Ethanol Modulation of Nicotinic Acetylcholine Receptor Currents in Cultured Cortical Neurons

Abstract

Ethanol, at physiologically relevant concentrations, significantly enhanced high-affinity neuronal nicotinic acetylcholine receptor (NnAChR) currents insensitive to alpha-bungarotoxin (alpha-BuTX-ICs) in cultured rat cortical neurons in a fast and reversible manner, as determined by standard whole-cell patch-clamp recording techniques. The enhancement was (mean +/- S.D.) 7.7 +/- 5% to 192 +/- 52% upon coapplication of 3 to 300 mM ethanol with 1 to 3 microM ACh. No plateau for this ethanol-induced enhancement of alpha-BuTX-ICs was reached. The maximal alpha-BuTX-IC evoked by very high concentrations of ACh also was increased upon coapplication of ethanol. In contrast, ethanol weakly inhibited low-affinity NnAChR currents sensitive to alpha-BuTX (alpha-BuTX-SCs) (5 +/- 4% to 29 +/- 6% inhibition by 10 to 300 mM ethanol at 300 to 1000 microM ACh). This neuronal preparation also enabled comparison of ethanol action on NnAChRs with its action on N-methyl-D-aspartate receptor currents and gamma-aminobutyric acid receptor currents within the same neurons. Ethanol (100 mM) was more potent at enhancing NnAChR alpha-BuTX-ICs (61 +/- 9% enhancement) than it was at enhancing gamma-aminobutyric acid receptor current (3 +/- 3% enhancement-not statistically significant) or at inhibiting N-methyl-D-aspartate receptor currents (approximately 35 +/- 7% inhibition). Thus, NnAChRs, particularly those insensitive to alpha-BuTX, may be sensitive conduits through which ethanol can mediate some of its actions in the brain.

Varenicline, an α4β2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

“…Results from in vitro (32)(33)(34) and genetic studies (35)(36)(37) show that ethanol interacts directly with ␣4␤2 nAChRs (30,31). Our data suggest that varenicline reduces the efficacy of ACh activity at nAChRs, leading to a reduction in ethanol intake by decreasing the rewarding properties of ethanol.…”

“…Results from in vitro studies have shown that ethanol directly activates the ␣4␤2 nAChR (32)(33)(34). The ␣4 nAChR gene may influence some of the common actions of nicotine and ethanol in the mouse because a polymorphism in the gene encoding the ␣4 subunit of the nAChR (Chrna4) is associated with ethanol intake in animals (35) and modulates ethanol withdrawal (36) and the ethanol effect on acoustic startle response (35,37).…”

Combined Exposure to Nicotine and Ethanol in Adolescent Mice Differentially Affects Anxiety Levels during Exposure, Short-Term, and Long-Term Withdrawal

“…Accordingly, the nicotinic receptor is a site at which nicotine and ethanol may interact. Corroborating this suggestion, it has been demonstrated that ethanol enhances agonist-induced ion flux through nicotinic receptors (Aistrup et al, 1999;Cardoso et al, 1999) and that ethanol-induced stimulation of mesolimbic dopamine systems involves the activation of nicotinic receptors (Soderpalm et al, 2000). Despite these findings, there have been relatively few animal studies of the basic neurobiology of the combined nicotine and ethanol exposure, and while some studies suggest that nicotine has a modulatory effect on ethanol effects through its cholinergic actions, others show no marked interactions and still others show augmented effects (Bachtell and Ryabinin, 2001;Penland et al, 2001;Tizabi et al, 2002Tizabi et al, , 2003.…”

Mechanisms of Action of Cognitive Enhancers on Neuroreceptors

“…23) This raises the question of whether nefiracetam potentiation at high ACh concentrations is due to an increase in the total receptors available for activation by rapid exocytosis of the receptors or changes in single-channel properties. The latter may include: 1) an increase in single-channel conductance; 2) an increase in open probability; 3) a prolongation of open time; and 4) a combination of any of the three.…”