The effects of selective serotonin reuptake inhibitors on extracellular 5-HT levels in the hippocampus of 5-HT(1B) receptor knockout mice.
The effects of two selective serotonin reuptake inhibitors on 5-hydroxy-tryptamine (5-HT) in the hippocampus were studied in wildtype and in 5-HT(1B) receptor knockout mice using in vivo microdialysis. Basal 5-HT levels in the hippocampus were not different between the two genotypes. The functional absence of 5-HT(1B) receptors was examined in the knockout mice by local infusion of the 5-HT(1B) receptor agonist, 1,4-Dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one (CP93129) into the hippocampus. CP93129 (1 microM) decreased 5-HT levels in wildtype mice, but not in 5-HT(1B) knockout mice. Systemic administration of the selective 5-HT reuptake inhibitor paroxetine (5 mg/kg, i.p.) increased extracellular 5-HT levels. The increase of 5-HT in 5-HT(1B) knockout mice was almost twofold higher than in wildtype mice. Systemic administration of selective 5-HT reuptake inhibitors stimulates both terminal 5-HT(1B) autoreceptors and somatodendritic 5-HT(1A) autoreceptors. Therefore, the selective 5-HT reuptake inhibitor, fluvoxamine, was applied locally into the hippocampus to investigate the role of the terminal 5-HT(1B) autoreceptors. Local administration of 0.3 microM fluvoxamine resulted in comparable increases in extracellular 5-HT in both genotypes, whereas 1.0 microM fluvoxamine produced a twofold greater increase in 5-HT levels in 5-HT(1B) knockout as compared to wildtype mice. In conclusion, the differences in hippocampal 5-HT output between wildtype and 5-HT(1B) knockout mice after local or systemic administration of selective 5-HT reuptake inhibitors show that 5-HT(1B) autoreceptors play a significant role in the inhibition of 5-HT release at serotonergic nerve terminals. In addition, the different dose-response to fluvoxamine suggests that 5-HT(1B) knockout mice have possible adaptations of 5-HT transporters in order to compensate for the loss of the terminal 5-HT(1B) autoreceptor.
De Groote
Lotte
L
Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands. L.deGroote@psych.azu.nl
Olivier
Berend
B
Westenberg
Herman G M
HG
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D016666:Fluvoxamine / Q000494:pharmacology; D005838:Genotype; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007274:Injections, Intraperitoneal; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017551:Microdialysis; D017374:Paroxetine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012701:Serotonin / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors
D016666:Fluvoxamine; D017374:Paroxetine; D011725:Pyridines; D011758:Pyrroles; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one