In vivo efflux of serotonin in the dorsal raphe nucleus of 5-HT1A receptor knockout mice.
In the dorsal raphe nucleus (DR), extracellular serotonin (5-HT) regulates serotonergic transmission through 5-HT1A autoreceptors. In this work we used in vivo microdialysis to examine the effects of stressful and pharmacological challenges on DR 5-HT efflux in 5-HT1A receptor knockout (5-HT1A-/-) mice and their wild-type counterparts (5-HT1A+/+). Baseline 5-HT concentrations did not differ between both lines of mice, which is consistent with a lack of tonic control of 5-HT1A autoreceptors on DR 5-HT release. (R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT, 0.5 mg/kg) reduced 5-HT levels to 30% of basal values in 5-HT1A+/+ mice, but not in 5-HT1A-/- mice. The selective 5-HT1B receptor agonist 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (CP 93129, 300 micro m) reduced dialysate 5-HT to the same extent (30-40% of baseline) in the two genotypes, which suggests a lack of compensatory changes in 5-HT1B receptors in the DR of such mutant mice. Both a saline injection and handling for 3 min increased DR dialysate 5-HT in mutants, but not in 5-HT1A+/+ mice. Fluoxetine (5 and 20 mg/kg) elevated 5-HT in a dose-dependent manner in both genotypes. However, this effect was markedly more pronounced in the 5-HT1A-/- mice. The increased responsiveness of the extracellular 5-HT in the DR of 5-HT1A receptor knockout mice reflects a lack of the autoinhibitory control exerted by 5-HT1A autoreceptors.
Department of Neurochemistry, Instituto de Investigaciones Biomédicas de Barcelona, CSIC (IDIBAPS), Barcelona, Spain.
Analía
A
Bortolozzi
Mercè
M
Amargós-Bosch
Miklos
M
Toth
Francesc
F
Artigas
Albert
A
Adell
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D045604:Extracellular Fluid / Q000737:chemistry / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D006234:Handling, Psychological; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism*; D044282:Receptor, Serotonin, 5-HT1A / Q000172:deficiency / Q000235:genetics*; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D012965:Sodium Chloride / Q000494:pharmacology; D013312:Stress, Physiological / Q000378:metabolism
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D005473:Fluoxetine; D011725:Pyridines; D011758:Pyrroles; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D012965:Sodium Chloride; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one