Claustre Y, Leonetti M, Santucci V, Bougault I, Desvignes C, Rouquier L et al. Effects of the beta(3)-adrenoceptor (Adrb3) agonist SR58611A (amibegron) on serotonergic and noradrenergic transmission in the rodent: Relevance to its antidepressant/anxiolytic-like profile. Neuroscience 156: 353-364
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.
"In situ hybridisation has further revealed β2-adrenergic receptors in the thalamic intralaminar nuclei, cerebellar cortex  and superficial dorsal horn of spinal cord . β3-adrenergic receptor mRNA has been detected in homogenates of frontal, temporal and parietal cortex, hippocampus, striatum and midbrain by reverse transcription/polymerase chain reaction methods , . "
[Show abstract][Hide abstract] ABSTRACT: Coherence between the bioelectric activity of sensorimotor cortex and contralateral muscles can be observed around 20 Hz. By contrast, physiological tremor has a dominant frequency around 10 Hz. Although tremor has multiple sources, it is partly central in origin, reflecting a component of motoneuron discharge at this frequency. The motoneuron response to ∼20 Hz descending input could be altered by non-linear interactions with ∼10 Hz motoneuron firing. We investigated this further in eight healthy human subjects by testing the effects of the beta-adrenergic agents propranolol (non-selective β-antagonist) and salbutamol (β(2)-agonist), which are known to alter the size of physiological tremor. Corticomuscular coherence was assessed during an auxotonic precision grip task; tremor was quantified using accelerometry during index finger extension. Experiments with propranolol used a double-blind, placebo-controlled crossover design. A single oral dose of propranolol (40 mg) significantly increased beta band (15.3-32.2 Hz) corticomuscular coherence compared with placebo, but reduced tremor in the 6.2-11.9 Hz range. Salbutamol (2.5 mg) was administered by inhalation. Whilst salbutamol significantly increased tremor amplitude as expected, it did not change corticomuscular coherence. The opposite direction of the effects of propranolol on corticomuscular coherence and tremor, and the fact that salbutamol enhances tremor but does not affect coherence, implies that the magnitude of corticomuscular coherence is little influenced by non-linear interactions with 10 Hz oscillations in motoneurons or the periphery. Instead, we suggest that propranolol and salbutamol may affect both tremor and corticomuscular coherence partly via a central site of action.
PLoS ONE 11/2012; 7(11):e49088. DOI:10.1371/journal.pone.0049088 · 3.23 Impact Factor
"Early studies identified that human β3AR was mainly expressed on the surface of both white and brown adipocytes, mediating metabolic effects such as lipolysis and thermogenesis21. More recent reports showed that β3AR is also an attractive target for drugs against overactive bladder22,23, anxiety and depressive disorders24,25. Understanding the mechanism of β3AR activation should facilitate rational drug discovery and the design of new types of β3AR agonists. In this study, we employed site-directed mutagenesis and molecular docking to explore the detailed function of the conserved aromatic cluster F2135.47/F3096.52/F3086.51 in β3AR. "
[Show abstract][Hide abstract] ABSTRACT: To explore the function of the conserved aromatic cluster F213(5.47), F308(6.51), and F309(6.52) in human β3 adrenergic receptor (hβ3AR).
Point mutation technology was used to produce plasmid mutations of hβ3AR. HEK-293 cells were transiently co-transfected with the hβ3AR (wild-type or mutant) plasmids and luciferase reporter vector pCRE-luc. The expression levels of hβ3AR in the cells were determined by Western blot analysis. The constitutive signalling and the signalling induced by the β3AR selective agonist, BRL (BRL37344), were then evaluated. To further explore the interaction mechanism between BRL and β3AR, a three-dimensional complex model of β3AR and BRL was constructed by homology modelling and molecular docking.
For F308(6.51), Ala and Leu substitution significantly decreased the constitutive activities of β3AR to approximately 10% of that for the wild-type receptor. However, both the potency and maximal efficacy were unchanged by Ala substitution. In the F308(6.51)L construct, the EC(50) value manifested as a "right shift" of approximately two orders of magnitude with an increased E(max). Impressively, the molecular pharmacological phenotype was similar to the wild-type receptor for the introduction of Tyr at position 308(6.51), though the EC(50) value increased by approximately five-fold for the mutant. For F309(6.52), the constitutive signalling for both F309(6.52)A and F309(6.52)L constructs were strongly impaired. In the F309(6.52)A construct, BRL-stimulated signalling showed a normal E(max) but reduced potency. Leu substitution of F309(6.52) reduced both the E(max) and potency. When F309(6.52) was mutated to Tyr, the constitutive activity was decreased approximately three-fold, and BRL-stimulated signalling was significantly impaired. Furthermore, the double mutant (F308(6.51)A_F309(6.52)A) caused the total loss of β3AR function. The predicted binding mode between β3AR and BRL revealed that both F308(6.51) and F309(6.52) were in the BRL binding pocket of β3AR, while F213(5.47) and W305(6.48) were distant from the binding site.
These results revealed that aromatic residues, especially F308(6.51) and F309(6.52), play essential roles in the function of β3AR. Aromatic residues maintained the receptor in a partially activated state and significantly contributed to ligand binding. The results supported the common hypothesis that the aromatic cluster F[Y]5.47/F[Y]6.52/F[Y]6.51 conserved in class A G protein-coupled receptor (GPCR) plays an important role in the structural stability and activation of GPCRs.
"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. "
[Show abstract][Hide abstract] ABSTRACT: Norepinephrine (NE) is known to play an integral role in the neurobiological response to stress. Exposure to stressful stimuli increases NE levels in brain regions that regulate stress and anxiety, like the basolateral amygdala (BLA). NE is thought to increase excitability in these areas through α- and Β-adrenoceptors (ARs), leading to increased anxiety. Surprisingly, recent studies have shown that systemic Β3-AR agonist administration decreases anxiety-like behaviors, suggesting that Β3-ARs may inhibit excitability in anxiety-related brain regions. Therefore, in this study we integrated electrophysiological and behavioral approaches to test the hypothesis that the anxiolytic effects of Β3-AR agonists may be mediated by an increase in BLA GABAergic inhibition. We examined the effect of a selective Β3-AR agonist, BRL37344 (BRL), on GABAergic synapses arising from local circuit interneurons and inhibitory synapses originating from a recently described population of cells called lateral paracapsular (LPCS) interneurons. Surprisingly, BRL selectively enhanced LPCS-evoked inhibitory postsynaptic currents (eIPSCs) with no effect on local GABAergic inhibition. BRL also had no effect on glutamatergic synaptic excitation within the BLA. BRL potentiation of LPCS eIPSCs was blocked by the selective Β3-AR antagonist, SR59230A, or by intracellular dialysis of Rp-CAMPS (cAMP-dependent protein kinase inhibitor), and this enhancement was not associated with any changes in spontaneous IPSCs or LPCS paired-pulse ratio. BRL also increased the amplitude of unitary LPCS IPSCs (uIPSCs) with no effect on uIPSC failure rate. Finally, bilateral BLA microinjection of BRL reduced anxiety-like behaviors in an open-field assay and the elevated plus-maze. Collectively, these data suggest that Β3-AR activation selectively enhances LPCS, but not local, BLA GABAergic synapses, and that increases in LPCS-mediated inhibition may contribute to the anxiolytic profile of Β3-AR agonists.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2010; 35(9):1886-96. DOI:10.1038/npp.2010.59 · 7.05 Impact Factor
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