Abstract

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_Areceptors and to inhibitN-methyl-d-aspartate receptors increases with carbon chain length, we have found thatn-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 ofn-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 EC₂₀₀) and inhibition (log IC₅₀) 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 ofn-octanol to inhibit ACh currents, possibly resulting from an allosteric mechanism.