PROTEIN-KINASE-C IN RAT-BRAIN CORTEX AND HIPPOCAMPUS - EFFECT OF REPEATED ADMINISTRATION OF FLUOXETINE AND DESIPRAMINE

1 Recent evidence indicates that changes in the activity of cyclic AMP-dependent protein kinase may be involved in neuroadaptive mechanisms after chronic treatment with antidepressants. The aim of this study was to investigate the effect of repeated administration of fluoxetine (FL) and desipramine (DMI) on the distribution and activity of protein kinase C (PKC) in subcellular fractions of rat cortex (Cx) and hippocampus (Hc) under basal conditions and in response to a single in vivo administration of 5-HT2A/2C agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). 2 Rats were treated for 21 days with FL (5 mg kg(-1) day(-1), i.p.) or DMI (10 mg kg(-1) day(-1), i.p.). DOI was injected to groups of rats receiving repeated doses of antidepressants or to control rats 1 h before ex vivo PKC assay. Distribution of PKC was determined by [H-3]-phorbol-12,13-dibutyrate ([H-3]-PDBu) binding and PKC activity by the Amersham enzyme assay system. 3 Autoradiography of tissue sections revealed decreased [H-3]-PDBu binding in CA(1) region of hippocampus (by 18%) and paraventricular thalamic nucleus (by 28%) of rats after repeated administration of FL. 4 In vitro exposure of brain sections to 50 mu M FL resulted in significant decreases (by 23 - 32%) of [H-3]- PDBu binding in six out of seven regions examined; exposure to 100 mu M FL reduced [3H]-PDBu;binding (by 36 - 52%) in all regions. In contrast, exposure of brain sections to 100 mu M DMI failed to alter specific [H-3]-PDBu binding in brain sections. 5 The activity of PKC in subcellular fractions of Cx and He was significantly (by 40-50%) decreased in rats given repeated doses of FL or DMI. A single administration of either drug Was without effect. 6 A single in vive administration of DOI to control rats resulted in reduced PKC activity (by 30-40%) in the particulate fraction of both Cx and He. This response to DOI was similar in DMI-treated rats but was not seen in rats given repeated doses of FL. A single administration of DOI to animals given repeated doses of FL resulted in PKC activities higher than those seen in rats treated with FL alone. 7 The results indicate that repeated administration of FL and DMI produced similar changes in basal PKC activity but differentially affected the PKC response to the 5-HT2A/2C receptor agonist, DOI. The effect on basal PKC activity may result from a post-receptor action of antidepressants; the alteration of PKC response to DOI after fluoxetine could be due to receptor-mediated desensitization of the signalling system.