The α4β2 nicotinic acetylcholine-receptor partial agonist varenicline inhibits both nicotine self-administration following repeated dosing and reinstatement of nicotine seeking in rats

O’Connor, Eoin C.; Parker, Dale; Rollema, Hans; Mead, Andy N.

doi:10.1007/s00213-009-1739-5

Cited by 117 publications

(139 citation statements)

References 52 publications

(72 reference statements)

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“…In rats, varenicline attenuates alcohol intake and operant alcohol-self administration, with either no effect on water intake and sucrose self-administration (Steensland et al, 2007) or an increase in the latter behavior (Wouda et al, 2011). These and related data (Le Foll et al, 2011;O'Connor et al, 2009) suggest that varenicline selectively dampens behaviors maintained by pharmacological, as opposed to non-drug reinforcers (Guillem and Peoples, 2010).…”

Section: Introductionmentioning

confidence: 78%

“…In humans, varenicline reduced alcohol craving and cue-elicited activation of the orbitofrontal cortex, with no effect on drinking behavior (Schacht et al, 2014). Varenicline dose-dependently attenuated cue-induced reinstatement of alcohol-seeking in rats (Funk et al, 2016;Wouda et al, 2011), congruent with doserelated reductions in cue-induced cocaine- (Guillem and Peoples, 2010) and nicotine-seeking (Le Foll et al, 2011, but see Wouda et al, 2011, andO'Connor et al, 2009). Moreover, varenicline reduced transient increases in oral alcohol intake produced by repeated bouts of abstinence from alcohol in mice (Sajja and Rahman, 2013).…”

Section: Introductionmentioning

confidence: 93%

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Varenicline Reduces Context-Induced Relapse to Alcohol-Seeking through Actions in the Nucleus Accumbens

Lacroix

Pettorelli

Maddux

et al. 2016

Neuropsychopharmacol

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Varenicline, a pharmacotherapy for tobacco addiction, reduces alcohol consumption in humans and rodents. The therapeutic potential of varenicline would escalate if it also diminished conditioned responses elicited by alcohol-predictive cues, which can precipitate relapse in abstinent individuals. We investigated this application, along with the underlying neural substrates, using a robust preclinical assay in which relapse to alcohol-seeking was triggered by re-exposure to an alcohol-associated environmental context. Male, Long-Evans rats received Pavlovian conditioning sessions in which one auditory conditioned stimulus (CS+) was paired with 15% ethanol and a second conditioned stimulus (CS − ) was not. Ethanol was delivered into a port for oral consumption and port entries triggered by each CS were recorded. Extinction was then conducted in a different context where the CS+ and CS − were presented without ethanol. To stimulate relapse, both cues were subsequently presented without ethanol in the prior conditioning context. Systemic varenicline (0, 0.5 or 2.5 mg/kg; intraperitoneal) blocked context-induced relapse to alcohol-seeking without affecting the ability to make a port entry. It also reduced context-induced relapse to sucrose-seeking, but only at the 2.5 mg/kg dose. Neuropharmacological studies showed that context-induced relapse to alcohol-seeking was attenuated by bilateral microinfusion of varenicline (0.3 μl/side) into the nucleus accumbens (NAc; 0 or 3.5 μg), but not the ventral tegmental area (0, 2 or 4 μg). These data show for the first time that varenicline reduces relapse triggered by contexts that predict alcohol, and suggest that nicotinic acetylcholine receptors in the NAc are critical for this effect.

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Section: Introductionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 93%

Varenicline Reduces Context-Induced Relapse to Alcohol-Seeking through Actions in the Nucleus Accumbens

Lacroix

Pettorelli

Maddux

et al. 2016

Neuropsychopharmacol

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“…As with manipulations of smoking deprivation and satiety described above, smoking cessation medications have been shown to attenuate tonic cigarette craving but not cue-elicited craving (for a review see Ferguson & Shiffman, 2009). This dissociation has been found with nicotine replacement therapy (Havermans, Debaere, Smulders, Wiers, & Jansen, 2003;Morissette, Palfai, Gulliver, Spiegel, & Barlow, 2005;Niaura et al, 2005;Rohsenow et al, 2007;Shiffman et al, 2003;Tiffany, Cox, & Elash, 2000;Waters et al, 2004), bupropion (Hussain et al, 2010) and varenicline (Brandon et al, 2011;Franklin et al, 2011;Hitsman et al, under review;Hitsman, Niaura, Shadel, Britt, & Price, 2006; for related animal data see O'Connor, Parker, Rollema, & Mead, 2010). Dual-controller theory explains these dissociations by suggesting that although pharmacotherapies modulate the expected value smoking and thus impact on goal-directed tobacco-seeking, they do not modify expected drug probability and so leave cue-elicited tobacco-seeking intact.…”

Section: Introductionmentioning

confidence: 95%

Goal-directed and transfer-cue-elicited drug-seeking are dissociated by pharmacotherapy: Evidence for independent additive controllers.

