Effects of the beta3-adrenoceptor (Adrb3) agonist SR58611A (amibegron) on serotonergic and noradrenergic transmission in the rodent: relevance to its antidepressant/anxiolytic-like profile.

Sanofi-Aventis, B.P.110, 92225 Bagneux Cedex, France.
Neuroscience (Impact Factor: 3.33). 08/2008; 156(2):353-64. DOI: 10.1016/j.neuroscience.2008.07.011
Source: PubMed

ABSTRACT 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.

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    • "The interaction of β 3-ARs activity with other neurotransmissions which has been shown to play important roles in depression and anxiety, has further strengthened the previously described theories . In fact, the activation of the β3-AR has been suggested to increase brain serotonin synthesis (Consoli et al., 2007) whereas amibegron anxiolytic-and antidepressant-like activities might be mediated, at least in part, via the increase of brain serotonergic and noradrenergic neurotransmissions (Claustre et al., 2008). Finally, it was proposed that neuronal production can be increased via the activation of both neurogenic precursors and stem cells through β3- ARs and points out a new therapeutic target for novel antidepressants (Jhaveri et al., 2010). "
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    • "In addition, these data provide the first evidence of a behavioral role for LPCS interneurons, as the selective enhancement of LPCS synapses was sufficient to produce robust decreases in anxiety-related behaviors. It should, however, be noted that b3-AR mRNA has been detected in many other brain regions and b3-AR activation can increase 5-HT transmission , possibly through a peripheral mechanism, as well as NE neurotransmitter levels through a direct increase in the firing rate of LC neurons (Claustre et al, 2008). Therefore, it seems likely that b3-ARs in multiple brain regions may be important in the regulation of anxiety-like behaviors. "
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    • "demand reagents for GPR40 (Assay ID: Mm00809442 s1) as previously described (Claustre et al., 2008). Adult male mice in the N3 generation (87.5% C57BL/6J and 12.5% 129/SvEv) were used in the current study. "
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