A key role for the N/OFQ-NOP receptor system in modulating nicotine taking in a model of nicotine and alcohol co-administration.

Andrea Cippitelli,Gloria Brunori,Nurulain T Zaveri,Lawrence Toll,Ginamarie Debevec,Jennifer Schoch

doi:10.1038/srep26594

Abstract

Alcohol and nicotine are often co-abused. Although the N/OFQ-NOP receptor system is considered a potential target for development of drug abuse pharmacotherapies, especially for alcoholism, little is known about the role of this system in nicotine dependence. Furthermore, the effect of prior history of nicotine dependence on subsequent nicotine and alcohol taking is understudied. Using an operant co-administration paradigm, in which rats concurrently self-administer nicotine and alcohol, we found that nicotine dependent rats increased nicotine self-administration over time as compared to non-dependent animals, while patterns of alcohol lever pressing did not change between groups. Pretreatment with the potent NOP receptor agonist AT-202 (0.3–3 mg/kg) increased nicotine lever pressing of both dependent and non-dependent groups, whereas the selective antagonist SB612111 (1–10 mg/kg) elicited a clear reduction of nicotine responses, in both dependent and non-dependent rats. In parallel, AT-202 only produced minor changes on alcohol responses and SB612111 reduced alcohol taking at a dose that also reduced locomotor behavior. Results indicate that a history of nicotine dependence affects subsequent nicotine- but not alcohol-maintained responding, and that NOP receptor antagonism, rather than agonism, blocks nicotine self-administration, which strongly suggests a critical role for the endogenous N/OFQ in the modulation of nicotine reinforcement processes.

Highlights

Worldwide, 6 million people, including 480,000 in the United States, die premature deaths from smoking-induced disease each year
NOP receptors and nociceptin/orphanin FQ (N/OFQ) are found in high concentrations in brain regions known to be involved in drug abuse, including the ventral tegmental area (VTA), nucleus accumbens (NAcc), prefrontal cortex, amygdala, and medial habenula (MHb)[12,13,14,15]
A role of endogenous nociceptin in modulating the acute effects of nicotine has been hypothesized based an increase in the sensitivity to nicotine in NOP receptor knockout mice[28], it is unknown whether NOP receptor agonists are able to block nicotine reward

Summary

Introduction

6 million people, including 480,000 in the United States, die premature deaths from smoking-induced disease each year. N/OFQ and small molecule agonists have been demonstrated to block conditioned place preference (CPP) of morphine, alcohol, cocaine, and methamphetamine[16,17,18,19,20] This is consistent with the observation that NOP receptor agonists block a drug-induced increase in extracellular dopamine in the rat NAcc[21,22]. Using a similar methodology we determined that the α3β4 nAChR partial agonist AT-1001 could attenuate nicotine self-administration, while it was mostly inactive in blocking alcohol self-administration when both drugs are available in the operant chamber This is unlike varenicline, which was effective in blocking both nicotine and alcohol taking[31]. The current results indicate that prior nicotine dependence affects nicotine but not alcohol self-administration, and surprisingly that NOP receptor antagonists, rather than agonists, can block nicotine self-administration

Methods

Results

Conclusion