Hogarth

2012

Journal of Experimental Psychology: Animal Behavior Processes

138

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According to contemporary learning theory, drug-seeking behaviour reflects the summation of two dissociable controllers. Whereas goal-directed drug-seeking is determined by the expected current incentive value of the drug, stimulus-elicited drug-seeking is determined by the expected probability of the drug independently of its current incentive value, and these two controllers contribute additively to observed drug-seeking. One applied prediction of this model is that smoking cessation pharmacotherapies selectively attenuate tonic but not cueelicited craving because they downgrade the expected incentive value of the drug but leave expected probability intact. To test this, the current study examined whether nicotine replacement therapy (NRT) nasal spray would modify goal-directed tobacco choice in a human outcome devaluation procedure, but leave cue-elicited tobacco choice in a Pavlovian to instrumental transfer (PIT) procedure intact. Smokers (n=96) first underwent concurrent choice training in which two responses earned tobacco or chocolate points respectively.Participants then ingested either NRT nasal spray (1mg) or chocolate (147g) to devalue one outcome. Concurrent choice was then tested again in extinction to measure goal-directed control of choice, and in a PIT test to measure the extent to which tobacco and chocolate stimuli enhanced choice of the same outcome. It was found that NRT modified tobacco choice in the extinction test but not the extent to which the tobacco stimulus enhanced choice of the tobacco outcome in the PIT test. This dissociation suggests that the propensity to engage in drug-seeking is determined independently by the expected value and probability of the drug, and that the partial efficacy of pharmacotherapy is due to its selective effect on expected drug value.

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“…In-deed, numerous studies have shown that varenicline, a Food and Drug Administration-approved drug widely used to help people quit smoking, potently acts as a partial agonist at ␣4␤2* nAChRs (Coe et al, 2005;Gonzales et al, 2006;Jorenby et al, 2006;Rollema et al, 2007). This action at ␣4␤2* nAChRs is postulated to block the reinforcing effects of nicotine while also relieving craving and withdrawal symptoms (Biala et al, 2010;O'Connor et al, 2010;De Biasi and Dani, 2011;George et al, 2011). However, smoking relapse rates remain high even with varenicline treatment (McNeil et al, 2010;Raupach and van Schayck, 2011).…”

Section: Introductionmentioning

confidence: 99%

Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum

Bordia

Hrachova

Chin

et al. 2012

J Pharmacol Exp Ther

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Extensive evidence indicates that varenicline reduces nicotine craving and withdrawal symptoms by modulating dopaminergic function at ␣4␤2* nicotinic acetylcholine receptors (nAChRs) (the asterisk indicates the possible presence of other nicotinic subunits in the receptor complex). More recent data suggest that ␣6␤2* nAChRs also regulate dopamine release and mediate nicotine reinforcement. The present experiments were therefore done to test the effect of varenicline on ␣6␤2* nAChRs and their function, because its interaction with this subtype is currently unclear. Receptor competition studies showed that varenicline inhibited ␣6␤2* nAChR binding (K i ϭ 0.12 nM) as potently as ␣4␤2* nAChR binding (K i ϭ 0.14 nM) in rat striatal sections and with ϳ20-fold greater affinity than nicotine. Functionally, varenicline was more potent in stimulating ␣6␤2* versus ␣4␤2* nAChR-mediated [3 H]dopamine release from rat striatal synaptosomes with EC 50 values of 0.007 and 0.086 M, respectively. However, it acted as a partial agonist on ␣6␤2* and ␣4␤2* nAChR-mediated [ 3 H]dopamine release with maximal efficacies of 49 and 24%, respectively, compared with nicotine. We also evaluated varenicline's action in striatum of monkeys, a useful animal model for comparison with humans. Varenicline again potently inhibited monkey striatal ␣6␤2* (K i ϭ 0.13 nM) and ␣4␤2* (K i ϭ 0.19 nM) nAChRs in competition studies. Functionally, it potently stimulated both ␣6␤2* (EC 50 ϭ 0.014 M) and ␣4␤2* (EC 50 ϭ 0.029 M) nAChR-mediated [ 3 H]dopamine release from monkey striatal synaptosomes, again acting as a partial agonist relative to nicotine at both subtypes. These data suggest that the ability of varenicline to interact at ␣6␤2* nAChRs may contribute to its efficacy as a smoking cessation aid.

show abstract

The α4β2 nicotinic acetylcholine-receptor partial agonist varenicline inhibits both nicotine self-administration following repeated dosing and reinstatement of nicotine seeking in rats

Abstract: The effects of varenicline on nicotine-induced reinstatement of drug-seeking are consistent with the demonstrated clinical efficacy of varenicline for smoking cessation.

Cited by 117 publications

References 52 publications

Varenicline Reduces Context-Induced Relapse to Alcohol-Seeking through Actions in the Nucleus Accumbens

Varenicline Reduces Context-Induced Relapse to Alcohol-Seeking through Actions in the Nucleus Accumbens

Goal-directed and transfer-cue-elicited drug-seeking are dissociated by pharmacotherapy: Evidence for independent additive controllers.

Varenicline Is a Potent Partial Agonist at α6β2* Nicotinic Acetylcholine Receptors in Rat and Monkey Striatum

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