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NOP receptor antagonism attenuates reinstatement of alcohol-seeking through modulation of the mesolimbic circuitry in male and female alcohol-preferring rats

Abstract

In patients suffering from alcohol use disorder (AUD), stress and environmental stimuli associated with alcohol availability are important triggers of relapse. Activation of the nociceptin opioid peptide (NOP) receptor by its endogenous ligand Nociceptin/Orphanin FQ (N/OFQ) attenuates alcohol drinking and relapse in rodents, suggesting that NOP agonists may be efficacious in treating AUD. Intriguingly, recent data demonstrated that also blockade of NOP receptor reduced alcohol drinking in rodents. To explore further the potential of NOP antagonism, we investigated its effects on the reinstatement of alcohol-seeking elicited by administration of the α2 antagonist yohimbine (1.25 mg/kg, i.p.) or by environmental conditioning factors in male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The selective NOP receptor antagonist LY2817412 (0.0, 3.0, 10.0, and 30.0 mg/kg) was first tested following oral (p.o.) administration. We then investigated the effects of LY2817412 (1.0, 3.0, 6.0 μg/μl/rat) microinjected into three candidate mesolimbic brain regions: the ventral tegmental area (VTA), the central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc). We found that relapse to alcohol seeking was generally stronger in female than in male rats and oral administration of LY2817412 reduced yohimbine- and cue-induced reinstatement in both sexes. Following site-specific microinjections, LY2817412 reduced yohimbine-induced reinstatement of alcohol-seeking when administered into the VTA and the CeA, but not in the NAc. Cue-induced reinstatement was suppressed only when LY2817412 was microinjected into the VTA. Infusions of LY2817412 into the VTA and the CeA did not alter saccharin self-administration. These results demonstrate that NOP receptor blockade prevents the reinstatement of alcohol-seeking through modulation of mesolimbic system circuitry, providing further evidence of the therapeutic potential of NOP receptor antagonism in AUD.

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Fig. 1: Effect of Systemic Administration of LY2817412 on Yohimbine-Induced Reinstatement of Alcohol Seeking in Male and Female msP Rats.
Fig. 2: Effect of Systemic Administration of LY2817412 on Cue-Induced Reinstatement of Alcohol-Seeking in Male and Female msP Rats.
Fig. 3: Effect of Intra-VTA, Intra-CeA and Intra-NAc Administration of LY2817412 on Yohimbine‐Induced Reinstatement of Alcohol Seeking in Male and Female msP rats.
Fig. 4: Effect of Intra-VTA, Intra-CeA and Intra-NAc Administration of LY2817412 on Cue‐Induced Reinstatement of Alcohol Seeking in Male and Female msP rats.
Fig. 5: Effect of Intra-VTA and Intra-CeA Administration of LY2817412 on Saccharin Self-Administration in Male and Female msP rats.

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Acknowledgements

We wish thank Linda M. Rorick-Kehn for the scientific inputs and thoughtful comments on the work. We also thank Rina Righi, Agostino Marchi, Mariangela Fiorelli for animal care as well as Alfredo Fiorelli for his excellent technical support. Authors gratefully thank Federica Benvenuti, Marina Antonini, Martina Mondaini, and Maria Sole Centanni for their support in behaviorally testing the animals. This work was supported by the National Institutes of Health, grant RO1 AA014351 (to FW and RC) from the National Institute on Alcohol Abuse and Alcoholism.

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AMB and RC were responsible for the study concept and design. AMB performed surgeries, behavioral testing, data analysis and wrote the paper. YF performed surgeries and behavioral tests. SS, AD, and SDC performed behavioral tests. MP, MU, FW, and RC provided critical revision of the paper for important intellectual content. RC and MP contributed to write the paper. All authors critically reviewed the content and approved the final version for publication.

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Correspondence to Roberto Ciccocioppo.

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Borruto, A.M., Fotio, Y., Stopponi, S. et al. NOP receptor antagonism attenuates reinstatement of alcohol-seeking through modulation of the mesolimbic circuitry in male and female alcohol-preferring rats. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01096-1

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