We tested the hypothesis that the time course of neurochemical adaptation that occurs during chronic imipramine treatment varies among specific brain regions. Down-regulation of brain beta-adrenergic receptors was used as a model of antidepressant-induced neural adaptation. Beta-adrenergic receptors were assessed by quantitative autoradiographic analysis of [125I]-pindolol binding after different periods of imipramine treatment. The duration of imipramine treatment required to down-regulate the receptors varied markedly among different brain regions. Select cortical regions exhibited a reduction in [125I]-pindolol binding after only two injections of imipramine. These rapidly adapting cortical regions included the medial prefrontal, ventrolateral orbital, and piriform cortices. In contrast, some brain regions required a 3-week treatment period before down-regulation of beta-adrenergic receptors was observed. Such slowly adapting regions included subdivisions of the hypothalamus and amygdala. Other brain regions examined required intermediate periods of imipramine treatment, of 4 to 14 days, to produce a reduction in beta-adrenergic binding. It is possible that differential rates of neural adaptation among brain regions are related to the time course of therapeutic response to antidepressant drug treatment.