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 microdialysis in awake, unrestrained wild-type 5-HT(1A) and 5-HT(1B) 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-HT(1A) 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-HT(1B) 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-HT(1A) receptor antagonist WAY 100635 (0.1 mg/kg i.p.) or the 5-HT(1B/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-HT(1A) 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-HT(1B) receptor is relatively greater in the hippocampus and possibly other brain regions innervated by the median raphe nucleus.
Knobelman
D A
DA
Department of Pharmacology and Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6140, USA.
Hen
R
R
Lucki
I
I
D000818:Animals; D019540:Area Under Curve; D017660:Autoreceptors / Q000187:drug effects* / Q000235:genetics*; D001923:Brain Chemistry / Q000235:genetics* / Q000502:physiology*; D005110:Extracellular Space / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000235:genetics* / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D017660:Autoreceptors; D005473:Fluoxetine; D010879:Piperazines; D011725:Pyridines; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide