Effects of the beta3-adrenoceptor (Adrb3) agonist SR58611A (amibegron) on serotonergic and noradrenergic transmission in the rodent: relevance to its antidepressant/anxiolytic-like profile.
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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ABSTRACT: It is clear that activated β3-adrenoceptor can improve disorders of lipid metabolism, however there are few reports concerning the anti-atherosclerotic effects of β3-adrenoceptor in the artery of apolipoprotein E knockout (Apoe(-/-)) mice. In the present study, we aimed at investigating the effects of β3-adrenoceptor on lipids, atherosclerosis plaques, scavenger receptor class B type 1 and its signal transduction in Apoe(-/-) mice. Ten C57BL/6J mice were used as a control, and fifty age-matched Apoe(-/-) mice were randomly divided into five groups: atherosclerotic model (saline), positive control (atorvastatin), low-dose β3-adrenoceptor agonist, high-dose β3-adrenoceptor agonist and β3-adrenoceptor antagonist groups. After 26 weeks on the high-fat diet, the mice received the above treatments for 12 weeks. Thoracic aortas, serum lipids, SR-B1, P-MeK1/2, P-ErK1/2 and protein kinase Cα(PKCα) activity were detected. We found that the levels of serum total cholesterol, triglyceride, very low-density lipoprotein/low-density lipoprotein cholesterol and the area of atherosclerotic plaques were significantly decreased in β3-adrenoceptor agonist-treated mice (P<0.01), while the levels of high-density lipoprotein cholesterol, thoracic aortic lumen area, activity of liver PKCα, the protein expression of SR-B1, P-MeK1/2 and P-ErK1/2 were significantly increased (P<0.01), compared with the atherosclerotic model mice. Effects of the high-dose agonist were superior to those of the low-dose (P<0.01). These findings suggest that activation of β3-adrenoceptor reduce the plaque area in the thoracic aorta and play an important anti-atherosclerotic role by regulating lipid metabolism disorders and the SR-B1 signal transduction pathway.European journal of pharmacology 07/2013; · 2.59 Impact Factor
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ABSTRACT: Major depression is characterized by a diminished activity of the brain serotonergic system as well as by the flattening of plasma cortisol levels. Nicotine improves mood in patients with major depression and in experimentally depressed animals by increasing brain serotonin (5-HT), noradrenaline and dopamine levels. The present study was directed to determine if flattening plasma glucocorticoid levels changes nicotine's stimulatory effects upon 5-HT DRN neurons. The experiments were performed in brain slices obtained from rats previously (14 days) adrenalectomised and implanted subcutaneously with one pellet containing 75mg of corticosterone (Adx+CSR rats). Whole cell voltage and current clamp techniques were used to study the activity of immunocitochemically identified 5-HT DRN neurons. Administration of nicotine (1μM) in sham-operated animals produced stimulatory effects in all 5-HT DRN neurons studied. In Adx+CSR rats however, nicotine inhibited 75% of 5-HT DRN neurons and increased the potassium-dependent inward rectifying current. The inhibitory effect of nicotine upon 5-HT DRN neurons was dependent on serotonin release inside the DRN, since it was converted into a stimulatory response by the selective antagonist of 5-HT1A receptors N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridyl)cyclohexanecarboxamide (WAY100635, 25nM). Adx+CSR rats also presented an increased function of 5-HT1A autoreceptors, since, in these rats, serotonin (1-10μM) produced a higher increase in the potassium dependent inward rectifying current in comparison with sham-operated animals. Serotonin release inside DRN was mediated by α4β2 nicotinic acetylcholine receptors since the selective antagonist of these receptors dihydro-β-erytroidine hydrobromide (DHβE, 100nM) blocked the inhibitory effects of nicotine 5-HT DRN neurons. These data indicate that, in the experimental model of adrenalectomised rats implanted with corticosterone pellets, nicotine increases the function of 5-HT1A receptors of 5-HT DRN neurons.Brain research bulletin 07/2013; · 2.18 Impact Factor
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ABSTRACT: The interaction between ethanol (EtOH) and anxiety plays an integral role in the development and maintenance of alcoholism. Many medications in pre-clinical or clinical trials for the treatment of alcoholism share anxiolytic properties. However, these drugs typically have untoward side effects, such as sedation or impairment of motor function that may limit their clinical use. We have recently demonstrated that BRL 37344 (BRL), a selective β3-adrenoceptor (AR) agonist, enhances a discrete population of GABAergic synapses in the basolateral amygdala (BLA) that mediates feed-forward inhibition from lateral paracapsular (LPC) GABAergic interneurons onto BLA pyramidal cells. Behavioral studies revealed that intra-BLA infusion of BRL significantly reduced measures of unconditioned anxiety-like behavior without locomotor depressant effects. The present studies tested the effect of BRL (0.1, 0.5, or 1.0 μg/side) on EtOH self-administration using an intermittent access home cage two-bottle choice procedure and limited access operant responding for EtOH or sucrose. Intra-BLA infusion of BRL did not reduce home cage, intermittent EtOH self-administration. However, using an operant procedure that permits the discrete assessment of appetitive (seeking) and consummatory measures of EtOH self-administration, BRL reduced measures of EtOH and sucrose seeking, but selectively reduced operant responding for EtOH during extinction probe trials. BRL had no effect on consummatory behaviors for EtOH or sucrose. Together, these data suggest that intra-BLA infusion of BRL significantly reduces motivation to seek EtOH and provide initial evidence that β3-ARs and LPC GABAergic synapses may represent promising targets for the development of novel pharmacotherapies for the treatment of alcoholism.Psychopharmacology 08/2013; · 4.06 Impact Factor