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Vol. 298, Issue 3, 1083-1091, September 2001

Genetic Regulation of Extracellular Serotonin by 5-Hydroxytryptamine1A and 5-Hydroxytryptamine1B Autoreceptors in Different Brain Regions of the Mouse

Deborah A. Knobelman, René Hen and Irwin Lucki

Departments of Pharmacology and Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania (D.A.K., I.L.); and Center for Neurobiology and Behavior, Columbia University, New York, New York (R.H.)

The regulation of extracellular levels of 5-hydroxytryptamine (serotonin) (5-HT) in the striatum and ventral hippocampus was studied using in vivo microdialysis in awake, unrestrained wild-type 5-HT1A and 5-HT1B receptor knockout mice. Systemic administration of the selective serotonin reuptake inhibitor fluoxetine evoked a significant dose-dependent increase in extracellular 5-HT in both the striatum and hippocampus at both 2.5 mg/kg (i.p.) and 20 mg/kg (i.p.) in wild-type mice. In 5-HT1A receptor knockout mice, the response to 2.5 mg/kg fluoxetine was significantly augmented in the striatum but not the hippocampus, whereas the response to 20 mg/kg fluoxetine was significantly greater in both brain regions. In 5-HT1B receptor knockout mice, the increase of extracellular 5-HT was augmented in the hippocampus but not the striatum at both doses of fluoxetine. The response pattern to fluoxetine alone in 5-HT receptor mutant mice corresponded with the effects of fluoxetine given with either the 5-HT1A receptor antagonist WAY 100635 (0.1 mg/kg i.p.) or the 5-HT1B/1D receptor antagonist GR 127935 (0.056 mg/kg) in wild-type mice. These results indicate common topographical regulation of 5-HT release in different brain regions by genetic mutation and pharmacological challenges. The 5-HT1A autoreceptor plays a larger role in regulating 5-HT release in the striatum and possibly other brain regions innervated by the dorsal raphe nucleus, whereas the role of the 5-HT1B receptor is relatively greater in the hippocampus and possibly other brain regions innervated by the median raphe nucleus.

0022-3565/01/2983-1083$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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