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Studies on the effects of saccharin on synaptic transmission in the hippocampus Morishita, Wade Katsuji


Saccharin has been shown to block long-term potentiation (LTP) of the hippocampal CA1 neuronal excitatory postsynaptic potentials (EPSPs) (Chirwa, 1988; Morishita et. al.. 1992). The mechanisms involved in this action were, however, unknown. The present electrophysiological investigation on guineapig hippocampal slices was undertaken to determine whether saccharin interfered with LTP by modulating the excitatory and the inhibitory synaptic transmission or the excitability of the CA1b, neurons. Application of 10 mM saccharin for 10 minutes did not alter the field or intracellular EPSPs in CA1b neurons elicited by low frequency stimulation of the stratum radiatum but prevented LTP of the EPSPs following a brief tetanic stimulation of the afferents. A post-tetanic application of saccharin did not prevent LTP from developing, indicating that the induction and not the maintenance of LTP was blocked by the drug. This agent also inhibited LTP induced by pairing sustained postsynaptic depolarization with low frequency activation of the stratum radiatum. Saccharin, at the concentrations that blocked LTP, did not alter the membrane potential or input resistance of the neurons. Since the induction of LTP appears to require the activation of N-methyl- D-aspartate (NMDA) receptors (Collingridge et. al.. 1983) and is modulated by activation of the A and B subtypes of y-aminobutyric acid (GABA) receptors (Wigstrom and Gustafsson, 1988; Davies et. al.. 1991). a variety of intracellular experiments were conducted to determine whether the blockade of LTP by saccharin was the result of the drug acting on these receptor systems. The depolarization of CAlb neurons produced by a tetanic stimulation i n normal medium or by brief applications of NMDA in either a Mg2+-free medium or a Mg2+-free medium containing 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a drug that antagonizes non-NMDA glutamate receptors, was not significantly altered in the presence of saccharin. Moreover, the slope and the height of the intracellular EPSP evoked in a Mg2+-free medium containing CNQX as well as in a normal medium containing 2-amino-5-phosphonovalerate (APV), a drug that antagonizes NMDA receptors, were also not significantly altered by the drug. These results suggested that saccharin blocked the induction of LTP by mechanisms that did not involve a blockade of the NMDA and the non-NMDA glutamate receptors. "Input-output" (I-O) curves constructed from the EPSPs and the inhibitory postsynaptic potentials (IPSPs) revealed that saccharin selectively increased the height of the IPSP. Pharmacological separation of the IPSP into its GABA receptor-mediated fast, and GABAg receptor-mediated slow components revealed that saccharin significantly increased the duration and height of the fast IPSP but decreased the height of the slow IPSP. In neurons injected with QX-314 (to block the postsynaptic GABAB receptor-mediated IPSPs), paired-pulse depression of the fast IPSP evoked in a CNQX and APV containing medium was not significantly altered in the presence of saccharin, suggesting that the drug did not interfere with the presynaptic GABAB receptors. Saccharin prevented LTP of the field and intracellular EPSP when the fast IPSP was blocked by picrotoxinin, suggesting that the alteration of the fast IPSP by saccharin was not responsible for the ability of the drug to block LTP. Taken togther, the results from the present study suggest that saccharin blocks the induction of hippocampal LTP at a step beyond the activation of the NMDA and non-NMDA glutamate receptors. Actions of this agent on the GABAA and GABAB receptor-mediated responses also appear not to be responsible for its LTP-blocking action. It is possible that saccharin might have interfered with LTP-inducing growth-related substances (Chirwa and Sastiy, 1986; Morishita et. al.. 1992; Sastiy et. al.. 1988a; Sastiy et. al.. 1988b; Xle et. al.. 1991) or with intracellular facilitators of LTP.

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