LONG-TERM EFFECTS ON SEROTONIN TRANSPORTER MESSENGER-RNA EXPRESSION OF CHRONIC NEONATAL EXPOSURE TO A SEROTONIN REUPTAKE INHIBITOR

Chronic administration of clomipramine or other serotonin (5-hydroxytr yptamine, 5-HT) reuptake inhibitors to neonatal rats produces behaviou rs that resemble a depressive state in the adult animal, and this mode l is therefore regarded as a putative animal model of depression. Alte rations in the activity of the central 5-HT system are important in un derstanding the pathophysiology of depression, and therefore, we exami ned whether this model was associated with changes in the expression o f 5-HT1A receptor, 5-HT1B receptor, and 5-HT transporter mRNA in the d orsal raphe nucleus and the hippocampus. Wistar rats were injected twi ce daily with the serotonin reuptake inhibitors clomipramine and l]-1- (4-fluoro-phenyl)-1,3-dihydroiso-benzofurane, hydrochloride (code Lu 1 0-134-C) at doses of 15 mg kg(-1) or vehicle i.p. from postnatal day 8 for 14 days. Groups of rats (n = 10) were either killed the day after the last injection or left undisturbed for 69 days before they were k illed. The expression of 5-HT transporter, 5-HT1A receptor, and 5-HT1B receptor mRNA was examined in the dorsal raphe nucleus and in the CAI of the hippocampus by means of quantitative in situ hybridisation his tochemistry. Both compounds resulted in an increase in 5-HT transporte r mRNA expression (40% more than vehicle) in the dorsal raphe nucleus the day after the last injection (postnatal day 22). A small but signi ficant increase in 5-HT1B receptor mRNA expression in the CAl was seen after clomipramine, but not after Lu 10-134-C, probably reflecting cl omipramine's affinity for both the 5-HT and noradrenaline transporters as well as for a number of monoamine receptor sites. Levels of 5-HT1A receptor mRNA were unchanged. In contrast, 5-HT transporter mRNA expr ession in the dorsal raphe nucleus was significantly decreased in the adult after neonatal treatment with either of the two drugs compared t o vehicle. No changes in 5-HT1A receptor and 5-HT1B receptor mRNA expr ession were observed in any of the regions examined in these animals. The results show that the persistent depressive behaviour previously s hown in this model is also associated with changes in the expression o f 5-HT transporter mRNA. This long-term alteration in gene expression may result from disturbances in 5-HT neurotransmission in the brain of the neonatal animals. (C) 1998 Elsevier Science B.V. All rights reser ved.