Structural differences determine the relative selectivity of nicotinic compounds for native α4β2*-, α6β2*-, α3β4*- and α7-nicotine acetylcholine receptors

Grady, Sharon R.; Drenan, Ryan M.; Breining, Scott R.; Yohannes, Daniel; Wageman, Charles R.; Fedorov, N. A.; McKinney, Sheri; Whiteaker, Paul; Bencherif, Merouane; Lester, Henry A.; Marks, Michael J.

doi:10.1016/j.neuropharm.2010.01.013

Cited by 97 publications

(140 citation statements)

References 37 publications

(86 reference statements)

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“…As mentioned earlier, there are multiple nAChRs throughout the body, with the predominant populations in the striatum being the a4b2* and a6b2* nAChR subtypes Millar and Gotti, 2009;Quik and Wonnacott, 2011). Although initial studies suggested that varenicline was selective for a4b2* nAChRs, subsequent work showed that it also interacted with a6b2*, a3b4*, and a7 nAChRs (Coe et al, 2005;Mihalak et al, 2006;Grady et al, 2010;Ween et al, 2010;Chatterjee et al, 2011;Bordia et al, 2012). Varenicline's biological effects may thus be more similar to those of nicotine, which also stimulates multiple nAChR populations.…”

Section: Discussionmentioning

confidence: 94%

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

Zhang

Mallela

Sohn

et al. 2013

J Pharmacol Exp Ther

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Abnormal involuntary movements or dyskinesias are a serious complication of long-term L-DOPA treatment of Parkinson's disease, for which there are few treatment options. Accumulating preclinical data show that nicotine decreases L-DOPAinduced dyskinesias (LIDs), suggesting that it may be a useful antidyskinetic therapy for Parkinson's disease. Here, we investigated whether nicotinic acetylcholine receptor (nAChR) agonists reduced LIDs in nonhuman primates. We first tested the nonselective nAChR agonist 1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino [2,3-h][3]benzazepine (varenicline), which offers the advantage that it is approved by the U.S. Food and Drug Administration for use in humans. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys (n 5 23) were first administered L-DOPA/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Oral varenicline (0.03-0.10 mg/kg) decreased LIDs ∼50% compared with vehicle-treated monkeys, whereas nicotine treatment (300 mg/ml in drinking water) reduced LIDs by 70% in a parallel group of animals. We next tested the selective a4b2*/a6b2* nAChR agonist heptane] on LIDs in the same set of monkeys after a 10-week washout. We also tested TC-8831 in another set of MPTP-lesioned monkeys (n 5 16) that were nAChR drug-naïve. Oral TC-8831 (0.03-0.3 mg/kg) reduced LIDs in both sets by 30-50%. After a washout period, repeat TC-8831 dosing led to a greater decline in LIDs (60%) in both sets of monkeys that was similar to the effect of nicotine. Tolerance to any nAChR drug did not develop over the course of the study (3-4 months). NAChR drug treatment did not worsen parkinsonism or cognitive ability. These data suggest that nAChR agonists may be useful for the management of dyskinesias in L-DOPA-treated Parkinson's disease patients.

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Section: Discussionmentioning

confidence: 94%

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

Zhang

Mallela

Sohn

et al. 2013

J Pharmacol Exp Ther

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“…Very few studies have compared the effects of nicotine, cytisine, and varenicline on the brain reward system. Cytisine and varenicline have a similar affinity and efficacy for the nAChRs (a4b2*, a6b2*) that mediate the rewarding effects of nicotine (Papke et al, 2010;Grady et al, 2010;Picciotto and Kenny, 2013). Therefore, it is unlikely that the differences between varenicline and cytisine on ICSS thresholds are due to differences in nAChR binding and efficacy.…”

Section: Discussionmentioning

confidence: 99%

“…Cytisine has been used as a smoking cessation aid in Eastern European countries since the 1960s (Etter, 2006;West et al, 2011). Cytisine is a partial agonist at a4b2* and a6b2* nAChRs and a full agonist at a3b4* and a7 nAChRs (Salminen et al, 2004;Grady et al, 2010). The cytisine derivative varenicline is an US FDA-approved smoking cessation treatment and activates the same nAChRs as cytisine (Grady et al, 2010;Mihalak et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…The cytisine derivative varenicline is an US FDA-approved smoking cessation treatment and activates the same nAChRs as cytisine (Grady et al, 2010;Mihalak et al, 2006). Cytisine and varenicline have a similar efficacy at a4b2*, a3b4*, and a7 rodent nAChRs, but cytisine is more efficacious at a6b2* nAChRs (Grady et al, 2010;Salminen et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Varenicline and Cytisine Diminish the Dysphoric-Like State Associated with Spontaneous Nicotine Withdrawal in Rats

Igari

Alexander

et al. 2013

Neuropsychopharmacol

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Tobacco addiction is characterized by a negative mood state upon smoking cessation and relapse after periods of abstinence. Clinical studies indicate that negative mood states lead to craving and relapse. The partial a4/a6/b2* nicotinic acetylcholine receptor (nAChR) agonists varenicline and cytisine are widely used as smoking cessation treatments. Varenicline has been approved in the United States for smoking cessation and cytisine is used in Eastern European countries. Despite the widespread use of these compounds, very little is known about their effects on mood states. These studies investigated the effects of varenicline, cytisine, and the cytisine-derivative 3-(pyridin-3 0 -yl)-cytisine (3-pyr-Cyt) on brain reward function in nicotine-naive and nicotine-withdrawing rats. The cytisine-derivative 3-pyr-Cyt is a very weak a4b2* nAChR partial agonist and like cytisine and varenicline has antidepressant-like effects in animal models. The intracranial self-stimulation (ICSS) procedure was used to investigate the effects of these compounds on brain reward function. Elevations in ICSS thresholds reflect a dysphoric state and a lowering of thresholds is indicative of a potentiation of brain reward function. It was shown that acute administration of nicotine and varenicline lowered ICSS thresholds. Acute administration of cytisine or 3-pyr-Cyt did not affect ICSS thresholds. Discontinuation of chronic, 14 days, nicotine administration led to elevations in ICSS thresholds that lasted for about 2 days. Varenicline and cytisine, but not 3-pyr-Cyt, diminished the nicotine withdrawal-induced elevations in ICSS thresholds. In conclusion, these studies indicate that varenicline and cytisine diminish the dysphoric-like state associated with nicotine withdrawal and may thereby prevent relapse to smoking in humans.

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“…Varenicline binds to nicotinic acetylcholine receptors (nAChR), functioning as a potent, partial agonist at α4β2 nAChRs, a weak partial agonist at α3β2 and α6 nAChRs, a weak agonist at α3β4 nAChRs, and a potent full agonist at α7 nAChRs (Grady et al, 2010;Mihalak et al, 2006). Interestingly, nAChRs may contribute to cue-driven alcohol-seeking.…”

Section: Introductionmentioning

confidence: 99%

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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Structural differences determine the relative selectivity of nicotinic compounds for native α4β2-, α6β2-, α3β4*- and α7-nicotine acetylcholine receptors

Cited by 97 publications

References 37 publications

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

Nicotinic Receptor Agonists Reduce l-DOPA–Induced Dyskinesias in a Monkey Model of Parkinson's Disease

Varenicline and Cytisine Diminish the Dysphoric-Like State Associated with Spontaneous Nicotine Withdrawal in Rats

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

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