NOP receptor antagonism reduces alcohol drinking in male and female rats through mechanisms involving the central amygdala and ventral tegmental area.

Background and Purpose: Nociceptin/orphanin FQ (N/OFQ) peptide and its cognate receptor (NOP) are widely expressed in mesolimbic brain regions where they play an important role in modulating reward and motivation. Early evidence suggested that NOP receptor activation attenuates the rewarding effects of drugs of abuse, including alcohol. However, emerging data indicate that NOP receptor blockade also effectively attenuates alcohol drinking and relapse. To advance our understanding of the role of the N/OFQ-NOP receptor system in alcohol abuse, we examined the effect of NOP receptor blockade on voluntary alcohol drinking at the neurocircuitry level.
Experimental Approach: Using male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats, we initially evaluated the effects of the selective NOP receptor antagonist LY2817412 (3, 10, and 30 mg·kg ^-1 , p.o.) on alcohol consumption in a two-bottle free-choice paradigm. We then microinjected LY2817412 (3 and 6 μg·μl ^-1 per rat) in the central nucleus of the amygdala (CeA), ventral tegmental area (VTA), and nucleus accumbens (NAc).
Key Results: Peripheral LY2817412 administration dose-dependently and selectively reduced voluntary alcohol intake in male and female msP rats. Central injections of LY2817412 markedly attenuated voluntary alcohol intake in both sexes following administration in the CeA and VTA but not in the NAc.
Conclusion and Implications: The present results revealed that the CeA and VTA are neuroanatomical substrates that mediate the effects of NOP receptor antagonism on alcohol consumption. Overall, our findings support the potential of NOP receptor antagonism as a treatment strategy to attenuate alcohol use and addiction.
(© 2019 The British Pharmacological Society.)