ACUTE & CHRONIC BARBITURATES: IN VITRO BIOCHEMISTRY

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There is clear evidence from both this and other laboratories showing that barbiturates interact with excitatory amino acid (EAA) neurotransmitters. It is unclear, however, where barbiturates are acting to affect these transmitters. It is probable that they do not directly act on EAA receptors but rather affect receptor-mediated events. This proposal will test the hypothesis that the acute and chronic actions of barbiturates on the EAA-and potassium-induced influx of 45Ca++ and the elevation of cyclic guanosine monophosphate (cGMP) are secondary to an interaction with calcium channels associated with either the EAA receptor, neuronal depolarization and/or the presynaptic release of neurotransmitter. Primary cultures of cerebellar granule neurons are an excellent system for studying excitatory amino acid (EAA) receptors. Furthermore, in the preliminary results of this proposal I provide data showing that this system is also an excellent system to study the effects of barbiturates. Pentobarbital prevents the EAA-induced elevation of both cGMP and 45Ca++ influx n these neurons. In addition, exposing these neurons to pentobarbital for several days results in a hyperresponsiveness to the EAA-induced elevation of cGMP and 45Ca++ influx after pentobarbital is removed from the culture media. The major objective of this proposal is to examine the mechanisms by which barbiturates exert the above actions by focusing on the interaction of barbiturates with EAA receptor-lined calcium channels. A direct effect of several barbiturates on calcium channels will be examined using cGMP elevation, 45Ca++ influx and the release of glutamate as parameters to be followed. Experiments are designed which will separate the effects of barbiturates on EAA and calcium channels from the effects of barbiturates on the GABA receptor and chloride channels.