Long-term effects on serotonin transporter mRNA expression of chronic neonatal exposure to a serotonin reuptake inhibitor.
Chronic administration of clomipramine or other serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitors to neonatal rats produces behaviours that resemble a depressive state in the adult animal, and this model is therefore regarded as a putative animal model of depression. Alterations in the activity of the central 5-HT system are important in understanding the pathophysiology of depression, and therefore, we examined whether this model was associated with changes in the expression of 5-HT1A receptor, 5-HT1B receptor, and 5-HT transporter mRNA in the dorsal raphe nucleus and the hippocampus. Wistar rats were injected twice daily with the serotonin reuptake inhibitors clomipramine and 5-chloro-1-[3-(dimethylamino)propyl]-1-(4-fluoro-phenyl)-1,3-dihydroi so-benzofurane, hydrochloride (code Lu 10-134-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 killed. The expression of 5-HT transporter, 5-HT1A receptor, and 5-HT1B receptor mRNA was examined in the dorsal raphe nucleus and in the CA1 of the hippocampus by means of quantitative in situ hybridisation histochemistry. Both compounds resulted in an increase in 5-HT transporter mRNA expression (40% more than vehicle) in the dorsal raphe nucleus the day after the last injection (postnatal day 22). A small but significant increase in 5-HT1B receptor mRNA expression in the CA1 was seen after clomipramine, but not after Lu 10-134-C, probably reflecting clomipramine'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 expression in the dorsal raphe nucleus was significantly decreased in the adult after neonatal treatment with either of the two drugs compared to vehicle. No changes in 5-HT1A receptor and 5-HT1B receptor mRNA expression were observed in any of the regions examined in these animals. The results show that the persistent depressive behaviour previously shown in this model is also associated with changes in the expression of 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.
Department of Neurobiology, H. Lundbeck A/S, Valby-Copenhagen, Denmark.
H H
HH
Hansen
J D
JD
Mikkelsen
D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D015342:DNA Probes; D006624:Hippocampus / Q000378:metabolism; D017403:In Situ Hybridization; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D011903:Raphe Nuclei / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
D002352:Carrier Proteins; D015342:DNA Probes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493232:Slc6a4 protein, rat