2016
DOI: 10.1111/acer.13052
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A Novel, Orally Bioavailable Nociceptin Receptor Antagonist, LY2940094, Reduces Ethanol Self-Administration and Ethanol Seeking in Animal Models

Abstract: Background The nociceptin/orphanin-FQ (NOP; or opioid-receptor-like (ORL1)) receptor is localized in the mesolimbic reward pathway and has been suggested to play a role in feeding, mood, stress, and addiction. Since its deorphanization in 1995, there has been a clear dichotomy in the literature regarding whether an agonist or antagonist would provide therapeutic benefit. Specifically, literature reports indicate that NOP receptor antagonists produce efficacy in animal models of hyperphagia and antidepressant-l… Show more

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Cited by 57 publications
(49 citation statements)
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“…Further, systemic administration of NOP antagonists reduced alcohol self-administration in wildtype rats but was without effect in NOP-deficient rats (Kallupi et al, 2017). These results align with another report showing that oral administration of a NOP antagonist reduced alcohol consumption, motivation to work for alcohol, and stress (yohimbine)-induced reinstatement of alcohol-seeking behavior in rats (Rorick-Kehn et al, 2016). These effects produced by the nociceptin receptor antagonist were attributed to the drug blocking alcohol-induced dopamine release in the nucleus accumbens.…”
Section: Mechanisms Underlying Chronic Alcohol Stress and Drinkisupporting
confidence: 92%
See 1 more Smart Citation
“…Further, systemic administration of NOP antagonists reduced alcohol self-administration in wildtype rats but was without effect in NOP-deficient rats (Kallupi et al, 2017). These results align with another report showing that oral administration of a NOP antagonist reduced alcohol consumption, motivation to work for alcohol, and stress (yohimbine)-induced reinstatement of alcohol-seeking behavior in rats (Rorick-Kehn et al, 2016). These effects produced by the nociceptin receptor antagonist were attributed to the drug blocking alcohol-induced dopamine release in the nucleus accumbens.…”
Section: Mechanisms Underlying Chronic Alcohol Stress and Drinkisupporting
confidence: 92%
“…These effects produced by the nociceptin receptor antagonist were attributed to the drug blocking alcohol-induced dopamine release in the nucleus accumbens. Several explanations have been postulated to address these apparent contradictory results (NOP agonists and antagonists reduce alcohol consumption), including receptor translocation, ligand-biased receptor signaling, and brain regional differences in receptor variants (Rorick-Kehn et al, 2016). Future studies will need to resolve this issue as well as address the therapeutic potential of this target for treating alcohol use disorders and stress-related drinking in particular.…”
Section: Mechanisms Underlying Chronic Alcohol Stress and Drinkimentioning
confidence: 99%
“…Although the mechanisms by which antagonists engender such anxiolytic signatures in rodents is not understood, examples of antagonists producing effects previously thought to be agonist‐driven have been observed in alcohol studies that have led to speculations on mechanism relating to receptor adaptations (Rorick‐Kehn et al. ). In clinical investigation in MDD patients, LY2940094 separated from placebo in reducing HAMD scores but did not separate from placebo on either the Hamilton anxiety rating scale (HAMA) total score at Week 4 or the patient‐rated HADS anxiety subscale (Post et al.…”
Section: Discussionmentioning
confidence: 99%
“…2014a) and for reduction in ethanol intake (Rorick‐Kehn et al. ) suggest additional potential differentiating features of LY2940094 from conventional antidepressant drugs that would be valuable in an antidepressant. LY2940094 was also active in some assays that detect antioltyic drug effects after acute dosing (e.g., stress‐induced cGMP production, and stress‐induced freezing), findings not typically observed with acutely administered antidepressants.…”
Section: Discussionmentioning
confidence: 99%
“…Most research suggests that NOP agonism reduces alcohol self‐administration and alcohol‐motivated behaviors such as attenuation of ethanol (EtOH)‐motivated behaviors including self‐administration, conditioned place preference, and reinstatement to alcohol seeking (Ciccocioppo et al., , ; Economidou et al., , ; Kuzmin et al., , ), presumably due to suppression of dopamine synthesis and release (Zaveri, ). However, recent evidence suggests that NOP antagonism reduces alcohol self‐administration and alcohol seeking (Rorick‐Kehn et al., ).…”
mentioning
confidence: 99%