Genetic deletion or pharmacological blockade of nociceptin/orphanin FQ receptors in the ventral tegmental area attenuates nicotine-motivated behaviour
| Autor: | Veronica Lunerti, Michele Petrella, Esi Domi, Ana Domi, Massimo Ubaldi, Friedbert Weiss, Anna Maria Borruto, Roberto Ciccocioppo |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Pharmacology
Nicotine Knockout rat medicine.drug_class business.industry NOP Ventral Tegmental Area Nucleus accumbens Receptor antagonist Nociceptin Receptor Article Rats Ventral tegmental area Nociceptin receptor medicine.anatomical_structure Opioid Peptides Receptors Opioid medicine Animals Receptor business medicine.drug |
| Zdroj: | Br J Pharmacol |
| Popis: | 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. Intriguingly, studies on alcohol showed that also genetic deletion or pharmacological blockade of NOP receptors confer resilience to the development of alcohol abuse. Here, we used a genetic and pharmacological approach to evaluate the therapeutic potential of NOP antagonism in smoking cessation. EXPERIMENTAL APPROACH: Constitutive NOP 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 (0.0, 1.0 and 3.0 mg/kg) on nicotine self-administration. NOP blockade was further evaluated at the microcircuitry level, by microinjecting LY2817412 (0.0, 3.0 and 6.0 μg/μl) into the ventral tegmental area (VTA), nucleus accumbens (Alexander et al.) and central amygdala (CeA). KEY RESULTS: Genetic NOP deletion resulted in decreased nicotine intake, decreased motivation to self-administer the drug, 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 document that inhibition of NOP transmission attenuates the motivation for nicotine through mechanisms involving the VTA and suggest that NOP antagonism may represent a potential treatment for smoking cessation. |
| Databáze: | OpenAIRE |
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