title: Evidence that serotonin reuptake modulators increase the density of serotonin innervation in the forebrain.
abstract: The mechanism of action of commonly used antidepressants remains an issue of debate. In the experiments reported here we studied the effects of three representative compounds, the selective serotonin reuptake inhibitor fluoxetine, the selective serotonin reuptake enhancer tianeptine and the selective norepinephrine reuptake inhibitor desipramine on the structure of central serotonin pathways after a 4-week administration. We found that the serotonin modulators fluoxetine and tianeptine, but not desipramine, increase the density of 5-HT and serotonin transporter (SERT)-immunoreactive axons in the neocortical layer IV and certain forebrain limbic areas, such as piriform cortex and the shell region of nucleus accumbens. These changes were noted in the absence of a significant effect of serotonin antidepressants on the expression of tryptophan hydroxylase (TPH-2), i.e. the rate-limiting enzyme for 5-HT biosynthesis and of SERT at the mRNA level. In addition, we found that anterogradely filled terminal axons from injections of biotinylated dextran amine into the dorsal raphe showed significantly more branching in animals treated with fluoxetine compared with animals treated with liposyn vehicle. Our findings suggest that antidepressants may exert very selective structural effects on their cognate monoamine systems in normal animals and raise the possibility that neurotrophic mechanisms may play a role in their clinical efficacy.
authors.affiliation: Neuropathology Division, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205-2196, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhou
authors.forename: Kai-Xing
authors.initials: KX
authors.lastname: Huang
authors.forename: Alexsandar
authors.initials: A
authors.lastname: Kecojevic
authors.forename: Annie M
authors.initials: AM
authors.lastname: Welsh
authors.forename: Vassilis E
authors.initials: VE
authors.lastname: Koliatsos
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000648:ultrastructure; D001710:Biotin / Q000031:analogs & derivatives; D003891:Desipramine / Q000494:pharmacology; D003911:Dextrans; D005456:Fluorescent Dyes; D005473:Fluoxetine / Q000494:pharmacology*; D008032:Limbic System / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D019579:Neocortex / Q000378:metabolism / Q000648:ultrastructure; D009411:Nerve Endings / Q000187:drug effects / Q000648:ultrastructure; D009412:Nerve Fibers / Q000187:drug effects / Q000648:ultrastructure; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D011903:Raphe Nuclei / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013841:Thiazepines / Q000494:pharmacology*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D001710:Biotin; D003891:Desipramine; D003911:Dextrans; D005456:Fluorescent Dyes; D005473:Fluoxetine; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013841:Thiazepines; C076397:biotinylated dextran amine; C050504:tianeptine