Cellular actions of norepinephrine and their intracellular mediation in rat hippocampal CA3 pyramidal neurons.

Abstract

Pyramidal neurons in the CA3 region of the rat hippocampus are known targets of a noradrenergic projection from the locus coeruleus. However, the physiological actions of norepinephrine in these cells have remained largely unexplored. This dissertation research sought first to identify the electrophysiological effects of exogenously applied norepinephrine in CA3 pyramidal neurons in the rat. In addition, this study sought to determine which subtype(s) of adrenergic receptor were responsible for noradrenergically-induced effects in these cells and whether the actions of norepinephrine were mediated by the intracellular second messenger cyclic AMP. Intracellular recordings were obtained from CA3 pyramidal cells in vitro in rat hippocampal slices. Hippocampal slices were maintained submerged in a recording chamber beneath continuously flowing, oxygenated, artificial cerebrospinal fluid, and drugs were applied to the superfusate. The results of these experiments have demonstrated that norepinephrine produces depolarizations and hyperpolarizations in CA3 pyramidal neurons, but that these effects on resting membrane potential were small and quite variable. A much more robust action of norepinephrine in CA3 pyramidal neurons was found to be a reduction of the calcium-activated potassium conductance that is responsible for a slowly developing hyperpolarizing potential, the afterhyperpolarization (AHP) which follows bursts of action potentials in these neurons. This effect was shown to be mediated by the activation of a $\beta$-adrenergic receptor and did not appear to result from a reduction in voltage-dependent calcium entry. Furthermore, it was shown by use of agents which act beyond the $\beta$-adrenergic receptor to alter intracellular levels of cyclic AMP that the action of norepinephrine on the AHP was mediated by cyclic AMP. Finally this dissertation research revealed that the $\beta$-adrenergic receptor mediated reduction of the AHP does not necessarily lead to a blockade in accommodation of spike discharge in CA3 pyramidal cells. This latter finding indicates that the functional role of noradrenergic input to the CA1 and CA3 regions of the rat hippocampus is likely to be quite different.