Electrophysiological and electrochemical responses of NMDA in the cerebellum: interactions with noradrenergic pathway

Abstract

In the present experiments, we measured N -methyl-D-asparate (NMDA)-induced norepinephrine (NE) release and extracellular action potentials in the cerebellar cortex of urethane-anesthetized rats. The overflow of NE was measured using a Nafion coated-carbon fiber electrode and in vivo chronoamperometry. We found that both NMDA and quisqualate evoked NE release. Our previous work demonstrated that the electrophysiological activity of cerebellar Purkinje neurons could be either excited or inhibited by local NMDA application. It was reported that bicuculline antagonized NMDA-induced inhibition in Purkinje neurons, suggesting that a GABAergic mechanism was activated during NMDA application. We and others previously found that GABA-mediated electrophysiological depressions were enhanced by NE acting via β-adrenergic receptors while these responses were decreased by activation of α-adrenergic receptors. Since NMDA evokes overflow of endogenous NE, the electrophysiological depression induced by NMDA may contain an NE-mediated modulatory component. In this study, we first examined the interaction of NMDA with a β-adrenergic agonist. We found that local application of isoproterenol facilitated NMDA- or GABA-mediated electrophysiological depressions of the Purkinje neurons. Application of phenoxybenzamine, which antagonized the α-adrenergic response of synaptically released NE, also facilitated NMDA-elicited depression. In contrast, the depression induced by GABA, which did not induce NE overflow, was not potentiated by phenoxybenzamine. The facilitation of NMDA-induced depression by phenoxybenzamine was antagonized by the β-adrenergic antagonist timolol. Taken together, these data suggested that the noradrenergic pathway is involved in NMDA-induced electrophysiological responses in the cerebellum. NMDA may induce neuronal depression through modulation of GABAergic inhibition via NMDA-evoked NE release onto cerebellar Purkinje neurons.