DSP4-induced noradrenergic lesions increase β-adrenergic receptors and hippocampal electrophysiological responsiveness

Abstract

Following profound (>90%) depletions of norepinephrine (NE) by the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), the numbers of β-adrenergic receptors were significantly increased (20–25%) in rat hippocampal and somatosensory cortical membrane; however, the numbers of α 1-adrenergic receptors and the affinities of both types of receptors were unaffected. This selective up-regulation of β-adrenergic receptors was evident 1 week after DSP4 administration and was maintained for at least 2 more weeks. In electrphysiological experiments in the hippocampal slice preparation, responses to threshold as well as maximal concentrations of isoproterenol were enhanced 150% and 33%, respectively, in the DSP4-lesioned animals. The results demonstrate that nearly complete depletion of brain NE produced by administration of DSP4, like that produced by 6-hydroxydopamine, results in increased numbers of β- but not α-adrenergic receptors, and suggest that the density of the former are regulated by afferent noradrenergic fibers. Furthermore, the functional significance of the increased number of hippocampal β-adrenergic receptors is directly manifested in a greater electrophysiological responsiveness to an exogenously administered β-adrenergic receptor agonist.