Promoting activity of (α4)3(β2)2 nicotinic cholinergic receptors reduces ethanol consumption

Abstract

There is increasing interest in developing drugs that act at α4β2 nicotinic acetylcholine receptors (nAChRs) to treat alcohol use disorder. The smoking cessation agent varenicline, a partial agonist of α4β2 nAChRs, reduces alcohol intake, but its use can be limited by side effects at high therapeutic doses. There are two stoichiometric forms of α4β2 nAChRs, (α4) 3 (β2) 2 and (α4) 2 (β2) 3. Here we investigated the hypothesis that NS9283, a positive allosteric modulator selective for the (α4) 3 (β2) 2 form, reduces ethanol consumption. NS9283 increased the potency of varenicline to activate and desensitize (α4) 3 (β2) 2 nAChRs in vitro without affecting other known targets of varenicline. In male and female C57BL/6J mice, NS9283 (10 mg/kg) reduced ethanol intake in a two-bottle choice, intermittent drinking procedure without affecting saccharin intake, ethanol-induced incoordination or ethanol-induced loss of the righting reflex. Subthreshold doses of NS9283 (2.5 mg/kg) plus varenicline (0.1 mg/kg) synergistically reduced ethanol intake in both sexes. Finally, despite having no aversive valence of its own, NS9283 enhanced ethanol-conditioned place aversion. We conclude that compounds targeting the (α4) 3 (β2) 2 subtype of nAChRs can reduce alcohol consumption, and when administered in combination with varenicline, may allow use of lower varenicline doses to decrease varenicline side effects.

Midazolam, methamphetamine, morphine and nicotine intake in high‐drinking‐in‐the‐dark mice

“…83 Similarly, varenicline, a nicotinic acetylcholine receptor partial agonist that also functions as a smoking cessation aid, has been shown to reduce ethanol intake in mice. [84][85][86] The results herein suggest a divergence in the genes captured during the selection process in HDID-1 and HDID-2 mice that may increase susceptibility to generalized drug taking in the HDID-2 mice, at least for nicotine and opioids. Interestingly, naltrexone has been tested for efficacy in reducing ethanol intake in HDID-1 mice, and no significant reductions in intake were observed.…”

“…Bupropion, a norepinephrine–dopamine reuptake inhibitor that functions as a smoking cessation aid, has also been shown to reduce ethanol intake in mice 83 . Similarly, varenicline, a nicotinic acetylcholine receptor partial agonist that also functions as a smoking cessation aid, has been shown to reduce ethanol intake in mice 84–86 …”

Drug Development in Channelopathies: Allosteric Modulation of Ligand-Gated and Voltage-Gated Ion Channels

“…Therefore, NS9283 allosterically enhances the potency rather than affinity of orthosteric agonists at α4β2 nAChRs. NS9283 has shown prospective utilities in the management of cognitive dysfunction, pain, and alcohol use disorder . Similar to NS9283, CMPI did not competitively displace the binding of [ 3 H]-cytisine to α4β2 nAChRs but enhanced agonist-induced currents of the receptors, indicating the positive allosteric modulation of CPMI on the receptors. , Additionally, CPMI was found to be highly selective for (α4) 3 (β2) 2 nAChRs.…”

Neurobiological Mechanisms of Nicotine Reward and Aversion

“…In addition, the (a4b2) 2 (a4) nAChR positive allosteric modulator NS9283 (Mazzaferro et al, 2019) decreased nicotine self-administration in rats (Maurer et al, 2017). NS9283, cytisine, and varenicline also decreased ethanol intake in rats (Steensland et al, 2007;Bell et al, 2009;Sotomayor-Zarate et al, 2013;Wang et al, 2020). Hence, (a4b2) 2 (a4) nAChRs likely play an important role in the reinforcing properties of nicotine and other drugs of abuse, and compounds that modulate this nAChR stoichiometry may serve as novel therapeutics for substance use disorders (see Fig.…”