Mechanism of pharmacological action of nootropics in the hippocampus

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The use-dependent strengthening of a synaptic efficacy is known as a long-term potentiation. The long-term potentiation that occurs in the hippocampus is thought to be a cellular mechanisms associated with learning and memory. Since the long-term potentiation observed in the mossy fiber-CA3 system is potentiated by low concentrations of brain function potentiating drugs, it is conceivable that synapse between mossy fibers and CA3 pyramidal cells is one of common sites of actions of these drugs. Therefore, this project was conducted as a step to elucidate the mechanisms of pharmacological actions of brain function potentiating drugs in the hippocampus and the following results have been gotten.1. Bifemelane, a brain function potentiating drug, increased the high K^+ evoked release of L-glutamate from the mossy fiber terminals in the hippocampus of the guinea-pig. Such an increase may be at least partly mediated with the activation of protein kinase C in the mossy fiber terminals, as it was blocked by a kinase inhibitor, H-7, and bifemelane produced the translocation of protein kinase C from cytosol to membrane in the mossy fiber terminals. Bifemelane did not produce an increase in the evoked release of L-glutamate from nor translocation of protein kinase C in conventional synaptosomes that dose not contain mossy fiber terminals.2. There were specific binding sites for [^3H]bifemelane in the hippocampus of the guinea-pig and the density of such binding sites were higher in the CA3 than in the CAl. A high affinity binding sites for [^3H]bifemelane may not be monoamine uptake sites, as they were observed in the presence of imipramine. The specific binding of [^3H]bifemelane was inhibited by bifemelane at 1-1000 nM, but not by vinpocetine, indeloxazine, idebenone, piracetam and Ca hopatenate.