Effects of the beta3-adrenoceptor (Adrb3) agonist SR58611A (amibegron) on serotonergic and noradrenergic transmission in the rodent: relevance to its antidepressant/anxiolytic-like profile.
SR58611A is a selective beta(3)-adrenoceptor (Adrb3) agonist which has demonstrated antidepressant and anxiolytic properties in rodents. The present study confirmed the detection of Adrb3 mRNA transcript in rodent brain sub-regions and evaluated the effect of SR58611A on serotonergic and noradrenergic transmission in rats and mice in an attempt to elucidate the mechanism(s) underlying these properties. SR58611A (3 and 10 mg/kg, p.o.) increased the synthesis of 5-HT and tryptophan (Trp) levels in several rodent brain areas (cortex, hippocampus, hypothalamus, striatum). Moreover, SR58611A (10 mg/kg, p.o.) increased the release of 5-HT assessed by in vivo microdialysis in rat prefrontal cortex. Systemic (3 mg/kg, i.v.) or chronic administration of SR58611A (10 mg/kg, p.o.), in contrast to fluoxetine (15 mg/kg, p.o.), did not modify the activity of serotonergic neurons in the rat dorsal raphe nucleus. The increase in 5-HT synthesis induced by SR58611A was not observed in Adrb3s knockout mice, suggesting a selective involvement of Adrb3s in this effect. SR58611A (3 and 10 mg/kg, p.o.) did not modify norepinephrine synthesis and metabolism but increased its release in rat brain. Repeated administration of SR58611A (10 mg/kg, p.o.) did not modify basal norepinephrine release in rat prefrontal cortex whereas it prevented its tail-pinch stress-induced enhancement similarly to reboxetine (15 mg/kg, p.o.). Finally SR58611A increased the firing rate of noradrenergic neurons in the rat locus coeruleus following systemic (3 mg/kg, i.v.) or local (0.01 and 1 microM) but not chronic (10 mg/kg, p.o.) administration. These results suggest that the anxiolytic- and antidepressant-like activities of SR58611A involve an increase of brain serotonergic and noradrenergic neurotransmissions, triggered by activation of Adrb3s.
Claustre
Y
Y
Sanofi-Aventis, B.P.110, 92225 Bagneux Cedex, France. yves.claustre@sanofi-aventis.com
Leonetti
M
M
Santucci
V
V
Bougault
I
I
Desvignes
C
C
Rouquier
L
L
Aubin
N
N
Keane
P
P
Busch
S
S
Chen
Y
Y
Palejwala
V
V
Tocci
M
M
Yamdagni
P
P
Didier
M
M
Avenet
P
P
Le Fur
G
G
Oury-Donat
F
F
Scatton
B
B
Steinberg
R
R
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004347:Drug Interactions; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D051379:Mice; D017551:Microdialysis; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D000077593:Reboxetine; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D014364:Tryptophan / Q000378:metabolism
D018759:Adrenergic Uptake Inhibitors; D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D005473:Fluoxetine; D009025:Morpholines; D009638:Norepinephrine; D000077593:Reboxetine; D018343:Receptors, Adrenergic, beta-2; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; D013764:Tetrahydronaphthalenes; D014364:Tryptophan; C076252:amibegron