Stimulation of the beta3-Adrenoceptor as a novel treatment strategy for anxiety and depressive disorders.
The characterization of the first selective orally active and brain-penetrant beta3-adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stress-induced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the beta3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide. Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the beta3 adrenoceptor suggested that these effects of SR58611A are mediated by beta3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of beta3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.
Stemmelin
Jeanne
J
Sanofi-Aventis, CNS Research, Bagneux, France.
Cohen
Caroline
C
Terranova
Jean-Paul
JP
Lopez-Grancha
Matilde
M
Pichat
Philippe
P
Bergis
Olivier
O
Decobert
Michel
M
Santucci
Vincent
V
Françon
Dominique
D
Alonso
Richard
R
Stahl
Stephen M
SM
Keane
Peter
P
Avenet
Patrick
P
Scatton
Bernard
B
le Fur
Gérard
G
Griebel
Guy
G
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000374:Aggression / Q000187:drug effects; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D001008:Anxiety Disorders / Q000188:drug therapy* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D003071:Cognition / Q000187:drug effects; D003866:Depressive Disorder / Q000188:drug therapy* / Q000523:psychology; D003975:Diazepam / Q000494:pharmacology; D000431:Ethanol / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000494:pharmacology; D005849:Gerbillinae; D007099:Imipramine / Q000494:pharmacology; D007398:Interpersonal Relations; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics; D012890:Sleep / Q000187:drug effects; D019966:Substance-Related Disorders / Q000523:psychology; D013550:Swimming / Q000523:psychology; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000627:therapeutic use*
D058667:Adrenergic beta-3 Receptor Agonists; D000318:Adrenergic beta-Agonists; D014151:Anti-Anxiety Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D022702:Receptors, Adrenergic, beta-3; D013764:Tetrahydronaphthalenes; D005473:Fluoxetine; D000431:Ethanol; D007099:Imipramine; C076252:amibegron; D003975:Diazepam