Effects of Depressant Drugs on Sodium-Calcium Exchange in Resealed Synaptic Membranes

Abstract

Many drugs that act on the central nervous system (CNS) to produce neuronal depression may do so through alterations in the regulation of Ca2+ fluxes across neuronal membranes [17]. Such actions could involve decreases in either the amount of Ca2+ that is bound to the neuronal plasma membrane or enters the neuronal compartment through activation of volt- age-sensitive channels [4,18,21,25,26,28,42]. Decreases in depolarization-induced Ca2+ conductance produced by anionic or neutral drugs such as barbiturates or alcohols [25,26] would be expected to cause decreased neurotransmitter release and, secondarily, a failure in synaptic transmission. This assumption is based on the involvement of Ca2+ in the initiation of exocytotic release of certain transmitters. Such decreases in neurotransmitter release have indeed been observed following acute administration of these depressant drugs in vivo or following the in vitro application of these agents to neuronal preparations [14,20,34,41]. Yet, in certain preparations such as isolated striatal nerve endings, the neuromuscular junction, or the hippocampal slice preparation, an agent such as ethanol increases the release of endogenous transmitter substance [11,13,22,39]. This apparent discrepancy in the actions of a depressant drug such as ethanol may be due to the existence of multiple targets for its actions, and these may include cellular entities which maintain intracellular free calcium ion concentrations ([Ca2+]i) at a very low level (10-7 M).