1. ¹Sanofi-Aventis, CNS Research, Bagneux, France
2. ²Sanofi-Aventis, CNS Research, Montpellier, France
3. ³Department of Psychiatry, University of California, San Diego, CA, USA
4. ⁴Sanofi-Aventis, CNS Research, Toulouse, France

Correspondence: Dr G Griebel, Sanofi-Aventis, CNS Research, 31 ave PV-Couturier, 92220 Bagneux, France. Tel: +33 1 45 36 24 70; Fax: +33 1 45 36 20 70; E-mail: guy.griebel@sanofi-aventis.com

Received 5 February 2007; Revised 14 March 2007; Accepted 15 March 2007; Published online 25 April 2007.

Abstract

The characterization of the first selective orally active and brain-penetrant ₃-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 ₃ 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 ₃ adrenoceptor suggested that these effects of SR58611A are mediated by ₃ adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of ₃ adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.