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Nicotine increases alcohol self-administration in male rats via a ?-opioid mechanism within the mesolimbic pathway.

ABSTRACT: BACKGROUND AND PURPOSE:Alcohol and nicotine use disorders are commonly comorbid. Both alcohol and nicotine can activate opioid systems in reward-related brain regions, leading to adaptive changes in opioid signalling upon chronic exposure. The potential role of these adaptations for comorbidity is presently unknown. Here, we examined the contribution of ? and ?-opioid receptors to nicotine-induced escalation of alcohol self-administration in rats. EXPERIMENTAL APPROACH:Chronic nicotine was tested on alcohol self-administration and motivation to obtain alcohol. We then tested the effect of the ? antagonist CERC-501 and the preferential ? receptor antagonist naltrexone on basal and nicotine-escalated alcohol self-administration. To probe ? or ? receptor adaptations, receptor binding and G-protein coupling assays were performed in reward-related brain regions. Finally, dopaminergic activity in response to alcohol was examined, using phosphorylation of DARPP-32 in nucleus accumbens as a biomarker. KEY RESULTS:Nicotine robustly induced escalation of alcohol self-administration and motivation to obtain alcohol. This was blocked by naltrexone but not by CERC-501. Escalation of alcohol self-administration was associated with decreased DAMGO-stimulated ? receptor signalling in the ventral tegmental area (VTA) and decreased pDARPP-32 in the nucleus accumbens shell in response to alcohol. CONCLUSIONS AND IMPLICATIONS:Collectively, these results suggest that nicotine contributes to escalate alcohol self-administration through a dysregulation of ? receptor activity in the VTA. These data imply that targeting ? rather than ? receptors may be the preferred pharmacotherapeutic approach for the treatment of alcohol use disorder when nicotine use contributes to alcohol consumption.

SUBMITTER: Domi E

PROVIDER: S-EPMC7484560 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Nicotine increases alcohol self-administration in male rats via a μ-opioid mechanism within the mesolimbic pathway.

Domi Esi E Xu Li L Pätz Marvin M Nordeman Anton A Augier Gaëlle G Holm Lovisa L Toivainen Sanne S Augier Eric E Hansson Anita C AC Heilig Markus M

British journal of pharmacology 20200814 19

<h4>Background and purpose</h4>Alcohol and nicotine use disorders are commonly comorbid. Both alcohol and nicotine can activate opioid systems in reward-related brain regions, leading to adaptive changes in opioid signalling upon chronic exposure. The potential role of these adaptations for comorbidity is presently unknown. Here, we examined the contribution of μ and κ-opioid receptors to nicotine-induced escalation of alcohol self-administration in rats.<h4>Experimental approach</h4>Chronic nic ...[more]

PMID: 32697329

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Project description:IntroductionNicotine can robustly increase responding for conditioned reinforcers (CRs), stimuli that acquire reinforcing properties based on association with primary reinforcers. Menthol and licorice are tobacco flavoring agents also found in sweet foods (eg, candy and ice cream), making them putative CRs before they are consumed in tobacco. We sought to determine if intravenous self-administration (IVSA) of nicotine was enhanced by the inclusion of oral tobacco flavor CRs.MethodsMenthol (160 or 320 µM) or licorice root extract (0.1% or 1%) were established as CRs (paired with 20% sucrose) or "neutral" stimuli (paired with water) in separate groups. During subsequent IVSA tests, nicotine was delivered in conjunction with oral presentations of the CR.ResultsIn experiment 1, a menthol CR significantly shifted the peak nicotine dose from 15 µg/kg/infusion (Neutral group) to 3.25 µg/kg/infusion (CR group). In experiment 2, a menthol CR significantly increased operant licks for nicotine (3 µg/kg/infusion) relative to control groups. In experiment 3, both licorice and menthol CRs significantly increased operant licks for nicotine (7.5 µg/kg/infusion) relative to an "inactive" sipper. The licorice CR increased nicotine IVSA in proportion to the strength of the flavor, but both menthol concentrations increased nicotine IVSA to a similar extent.ConclusionTobacco flavor additives with conditioned reinforcing properties promote acquisition of nicotine self-administration at low unit doses and may have robust impact on tobacco consumption when nicotine yield is low.ImplicationsTobacco flavor additives are found in rewarding foods (eg, ice cream) and gain palatability based on associations with primary rewards (eg, sugar) making them "conditioned reinforcers." Nicotine increases the motivation for flavor conditioned reinforcers and the present studies show that tobacco flavor additives can interact with nicotine to promote more nicotine self-administration. The interaction between flavors additives and nicotine may promote nicotine exposure and subsequently dependence.

Project description:In patients suffering from alcohol use disorder (AUD), stress and environmental stimuli associated with alcohol availability are important triggers of relapse. Activation of the nociceptin opioid peptide (NOP) receptor by its endogenous ligand Nociceptin/Orphanin FQ (N/OFQ) attenuates alcohol drinking and relapse in rodents, suggesting that NOP agonists may be efficacious in treating AUD. Intriguingly, recent data demonstrated that also blockade of NOP receptor reduced alcohol drinking in rodents. To explore further the potential of NOP antagonism, we investigated its effects on the reinstatement of alcohol-seeking elicited by administration of the α2 antagonist yohimbine (1.25 mg/kg, i.p.) or by environmental conditioning factors in male and female genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The selective NOP receptor antagonist LY2817412 (0.0, 3.0, 10.0, and 30.0 mg/kg) was first tested following oral (p.o.) administration. We then investigated the effects of LY2817412 (1.0, 3.0, 6.0 μg/μl/rat) microinjected into three candidate mesolimbic brain regions: the ventral tegmental area (VTA), the central nucleus of the amygdala (CeA), and the nucleus accumbens (NAc). We found that relapse to alcohol seeking was generally stronger in female than in male rats and oral administration of LY2817412 reduced yohimbine- and cue-induced reinstatement in both sexes. Following site-specific microinjections, LY2817412 reduced yohimbine-induced reinstatement of alcohol-seeking when administered into the VTA and the CeA, but not in the NAc. Cue-induced reinstatement was suppressed only when LY2817412 was microinjected into the VTA. Infusions of LY2817412 into the VTA and the CeA did not alter saccharin self-administration. These results demonstrate that NOP receptor blockade prevents the reinstatement of alcohol-seeking through modulation of mesolimbic system circuitry, providing further evidence of the therapeutic potential of NOP receptor antagonism in AUD.

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Nicotine increases alcohol self-administration in male rats via a ?-opioid mechanism within the mesolimbic pathway.

Publications

Nicotine increases alcohol self-administration in male rats via a μ-opioid mechanism within the mesolimbic pathway.

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