Several pieces of evidence suggest that endogenous opioids and zinc may interact to regulate neuronal excitability within the hippocampal formation. The purpose of this project is to conduct a systematic investigation into the effects of zinc on hippocampal neuronal excitability, with an emphasis on its interaction with enkaphalin. The goal is to explain the nature of the effects of zinc and the mechanism(s) for its interaction with enkaphalin. First it was necessary to determine the manner in which zinc levels were to be altered. As an initial approach we chose to attempt to alter zinc levels by systemic administration of zinc chloride or the intraviral zinc chelator, dithizone. The biological assay used was occurrence of wet dog shakes and seizures following subcutaneous administration of kainic acid (KA). We were unable to confirm the report of Porsche (IRCS Med. Sci. 11: 599, 1983) that subcutaneously administered Zn Cl2 prevents KA induced seizures in rats. Instead, we found no effect of Zn C12 in doses up to and including 100 mg/kg. This was true whether zinc was given before or after KA. In contrast, intraperitoneal injection of dithizona (12.5-100 mg/kg) or diethyldithiocarbamate (100-400 mg/kg) has a profound and dose related effect on the effects of KA. When given 15 minutes after the subcutaneous injection of KA, they markedly potentiate KA activity. They also produce a transient decrease in hippocampal levels of enkephalin and dyrorphin. They also produce transient increases in the hippocampal levels of a number of amino acids (viz., taurine, glutamate, glutamine, and GABA). Those effects are associated with reduced levels of hippocampal zinc (as measured by Timm staining of the hippocampus). It appears, then, that dithizone and diethyldithiocarbamate may prove to be useful tools for exploring the actions of zinc on the hippocampus. Work in progress involves: (1) further characterization of the changes in peptide and amino acids induced by these compounds, and (2) examination of their electrophysiological effects on the hippocampus.
