Possible association of alcohol tolerance with increased synaptic Ca ²⁺ sensitivity

The inhibitory effect of ethanol on neurotransmitter release^1,2 has been suggested to be due to either reduced Ca²⁺ entry³ or increased removal of free intracellular Ca²⁺ from the synapse⁴. The use of the Ca²⁺ ionophore, A23187, to allow direct access of external Ca²⁺ to the presynaptic interior ⁵ should help to determine which of these two factors is the more important, as ethanol should inhibit A23187-induced release of transmitter only if increased Ca²⁺ removal from the synapse is important. Here we show in rat striatal slices that, although ³H-dopamine release evoked by depolarization with 40 mM K⁺ is inhibited by 50 mM ethanol, the release evoked by A23187 is enhanced by the presence of ethanol in vitro. The results suggest that ethanol reduces depolarization-induced transmitter release by reducing Ca²⁺ entry to the presynaptic terminal. However, for brain slices taken from rats made tolerant to ethanol, ³H-dopamine release in the absence of ethanol showed altered characteristics; both K ⁺ depolarization and A23187 released a significantly greater fraction of ³H-dopamine from these slices than from controls. Thus tolerance to the inhibitory effect of ethanol on release may develop by a mechanism involving increased sensitivity of the terminal to Ca²⁺ entry.