NEUROANATOMICAL SPECIFICITY AND DOSE DEPENDENCE IN THE TIME-COURSE OFIMIPRAMINE-INDUCED BETA-ADRENERGIC-RECEPTOR DOWN-REGULATION IN RAT-BRAIN

The time course of beta adrenergic receptor adaptation in response to chronic imipramine treatment (10 or 20 mg/kg) was assessed by quantita tive autoradiographic analysis of (125)l-pindolol binding in rat brain . Binding of the radioligand was assessed in 18 brain areas, including subregions of the hippocampus, amygdala, septum, hypothalamus and spe cific cerebral cortical regions. After only 2 days treatment with imip ramine at a dose of 20 mg/kg, select cortical regions exhibited a redu ction in (125)l-pindolol binding. These rapidly adapting cortical regi ons included the medial prefrontal, lateral frontal, ventrolateral orb ital and piriform cortices. After 7 or 21 days treatment with imiprami ne at 20 mg/kg, 16 of 18 brain regions examined exhibited significant reduction in (125)l-pindolol binding. The only regions examined that d id not show reduced (125)l-pindolol binding for these treatment condit ions were the caudate-putamen and anterior hypothalamic area. After 2 days treatment with 10 mg/kg of imipramine, down-regulation of beta ad renergic receptors was not observed in any region. After 7 days treatm ent with 10 mg/kg, down-regulation of beta adrenergic receptor binding was found only in certain cortical regions: medial prefrontal, latera l frontal, ventrolateral orbital and piriform cortices. Thus, the cort ical regions that were most rapidly affected with the 20 mg/kg dose of imipramine (ie., after 2 days) were also the first to respond with th e 10 mg/kg dose of the drug. After 21 days treatment with imipramine a t 10 mg/kg, (125)l-pindolol binding was reduced in 13 of the 18 region s examined. These data demonstrate that the duration of imipramine tre atment required to down-regulate the beta adrenergic receptors is dose -dependent and that there are marked regional differences in the rate of this drug-induced neurochemical adaptation. Neuroanatomical differe nces in the rate of antidepressant-induced neural adaptation could be related to the progressive time course observed for therapeutic respon ses to antidepressant drug treatment.