Extracellular serotonin in the prefrontal cortex is limited through terminal 5-HT(1B) autoreceptors: a microdialysis study in knockout mice.
BACKGROUND
Serotonin (5-HT) autoreceptors regulate extracellular 5-HT levels and have been suggested to limit the effects of acute treatment with selective serotonin reuptake inhibitors (SSRIs).


OBJECTIVE
The role of terminal 5-HT(1B) autoreceptors was assessed by comparing the effects of a SSRI on extracellular 5-HT in wild-type and 5-HT(1B) receptor knockout (KO) mice and by using a 5-HT(1B) receptor antagonist. Since systemic SSRI administration also activates somatodendritic 5-HT(1A) autoreceptors, a SSRI was administered locally to study the role of terminal 5-HT(1B) autoreceptors.


METHODS
In vivo microdialysis in wild-type and 5-HT(1B) receptor KO mice was used to study the effects of the 5-HT(1B) receptor agonist CP93129 (1 micro M), the SSRI fluvoxamine (0.3 micro M and 1.0 micro M) and the 5-HT(1B) receptor antagonist NAS-181 (1 micro M) on extracellular 5-HT in the medial prefrontal cortex.


RESULTS
The 5-HT increase induced by local SSRI administration was augmented in 5-HT(1B) KO mice relative to wild-type mice and was augmented by simultaneous administration of a 5-HT(1B) receptor antagonist in the latter genotype. Basal 5-HT levels did not differ between the two genotypes. Activation of 5-HT(1B) receptors by CP93129 decreased extracellular 5-HT, whereas 5-HT levels in wild-type mice were not affected by the 5-HT(1B) receptor antagonist NAS-181. In 5-HT(1B) KO mice, NAS-181 did not affect extracellular 5-HT and did not further increase the effect of fluvoxamine, showing that NAS-181 is a selective 5-HT(1B) receptor antagonist. The greater increase in 5-HT levels following combined administration of a SSRI with NAS-181 in wild-type mice, relative to 5-HT(1B) KO mice, suggests possible adaptive changes in the KO mice.


CONCLUSIONS
The present study shows that terminal 5-HT(1B) autoreceptors play a significant role in the regulation of 5-HT release in the prefrontal cortex.
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
D000704:Analysis of Variance; D000818:Animals; D017660:Autoreceptors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D001578:Benzopyrans / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005110:Extracellular Space / Q000378:metabolism; D016666:Fluvoxamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis / Q000379:methods; D009025:Morpholines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; 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*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013997:Time Factors
D017660:Autoreceptors; D001578:Benzopyrans; D016666:Fluvoxamine; D009025:Morpholines; D011725:Pyridines; D011758:Pyrroles; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C112429:2-(((3-(morpholinylmethyl)-2H-chromen-8-yl)oxy)methyl)morpholine; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one