FLUOXETINE INDUCES THE TRANSCRIPTION OF GENES ENCODING C-FOS, CORTICOTROPIN-RELEASING FACTOR AND ITS TYPE-1 RECEPTOR IN RAT-BRAIN

Fluoxetine is a serotonin re-uptake blocker commonly used to treat end ogenous depression. The present experiments were carried our to assess the effects of fluoxetine on c-fos induction throughout the rat brain . In addition, intron-directed in situ hybridization analysis was used to examine fluoxetine regulation of corticotropin-releasing factor he teronuclear gene transcription in the paraventricular nucleus of the h ypothalamus. Because the actions of corticotropin-releasing factor are mediated by membrane bound corticotropin-releasing factor type 1 rece ptors, we also evaluated the stimulation of such receptors after acute fluoxetine exposure. The immediate-early gene, c-fos, was markedly in duced in several telencephalic and diencephalic brain structures. For instance, a strong hybridized signal was apparent 30 min after fluoxet ine (10 mg/kg; intraperitoneal) administration in the caudate putamen, septal nucleus, bed nucleus of stria terminalis, anterodorsal preopti c area, paraventricular nucleus. supraoptic nucleus, ventromedial hypo thalamus and posterior hypothalamic nucleus. In addition, c-fos-expres sing neurons were also evident in discrete amygdaloid nuclei. This nuc lear induction was brief in duration, as levels of the immediate-early gene were mostly undetectable 90 min after drug administration. In co ntrast to the extensive induction of c-fos by fluoxetine throughout th e brain parenchyma, elevation of corticotropin-releasing factor hetero nuclear RNA levels were confined exclusively to neurosecretory nerve c ells of the paraventricular nucleus, with peak levels detected 30 min after fluoxetine exposure. Therefore, the time-course of corticotropin -releasing factor heteronuclear RNA closely paralleled that of c-fos. Significant changes in corticotropin-releasing factor type 1 receptor messenger RNA levels were also observed in the paraventricular nucleus but with a slow incremental biosynthesis of the receptor messenger RN A, as high levels were discernible only 360 min after fluoxetine treat ment. Finally, we failed to detect sex-related differences in the acut e response to fluoxetine, as both female and male rat brains showed a comparable induction of c-fos, corticotropin-releasing factor heteronu clear RNA and corticotropin-releasing Factor type 1 receptor expressio n within parvocellular neurosecretory nerve cells that govern the stre ss response. All of these findings are discussed in terms of specific sequences of nuclear events that couple fluoxetine-based serotonin inp ut with changes in gene expression in selective neurons. (C) 1998 IBRO . Published by Elsevier Science Ltd.