NOP Receptor Antagonists Decrease Alcohol Drinking in the Dark in C57BL/6J Mice

Background: The nociceptin/orphanin FQ opioid peptide (NOP) receptor and its endogenous ligand N/OFQ have been implicated in the regulation of drug and alcohol use disorders (AUD). In particular, evidence demonstrated that NOP receptor activation blocks reinforcing and motivating effects of alcohol across a range of behavioral measures, including alcohol intake, conditioned place preference, and vulnerability to relapse. Methods: Here, we show the effects of pharmacological activation and inhibition of NOP receptors on binge-like alcohol consumption, as measured by the “drinking in the dark” (DID) model in C57BL/6J mice. Results: We found that 2 potent and selective NOP agonists AT-202 (0, 0.3, 1, 3 mg/kg) and AT-312 (0, 0.3, 1 mg/kg) did not affect binge alcohol drinking at doses that do not affect locomotor activity. AT-202 also failed to alter DID behavior when administered to mice previously exposed to chronic alcohol treatment with an alcohol-containing liquid diet. Conversely, treatment with either the high affinity NOP receptor antagonist SB-612111 (0, 3, 10, 30 mg/kg) or the selective antagonist LY2817412 (0, 3, 10, 30 mg/kg) decreased binge drinking. SB-612111 was effective at all doses examined, and LY2817412 was effective at 30 mg/kg. Consistently, NOP receptor knockout mice consumed less alcohol compared to wild type. SB-612111 reduced DID and increased sucrose consumption at doses that do not appear to affect locomotor activity. However, the high dose of SB-612111 (30 mg/kg) reduced alcohol intake but failed to inhibit preference in a 2-bottle choice DID model that can assess moderate alcohol intake. Conclusions: The present results suggest that NOP receptor inhibition rather than activation may represent a valuable approach for treatment of AUD characterized by excessive alcohol consumption such as binge drinking

A Novel, Orally Bioavailable Nociceptin Receptor Antagonist, LY2940094, Reduces Ethanol Self-Administration and Ethanol Seeking in Animal Models

Background: The nociceptin/orphanin-FQ (or opioid receptor-like [ORL1]) receptor (NOP) 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, the literature reports indicate that NOP receptor antagonists produce efficacy in animal models of hyperphagia and antidepressant-like activity, whereas NOP agonists produce anxiolytic-like effects and dampen reward/addiction behaviors including ethanol consumption. Methods: We characterize here the potent, orally bioavailable NOP antagonist, LY2940094, in rodent models of ethanol consumption, including ethanol self-administration, progressive ratio operant self-administration, stress-induced reinstatement of ethanol seeking, and in vivo microdialysis in the nucleus accumbens. Results: LY2940094 dose dependently reduced homecage ethanol self-administration in Indiana alcohol-preferring (P) and Marchigian Sardinian alcohol-preferring (msP) rats, without affecting food/water intake or locomotor activity. Reduced ethanol intake in P rats did not show significant tolerance over 4 days of subchronic dosing. LY2940094 attenuated progressive ratio operant responding and break points for ethanol in P rats. Moreover, stress-induced reinstatement of ethanol seeking in msP rats was completely blocked by LY2940094. Furthermore, LY2940094 blocked ethanol-stimulated dopamine release in response to ethanol challenge (1.1 g/kg, intraperitoneally). Conclusions: Our findings demonstrate for the first time that blockade of NOP receptors attenuates ethanol self-administration and ethanol-motivated behaviors, stress-induced ethanol seeking, and ethanol-induced stimulation of brain reward pathways in lines of rats that exhibit excessive ethanol consumption. Results suggest that LY2940094 may have potential therapeutic utility in treating alcohol addiction

The Rapidly Acting Antidepressant Ketamine and the mGlu2/3 Receptor Antagonist LY341495 Rapidly Engage Dopaminergic Mood Circuits

ABSTRACT Ketamine is a rapidly acting antidepressant in patients with treatment-resistant depression (TRD). Although the mechanisms underlying these effects are not fully established, inquiry to date has focused on the triggering of synaptogenesis transduction pathways via glutamatergic mechanisms. Preclinical data suggest that blockade of metabotropic glutamate (mGlu2/3) receptors shares many overlapping features and mechanisms with ketamine and may also provide rapid efficacy for TRD patients. Central dopamine circuitry is recognized as an end target for mood regulation and hedonic valuation and yet has been largely neglected in mechanistic studies of antidepressant-relevant effects of ketamine. Herein, we evaluated the changes in dopaminergic neurotransmission after acute administration of ketamine and the mGlu2/3 receptor antagonist LY341495 [(2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid ] in preclinical models using electrophysiologic, neurochemical, and behavioral endpoints. When given acutely, both ketamine and LY341495, but not the selective serotonin reuptake inhibitor (SSRI) citalopram, increased the number of spontaneously active dopamine neurons in the ventral tegmental area (VTA), increased extracellular levels of dopamine in the nucleus accumbens and prefrontal cortex, and enhanced the locomotor stimulatory effects of the dopamine D 2/3 receptor agonist quinpirole. Further, both ketamine and LY341495 reduced immobility time in the tail-suspension assay in CD1 mice, which are relatively resistant to SSRI antidepressants. Both the VTA neuronal activation and the antidepressant phenotype induced by ketamine and LY341495 were attenuated by the a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-(9CI)-benzo[f]quinoxaline-7-sulfonamide, indicating AMPA-dependent effects. These findings provide another overlapping mechanism of action of ketamine and mGlu2/3 receptor antagonism that differentiates them from conventional antidepressants and thus support the potential rapidly acting antidepressant actions of mGlu2/3 receptor antagonism in patients