate or exacerbate anxiety-like performance in rats following a biphasic dose response function. In addition, divergent actions on anxiety-like performance have been observed in alcohol-withdrawn vs. control animals, suggesting alcohol-induced alteration of N/OFQ transmission. In order to differentiate between whether this divergence resulted from a "switch" in the actions of N/OFQ vs. increased sensitivity in N/OFQ transmission, we assessed the actions of low doses of N/OFQ (0, 0.125, 0.25, or 0.5 μg) on two tests of anxiety, the shock-probe defensive burying and elevated plus maze tests, three weeks after the termination of a six-day regimen of alcohol or vehicle administration via intragastric intubation. Consistent with increased sensitivity in N/OFQ resulting from a history of alcohol intake, administration of a low dose of N/OFQ (0.25 μg) selectively attenuated anxiety-like behaviors in animals with a history of alcohol intake while controls did not exhibit any changes in performance. The present results suggest that withdrawal from alcohol produces an enduring increase in sensitivity in N/OFQ transmission - a finding that is consistent with previous studies demonstrating altered transmission in related neuropeptide systems.