Reserpine and the role of axonal transport in the independent regulation of pre- and postsynaptic beta-adrenoreceptors.

The response of pre- and postsynaptic beta-adrenoreceptors to depletion of brain norepinephrine (NE) with reserpine in the rat was characterized by studying the anterograde and retrograde axonal transport of presynaptic receptors and the receptor binding changes induced in postsynaptic frontal cortex cells. Anterograde transport was shown to occur by the linear accumulation of [3H]dihydroalprenolol ([3H]DHA) binding sites (by in vitro binding assay) proximal to a 6-hydroxydopamine (6-OHDA) lesion placed in the ascending pathway of the locus coeruleus and was blocked by more proximal lesions in the pathway. Retrograde transport was demonstrated by the accumulation of [125I]iodocyanopindolol binding distal to similar lesions. Autoradiograms from sections of 6-OHDA injected brains were produced with [3H]DHA binding in the presence of the beta 2-agonist, zinterol, and suggested that the anterograde accumulation of binding sites was primarily of the beta 1-subtype. A single injection of reserpine (5 mg/kg, i.p.) produced a long lasting (6-8 weeks), biphasic decrease in cortical NE levels with nadirs and 4 and 28 days (10% and 45% of control, respectively). Frontal cortex binding of [3H]DHA increased to a maximum at 7-14 days and again at 28 days post-reserpine (230% and 167% of control, respectively). These increases were not prevented by the destruction of presynaptic noradrenergic nerve terminals with intraventricular administration of 6-OHDA 1 day prior to sacrifice and therefore appeared to take place solely in postsynaptic cells. Presynaptic, anterograde axonal transport of beta-receptors was completely blocked from 4-14 days post-reserpine, increased to 323% of control at 21 days, was blocked again at 6 weeks and returned to control by 8 weeks. Retrograde transport of beta-receptors followed a similar pattern suggesting that the presynaptic alterations in beta-receptors in noradrenergic neurons of the locus coeruleus take place independently from those in postsynaptic cortical beta-receptors as a response to NE depletion by reserpine.