Oxaprotiline: induction of central noradrenergic subsensitivity of its (+)-enantiomer

The effects of the tetracyclic antidepressant oxaprotiline and its two optically active enantiomers on the norepinephrine (NE) receptor coupled adenylate cyclase system were determined in slices of the rat cerebral cortex. While oxaprotiline does not change the response of the cyclic AMP generating system to NE after a single dose, chronic administration of the drug for 3 to 14 days down-regulates the receptor system. The noradrenergic subsensitivity is linked to a reduction in the Bmax value of beta-adrenergic receptors as assessed by (3H)-dihydroalprenolol binding without changes in the Kd value. The action of oxaprotiline on the NE receptor coupled adenylate cyclase system resides entirely in the (+)-enantiomer which is a potent inhibitor of the neuronal uptake of NE. The (-)-enantiomer of oxaprotiline which is a weak inhibitor of NE reuptake, failed, even in high doses, to modify the noradrenergic receptor system. Though not excluding co-regulatory factors in addition to NE, the studies support the view that an enhanced and persistent NE receptor interaction is one of the prerequisites for the in vivo down-regulation of central noradrenergic receptor function. The results also suggest that the therapeutic activity of oxaprotiline may reside in its (+)-enantiomer.