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. The goal is to explain the nature of the effects of zinc and the mechanism(s) for its modulation of hippocampal excitability. 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 the intraviral zinc chelators, dithizone and diethyldithiocarbamate (DEDTC). The biological assay used was occurrence of wet dog shakes and seizures following subcutaneous administration of kainic acid (KA). Intraperitoneal injection of dithizone (12.5-100 mg/kg) or DEDTC (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 dynorphin. They also produce transient increases in the hippocampal levels of a number of amino acids (viz., taurine, glutamate, glutamine, and GABA). These effects are associated with reduced levels of hippocampal zinc (as measured by Timm staining of the hippocampus). Work in progress is investigating the effect of DEDTC on seizure activity elicited by electrical stimulation of the perforant path (the major input to the hippocampal formation). Preliminary evidence suggests that, like for KA, DEDTC enhances seizure activity induced by stimulation of the perforant path. It appears, then, that dithizone and diethyldithiocarbamate may prove to be useful tools for exploring the - actions of zinc on the hippocampus. Other work in progress involves: (1) effects of injection of these agents locally in the hippocampus, and (2) examination of their electrophysiological effects on the hippocampus.
