Stimulation of the β3-Adrenoceptor as a Novel Treatment Strategy for Anxiety and Depressive Disorders

Abstract

The characterization of the first selective orally active and brain-penetrant b 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, stressinduced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the b 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 b 3 adrenoceptor suggested that these effects of SR58611A are mediated by b 3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of b 3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.

Chemogenetic and Optogenetic Activation of Gαs Signaling in the Basolateral Amygdala Induces Acute and Social Anxiety-Like States

“…Adapted from similar behavioral assays that model social anxiety-like states (Bailey and Crawley, 2009;Bruchas et al, 2011;Felix-Ortiz and Tye, 2014;Silverman et al, 2010), the social approach assay measures the time a mouse spends in the presence of a novel conspecific (social zone) (Figure 2a). Less time spent in the social zone indicates a social anxiety-like state that is reversible using traditional anxiolytics, such as diazepam (Stemmelin et al, 2007). We first demonstrated that animals expressing the empty vector eGFP control virus (n = 15) or rM3Ds BLA/CaMKIIα (n = 11) spent similar amounts of time investigating the empty cup (Figure 2b and c, top panels and Figure 2d; unpaired Student's t-test; t (24) = 1.109, P = 0.2785).…”

β3-Adrenoceptor as a Novel Treatment Strategy for Depressive Disorders

“…It is reported that SR58611A displays high efficacy and potency at the rat and humanβ3 receptor. The selectivity for rat β3 are 280-and 140-fold compared with β1 andβ2 receptors, and is inactive at a number of other central targets involved in the regulation of stress-related disorders [18]. Several studies reported that SR58611A has antidepressant effects in the animal model of depression [19].…”

“…In order to prove SR58611A has anti-depressant properties, some researchers placed cortical electrodes on the sensorimotor cortex of rats for reliable visual discrimination of wakefulness, slow-wave sleep and rapid eye movement or paradoxical sleep. In summary, although there is limited evidence, but there are some evidence that the pharmacological stimulation of β 3 -Adrenoceptor may represent an innovative approach for the treatment of depressive disorders [18].…”

“…According to Stemmelin J et al [18] they used two acute animal models (forced-swimming model, tonic immobility test) to investigate the effects of SR58611A and one chronic model (chronic mild stress models) for characterization of antidepressants. The forced-swimming test in rats is the most extensive used rodent model which can reflect a behavioral despair.…”

Dual- and Triple-Acting Agents for Treating Core and Co-morbid Symptoms of Major Depression: Novel Concepts, New Drugs

“…113 Curiously, an agonist at ␤ 3 receptors (essentially absent from healthy adult human brain, although data for depressed tissue do not appear to be available) was in development for depression, but was recently discontinued. 114,115 As regards 5-HT, the traditional candidates are 5-HT 1A receptors. This has never been clinically proven, not least owing to poor tolerability of agonists.…”