Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse

The regulation of extracellular levels of 5-hydroxytryptamine (serotonin) ( 5-HT) in the striatum and ventral hippocampus was studied using in vivo mic rodialysis in awake, unrestrained wildtype 5-HT1A and 5-HT1B receptor knock out mice. Systemic administration of the selective serotonin reuptake inhib itor fluoxetine evoked a significant dose-dependent increase in extracellul ar 5-HT in both the striatum and hippocampus at both 2.5 mg/kg (i.p.) and 2 0 mg/kg (i.p.) in wild-type mice. in 5-HT1A receptor knockout mice, the res ponse to 2.5 mg/kg fluoxetine was significantly augmented in the striatum b ut not the hippocampus, whereas the response to 20 mg/kg fluoxetine was sig nificantly greater in both brain regions. In 5-HT1B receptor knockout mice, the increase of extracellular 5-HT was augmented in the hippocampus but no t the striatum at both doses of fluoxetine. The response pattern to fluoxet ine alone in 5-HT receptor mutant mice corresponded with the effects of flu oxetine 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 w ild-type mice. These results indicate common topographical regulation of 5- HT release in different brain regions by genetic mutation and pharmacologic al challenges. The 5-HT1A autoreceptor plays a larger role in regulating 5- HT release in the striatum and possibly other brain regions innervated by t he dorsal raphe nucleus, whereas the role of the 5-HT1B receptor is relativ ely greater in the hippocampus and possibly other brain regions innervated by the median raphe nucleus.