Age-related subsensitivity of cerebellar Purkinje neurons to locally applied beta 1-selective adrenergic agonist

Abstract

Previous electrophysiological studies in aged rats have revealed a number of deficits in noradrenergic neurotransmission in the central nervous system. Such deficits include subsensitivity to the depressant effects of norepinephrine on cerebellar Purkinje neurons, which has been attributed specifically to altered beta adrenergic receptor-mediated processes. The objective of this study was to determine which beta adrenergic receptor subtype, beta 1 or beta 2, in responsible for this age-related subsensitivity. The effects of beta 1 and beta 2 agonists on spontaneous activity of Purkinje neurons was first examined in young rats and the selectivity of these agents was validated using selective beta 1 and beta 2 antagonists. The effects of the selective beta 1 and beta 2 agonists were then compared in young (3-month-old) and aged (18- and 26-month-old) Fischer 344 rats. These agents were applied to Purkinje neurons by pressure microejection from multibarreled micropipettes and the change in neuronal action potential discharge rate was recorded. Both dobutamine, a beta 1-selective agonist, and zinterol, a beta 2-selective agonist, induced dose-dependent inhibitions of Purkinje cell firing rate. Dobutamine-induced inhibitions were blocked by the selective beta 1 antagonist, ICI 89406 and not by the beta 2-selective antagonist, ICI 118551; conversely, zinterol-induced inhibitions were not blocked by ICI 89406 but were blocked by the presence of ICI 118551. Purkinje neurons of both groups of aged rats were significantly less sensitive to locally applied dobutamine than Purkinje cells of young rats. Subsensitivity to zinterol was not observed in either of the aged groups. These results suggest an age-related functional decline in beta 1 adrenergic receptor-mediated processes, with no concomitant change in beta 2 receptor-mediated processes. Since beta 1 adrenergic receptors modulate inhibitory afferent input to Purkinje neurons, a process that may be critical in maintaining intact motor function, this selective subsensitivity may be an important factor contributing to the motor dysfunctions often seen in the e elderly.