Neonatal treatment with clomipramine modifies the expression of estrogen receptors in brain areas of male adult rats.

The participation of estrogens in depression has been well recognized. To exert its effects, estradiol binds mainly to estrogen receptors ESR1 and ESR2 (α and ß, respectively), expressed in brain regions including the hippocampus, limbic regions and hypothalamic nuclei. In rodents, modified estrogen receptors expression in brain areas have been implicated in different signs similar to those observed in depressive patients. Neonatal clomipramine (CMI) treatment is a pharmacological manipulation that generates behavioral and neurochemical changes that persist throughout adulthood and resemble human depression. The aim of this study was to analyze whether CMI neonatal treatment modifies the expression of nuclear ESR1 and ESR2 in the hippocampus, amygdala basolateral (BLA), amygdala medial (MeA), hypothalamic medial preoptic area (mPOA) and raphe nucleus in male rats. Our results indicate that CMI treatment significantly induced an mRNA increase of ESR1 in the hypothalamus, additionally produce a reduction in the mRNA ESR2 expression in raphe accompanied of an increase in hypothalamus and amygdala. CMI treated rats show more immunorreactive cells to ESR1 (ESR1-ir) in mPOA, BLA, MeA, together with a reduction of these cells in the hippocampal CA1 region. Moreover, an increase in the number of immunorreactive cells to ESR2 (ESR2-ir), in BLA and MeA, was observed in CMI treated rats. Additionally, the hippocampal CA2 region and raphe nucleus showed a decrease in these cells. Also, neonatal CMI treatment induced a decrease in the number of cells of the pyramidal layer in CA1. Overall, the results suggest that neonatal CMI treatment in rats (during brain development) induces changes in estrogen receptors in different brain areas involved with the regulation of depressive-like behaviors.

Pharmacokinetics of chlorimipramine and its demethylated metabolite in blood and brain regions of rats treated acutely and chronically with chlorimipramine.

The pharmacokinetic profiles for chlorimipramine (CIM) and its demethylated metabolite desmethylchlorimipramine (DCIM) in blood and in specific brain regions were obtained in rats after acute or chronic treatment with 15 mg/kg of the tricyclic antidepressant CIM. In blood, chronic drug treatment resulted in 1) a decrease in the time to maximal concentration of DCIM; 2) increases in maximal concentrations of CIM and of DCIM; and 3) a decrease in T1/2 of elimination of both CIM and DCIM. These changes induced a small reduction in the area under the CIM curve and a 4-fold increase in the area under the DCIM curve. In brain, both CIM and DCIM were unevenly distributed after both treatment schedules. Maximal accumulations of CIM and DCIM elimination were greatly enhanced in all brain areas by the chronic treatment. In brain, the area under the CIM concentration-time curve was only slightly affected by the chronic treatment, chronic drug treatment induced a 4-fold increase in the DCIM area. The subcellular distribution of CIM and DCIM in brain was similar in the acutely and chronically treated animals. The highest specific activity was found in the soluble fraction. These results demonstrate 1) regional brain differences in CIM and DCIM distribution and accumulation; 2) differences in pharmacokinetics between acute and chronic tricyclic antidepressant drug treatment regimens; and 3) differences between blood and brain drug and metabolite pharmacokinetics were observed which suggest that generalizations based on blood parameters should be made with great caution.