Da. Knobelman et al., Regional patterns of compensation following genetic deletion of either 5-hydroxytryptamine(1A) or 5-hydroxytryptamine(1B) receptor in the mouse, J PHARM EXP, 298(3), 2001, pp. 1092-1100
Citations number
51
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Plasticity in serotonergic transmission in serotonin or 5-hydroxytryptamine
(5-HT) receptor mutants was examined by measuring the regulation of extrac
ellular 5-HT levels in the striatum and ventral hippocampus of 5-HT1A and 5
-HT1B receptor knockout mice using in vivo microdialysis. The efficacy of g
enetic deletion was verified by showing blunted regulation of extracellular
5-HT with selective 5-HT receptor agonists. 5-HT1A receptor knockout mice
failed to demonstrate reduction of extracellular 5-HT in response to system
ic administration of the 5-HT1A receptor agonist R-8-hydroxydipropylaminote
tralin (R-8-OH-DPAT) and 5-HT1B receptor knockout mice failed to demonstrat
e reduction of extracellular 5-HT in response to systemic administration of
the 5-HT1B receptor agonist CP 94,253. Plasticity also developed to deleti
on of the complementary autoreceptor. 5-HT1A receptor knockout mice demonst
rated a significantly greater response to CP 94,253 in the striatum, but no
t the ventral hippocampus, suggesting the development of enhanced sensitivi
ty of striatal 5-HT1B receptors. In 5-HT1B receptor knockout mice, R-8-OH-D
PAT evoked a significantly diminished response in the ventral hippocampus,
but not the striatum, suggesting the potential desensitization of 5-HT1A re
ceptors in the median raphe nucleus. The pattern of regional compensations
between somatodendritic and terminal autoreceptors was confirmed by pharmac
ological challenges using the selective serotonin reuptake inhibitor fluoxe
tine combined with either a 5-HT1A (WAY 100635) or a 5-HT1B/1D (GR 127935)
receptor antagonist. The regional pattern of compensation may be determined
by the preferential role of 5-HT1A or 5-HT1B receptors in regulating 5-HT
release. Taken together, these results demonstrate the development of regio
nal plasticity between complementary somatodendritic and terminal autorecep
tors after the genetic deletion of 5-HT1A or 5-HT1B receptors.