Dual action of n-alcohols on neuronal nicotinic acetylcholine receptors

Alcohol is known to modulate the activity of a variety of neuroreceptors an d ion channels. Recently, neuronal nicotinic acetylcholine receptors (nnACh Rs) have become a specific focus of study because not only are they potentl y modulated by alcohol but also they regulate the release of various transm itters, including gamma -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 GABAA receptors and to inhib it N-methyl-D-aspartate receptors increases with carbon chain length, we ha ve found that n-alcohols, depending on the carbon chain length, exert a dua l action, potentiation and inhibition, on nnAChRs in primary cultured rat c ortical neurons. The mechanism of dual action of n-alcohols on nnAChRs was further analyzed using human embryonic kidney cells expressing the alpha4 b eta2 subunits. Shorter chain alcohols from methanol to n-propanol potentiat ed acetylcholine (ACh)-induced currents, whereas longer chain alcohols from n-pentanol to n-dodecanol inhibited the currents. n-Butanol either potenti ated or inhibited the currents depending on the concentrations of ACh and b utanol. The parameters for both potentiation (log EC200) and inhibition (lo g IC50) were linearly related to carbon number, albeit with different slope s. The slope for potentiation was -0.299, indicating a change in free energ y change (Delta DeltaG) of 405 cal/mol/methylene group, whereas the slope f or inhibition was -0.584, indicating a Delta DeltaG of 792 cal/mol. These r esults 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.