Genetic deletion or pharmacological blockade of nociceptin/orphanin FQ receptors in the ventral tegmental area attenuates nicotine‐motivated behaviour

Abstract

Background and Purpose The nociceptin/orphanin FQ (N/OFQ)–nociceptin opioid‐like peptide (NOP) receptor system is widely distributed in the brain and pharmacological activation of this system revealed therapeutic potential in animal models of substance use disorder. Studies also showed that genetic deletion or pharmacological blockade of NOP receptors confer resistance to the development of alcohol abuse. Here, we have used a genetic and pharmacological approach to evaluate the therapeutic potential of NOP antagonism in smoking cessation. Experimental Approach Constitutive NOP receptor knockout rats (NOP−/−) and their wild‐type counterparts (NOP+/+) were tested over a range of behaviours to characterize their motivation for nicotine. We next explored the effects of systemic administration of the NOP receptor antagonist LY2817412 (1.0 & 3.0 mg·kg−1) on nicotine self‐administration. NOP receptor blockade was further evaluated at the brain circuitry level, by microinjecting LY2817412 (3.0 & 6.0 μg·μl−1) into the ventral tegmental area (VTA), nucleus accumbens (NAc) and central amygdala (CeA). Key Results Genetic NOP receptor deletion resulted in decreased nicotine intake, decreased motivation to self‐administer and attenuation of cue‐induced nicotine reinstatement. LY2817412 reduced nicotine intake in NOP+/+ but not in NOP−/− rats, confirming that its effect is mediated by inhibition of NOP transmission. Finally, injection of LY2817412 into the VTA but not into the NAc or CeA decreased nicotine self‐administration. Conclusions and Implications These findings indicate that inhibition of NOP transmission attenuates the motivation for nicotine through mechanisms involving the VTA and suggest that NOP receptor antagonism may represent a potential treatment for smoking cessation.

Abstinence-Induced Nicotine Seeking Relays on a Persistent Hypoglutamatergic State within the Amygdalo-Striatal Neurocircuitry

“…Analgesia during and after surgery was maintained with Metacam 1 mg/kg given by subcutaneous injections (5 mg/ml, Boehringer Ingelheim). A single catheter made from microrenathane tubing (ID = 0.020″, OD = 0.037″; Braintree Scientific) was implanted in the right jugular vein as previously described ( Shen et al, 2017 ; Domi et al, 2021 ). Immediately after surgery and for the subsequent 3 d, rats were treated with 10 mg/kg of subcutaneous enrofloxacin (50 mg/ml, Baytril) and allowed to one week recovery before starting the self-administration training.…”

Nicotine but not saline self-administering or yoked control conditions produces sustained neuroadaptations in the accumbens shell

“…Chronic jugular intravenous catheter implantation was conducted as previously described ( Domi et al, 2022 ). Briefly, animals were anesthetized with isoflurane anesthesia: 5% induction and 2% maintenance.…”

Epigenetic Modulation of Opioid Receptors by Drugs of Abuse

“…To illustrate, mice lacking NOP receptors show enhanced cocaine-induced locomotor sensitization [ 41 ]. Further, absence of NOP receptors in rats results in decreased motivation to self-administer nicotine, reduced nicotine intake, and attenuated cue-induced nicotine reinstatement [ 42 ]. Additionally, NOP receptor knockout mice consume less alcohol in a binge-like alcohol drinking paradigm [ 43 ].…”