Functional recovery after denervating lesions in the central nervous system (CNS) is particularly prominent if part of the lesioned projection is spared. Several plasticity mechanisms, such as collateral sprouting, hyperactivity of remaining axons and development of receptor supersensitivity, probably contribute to efficient recovery after subtotal lesions. Although denervation-induced collateral sprouting and presynaptic compensatory hyperactivity in spared axons have been described in various systems, any possible interaction or cooperation between the two mechanisms in restoring synaptic transmission in a partially denervated target has so far not been demonstrated. We have shown previously that partial adrenergic denervation of the hippocampus in adult rats is followed by a slow and protracted reinnervation by collateral sprouting from the spared adrenergic afferents. We now report that the partial adrenergic deafferentation is accompanied by a transient increase in turnover of the transmitter in remaining axons which subsides when the denervated region becomes reinnervated, and that the development of this compensatory hyperactivity is confined to the area of maximal denervation. The topographical specificity of the compensatory noradrenergic hyperactivity response, and the interaction between this hyperactivity and the collateral reinnervation process, strongly suggest that the changes in transmitter turnover in spared afferents after denervating lesions can be regulated by local mechanisms operating within the denervated target area.