Effects of chronic antidepressant treatments on 5-HT and NA transporters in rat brain: an autoradiographic study

Tricyclic antidepressants and serotonin (5-MT) uptake inhibitors rapidly bl ock uptake sites, or transporters; however, their therapeutic effects are o nly seen after 2-3 weeks of treatment. Thus, direct blockade of 5-HT and no radrenaline (NA) transporters cannot account entirely for their clinical ef ficacy, and other long-term changes may be involved. Adult Sprague Dawley r ats were treated for 21 days with daily injections of either desipramine, t rimipramine, fluoxetine, or venlafaxine; a fifth group that was used as a c ontrol, received daily saline injections. Identified cortical areas, hippoc ampal divisions and nuclei raphe dorsalis, raphe medialis and locus coerule us were examined by quantitative autoradiography using either [H-3]citalopr am to label 5-HT transporters, or [H-3]nisoxetine for NA uptake sites. Incr eases in [H-3]nisoxetine binding were found in the cingulate, frontal, pari etal, agranular insular, entorhinal and perirhinal cortices as well as in t he hippocampal divisions CA1, CA3, dentate gyrus and subiculum, and in nucl eus raphe dorsalis of trimipramine-treated animals compared to the control rats. Also, densities of NA transporters decreased in temporal cortex, CA2 and nucleus raphe dorsalis in fluoxetine-treated rats as compared to the co ntrols. Also, there was a decrease in NA transporters in the locus coeruleu s of the desipramine-treated animals as compared to the densities measured in the control group. Chronic treatment with desipramine or trimipramine, w hich do not directly inhibit 5-HT uptake, compared to fluoxetine and venlaf axine, lead to increases in 5-HT transporter densities in cingulate, agranu lar insular and perirhinal cortices. The present study shows differential r egion-specific effects of antidepressants on 5-HT and NA transporters, lead ing to distinct consequences in forebrain areas. (C) 2000 Elsevier Science Ltd. All rights reserved.