Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Apr;177(7):1525-1537.
doi: 10.1111/bph.14915. Epub 2020 Feb 3.

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

Anna Maria Borruto  1 , Yannick Fotio  1 , Serena Stopponi  1 , Gloria Brunori  1   2 , Michele Petrella  1 , Francesca Felicia Caputi  3 , Patrizia Romualdi  3 , Sanzio Candeletti  3 , Rajesh Narendran  4   5 , Linda M Rorick-Kehn  6 , Massimo Ubaldi  1 , Friedbert Weiss  7 , Roberto Ciccocioppo  1
Affiliations

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

Anna Maria Borruto et al. Br J Pharmacol. 2020 Apr.

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

The authors have no conflict of interest with the subject matter or materials discussed in the manuscript.

Figures

Figure 1
Figure 1
Effect of systemic LY2817412 administration on voluntary alcohol drinking in male and female msP rats. Male (n = 11) and female (n = 10) msP rats were subjected to a two‐bottle free‐choice (2BC) test. Following treatment with LY2817412 (3, 10, and 30 mg·kg−1) or vehicle, the voluntary intake of (a) alcohol, (b) water, and (c) food was recorded at 2, 8, and 24 hr in male and female msP rats. The data are expressed as mean ± SEM. * P < .05, significantly different from vehicle; # P < .05, significant difference between males and females; three‐way ANOVA followed by Newman–Keuls post hoc test)
Figure 2
Figure 2
Effect of intra‐CeA microinjection of LY2817412 on voluntary alcohol drinking in male and female msP rats. Male (n = 8) and female (n = 7) msP rats were implanted with bilateral cannulas in the CeA and then subjected to a two‐bottle free‐choice test. Following treatment with LY2817412 (3 and 6 μg·μl−1 per rat) or vehicle, the voluntary intake of (a) alcohol, (b) water, and (c) food was recorded at 2 hr in male and female msP rats. The data are expressed as mean ± SEM. * P < .05, significantly different from vehicle; two‐way ANOVA followed by Newman–Keuls post hoc test
Figure 3
Figure 3
Effect of intra‐VTA microinjections of LY2817412 on voluntary alcohol drinking in male and female msP rats. Male (n = 9) and female (n = 8) msP rats were implanted with bilateral cannulas in the VTA and then subjected to a two‐bottle free‐choice test. Following treatment with LY2817412 (3 and 6 μg·μl−1 per rat) or vehicle, the voluntary intake of (a) alcohol, (b) water, and (c) food was recorded 2 hr after drinking onset in both male and female msP rats. The data are expressed as mean ± SEM. * P < .05, significantly different from vehicle; two‐way ANOVA followed by Newman–Keuls post hoc test
Figure 4
Figure 4
Effect of intra‐NAc microinjections of LY2817412 on voluntary alcohol drinking in male and female msP rats. Male (n = 8) and female (n = 9) msP rats were implanted with bilateral cannulas in the NAc and then subjected to a two‐bottle free‐choice test. Following treatment with LY2817412 (3 and 6 μg·μl−1 per rat) or vehicle, the voluntary intake of (a) alcohol, (b) water, and (c) food was recorded at 2 hr in both male and female msP rats. The data are expressed as mean ± SEM. No significant effects of LY2817412 were observed; two‐way ANOVA followed by Newman–Keuls post hoc test
See this image and copyright information in PMC

References

    1. Alexander, S. P. H. , Christopoulos, A. , Davenport, A. P. , Kelly, E. , Mathie, A. , Alistair, P. , … CGTP Collaborators (2019). THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: G protein‐coupled receptors. British Journal of Pharmacology, 176, S21–S141. 10.1111/bph.14748 - DOI - PMC - PubMed
    1. Aujla, H. , Cannarsa, R. , Romualdi, P. , Ciccocioppo, R. , Martin‐Fardon, R. , & Weiss, F. (2013). Modification of anxiety‐like behaviors by nociceptin/orphanin FQ (N/OFQ) and time‐dependent changes in N/OFQ‐NOP gene expression following ethanol withdrawal. Addiction Biology, 18, 467–479. 10.1111/j.1369-1600.2012.00466.x - DOI - PMC - PubMed
    1. Aziz, A. M. , Brothers, S. , Sartor, G. , Holm, L. , Heilig, M. , Wahlestedt, C. , & Thorsell, A. (2016). The nociceptin/orphanin FQ receptor agonist SR‐8993 as a candidate therapeutic for alcohol use disorders: Validation in rat models. Psychopharmacology, 233, 3553–3563. 10.1007/s00213-016-4385-8 - DOI - PMC - PubMed
    1. Becker, H. C. , & Lopez, M. F. (2004). Increased ethanol drinking after repeated chronic ethanol exposure and withdrawal experience in C57BL/6 mice. Alcoholism, Clinical and Experimental Research, 28, 1829–1838. - PubMed
    1. Bunzow, J. R. , Saez, C. , Mortrud, M. , Bouvier, C. , Williams, J. T. , Low, M. , & Grandy, D. K. (1994). Molecular cloning and tissue distribution of a putative member of the rat opioid receptor gene family that is not a μ, δ or κ opioid receptor type. FEBS Letters, 347, 284–288. 10.1016/0014-5793(94)00561-3 - DOI - PubMed

Publication types