Dual Action of n-Alcohols on Neuronal Nicotinic Acetylcholine Receptors

Alcohol is known to modulate the activity of a variety of neuroreceptors and ion channels. Recently, neuronal nicotinic acetylcholine receptors (nnAChRs) have become a specific focus of study because not only are they potently modulated by alcohol but also they regulate the release of various transmitters, including γ-aminobutyric acid (GABA) and dopamine, which play an important role in the behavioral effects of ethanol. Whereas the potency of normal alcohols ( n -alcohols) to potentiate GABA A receptors and to inhibit N -methyl- d -aspartate receptors increases with carbon chain length, we have found that n -alcohols, depending on the carbon chain length, exert a dual action, potentiation and inhibition, on nnAChRs in primary cultured rat cortical neurons. The mechanism of dual action of n -alcohols on nnAChRs was further analyzed using human embryonic kidney cells expressing the α4β2 subunits. Shorter chain alcohols from methanol to n -propanol potentiated acetylcholine (ACh)-induced currents, whereas longer chain alcohols from n -pentanol to n -dodecanol inhibited the currents. n -Butanol either potentiated or inhibited the currents depending on the concentrations of ACh and butanol. The parameters for both potentiation (log EC 200 ) and inhibition (log IC 50 ) were linearly related to carbon number, albeit with different slopes. The slope for potentiation was −0.299, indicating a change in free energy change (ΔΔG) of 405 cal/mol/methylene group, whereas the slope for inhibition was −0.584, indicating a ΔΔG of 792 cal/mol. These results suggest that potentiating and inhibitory actions are exerted through two different binding sites. Ethanol decreased the potency of n -octanol to inhibit ACh currents, possibly resulting from an allosteric mechanism.