The long term effects of specific noradrenergic denervation of rat cerebral cortex were considered in parallel studies of in vitro noradrenergic receptor binding and isoproterenol-induced adenosine 3′:5′-monophosphate (cycle AMP) generation and of in vivo oxidative metabolism. Noradrenergic denervation was achieved by the local, unilateral injection of 6-hydroxydopamine into the locus ceruleus. Cerebral noradrenaline remained depleted throughout the 8-week duration of the study. Ligand-binding assays showed increased beta-adrenergic receptors 2 weeks after locus ceruleus lesion with recovery occurring by 4 weeks. There were no changes in alpha 1-adrenergic receptors. Isoproterenol-induced cyclic AMP generation increased at 2 weeks after lesion but recovered at 8 weeks. Dual wavelength reflection spectrophotometric measurements of cytochrome oxidase reduction/oxidation and local blood volume shifts, provoked in situ by direct cortical stimulation, also demonstrated abnormalities at 2 weeks with recovery by 4 weeks after lesion. Thus, in vivo and in vitro changes after locus ceruleus lesion are reversible and the time course of these changes is related temporally. These data suggest that cerebral cortex has adaptive capabilities which are activated to compensate for prolonged noradrenaline depletion. We also speculate that there may be a causal relationship between the in vitro and in vivo parameters studied.