There is clinical and experimental evidence that monoamine neurons respond to lesions with a wide range of compensatory adaptations aimed at preserving their functional integrity. Neurotoxin-induced lesions are followed by increased synthesis and release of transmitter from residual monoamine fibers and by axonal sprouting. However, the fate of lesioned neurons after long survival periods remains largely unknown. Whether regenerative sprouting may contribute significantly to recovery of function following lesions which induce cell loss has been questioned. We have previously analyzed the response of locus coeruleus (LC) neurons to systemic administration of the noradrenergic (NE) neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) to adult rats. This drug causes ablation of nearly all LC axon terminals within 2 weeks after administration, followed by a profound loss of LC cell bodies 6 months later. The present study was conducted to determine the fate of surviving LC neurons and to characterize their potential for regenerative sprouting during a 16 month period after DSP-4 treatment. The time-course and extent of LC neuron degeneration were analyzed quantitatively in Nissl-stained sections, and the regenerative response of residual neurons was characterized by dopamine-beta-hydroxylase immunohistochemistry. The results document that LC neurons degenerate gradually after DSP-4 treatment, cell loss reaching on average 57% after 1 year. LC neurons which survive the lesion exhibit a vigorous regenerative response, even in those animals in which cell loss exceeds 60-70%. This regenerative process leads progressively to restoration of the NE innervation pattern in the forebrain, with some regions becoming markedly hyperinnervated. In stark contrast to the forebrain, very little reinnervation takes place in the brainstem, cerebellum and spinal cord. These findings suggest that regenerative sprouting of residual neurons is an important compensatory mechanism by which the LC may regain much of its functional integrity in the presence of extensive cell loss. Furthermore, regeneration of LC axons after DSP-4 treatment is region-specific, suggesting that the pattern of reinnervation is controlled by target areas. Elucidation of the factors underlying recovery of LC neurons after DSP-4 treatment may provide insights into the compensatory mechanisms of central neurons after injury and in disease states.