EVIDENCE FOR DIFFERENT INTERACTIONS BETWEEN β1- AND β2-ADRENOCEPTOR SUBTYPES WITH ADENYLYL CYCLASE IN THE RAT BRAIN: A CONCENTRATION–RESPONSE STUDY USING FORSKOLIN

Q2 · MEDICINE

Article

Author: Morin, Didier ; Tillement, Jean-Paul ; Urien, Saik ; Sapena, Rosa

The aim of this study was to investigate beta(1)- and beta(2)-adrenoceptor signalling systems in the rat brain studying the synergistic effects between beta-adrenoceptor agonists and forskolin- induced activation of adenylyl cyclase. Experiments were performed in slices from cerebral cortex and cerebellum because they contain mainly beta(1)- and almost exclusively beta(2)- adrenoceptors, respectively. Five beta-adrenergic agonists were used, clenbuterol, flerobuterol, isoproterenol, salbutamol, and tulobuterol. All agonists stimulated cyclic AMP accumulation in the cerebral cortex but flerobuterol was inactive in the cerebellum. Forskolin amplified the generation of cyclic AMP. Forskolin potentiation was observed in glial cells but not in neurons and was not dependent on the number of beta-adrenoceptors. In return the amplitude of the potentiation was highly dependent on the intrinsic activity of the agonist in the cerebral cortex whereas it was constant whatever the agonist tested in the cerebellum. To analyse this difference we developed a modelling approach using a concentration-response study. Isoproterenol and forskolin stimulations of cyclic AMP production were studied either alone or in combination with increasing concentrations of forskolin and isoproterenol, respectively. In the cerebral cortex isoproterenol and forskolin were both able to potentiate the cyclic AMP accumulation induced by the other compound, whereas, in the cerebellum, isoproterenol was unable to increase the stimulation induced by forskolin. The results support the hypothesis that beta(1)- and beta(2)-adrenoceptors display distinct mechanisms of action in the signalling system by which they stimulate the accumulation of cyclic AMP.

01 Mar 2000·Biochemical PharmacologyQ2 · MEDICINE

Effect of the β-adrenoceptor agonist flerobuterol on serotonin synthesis in the rat brain

Q2 · MEDICINE

Article

Author: Mirko Diksic ; Ko Tsuiki ; Pierre Blier

The influence of 2- and 14-day treatments with flerobuterol, a preferential beta(2)-adrenoceptor agonist, on regional serotonin (5-HT) synthesis in the rat brain was studied by autoradiography using alpha-[(14)C]methyl-L-tryptophan. Flerobuterol was delivered at a rate of 0.5 mg/kg/day using osmotic pumps implanted s.c. The 2-day flerobuterol treatment significantly increased plasma Trp, both free and total, and decreased plasma Leu and Ile. This resulted in a significant increase in the facilitated transport of Trp. There was a significant increase in the synthesis of 5-HT in the 2-day treatment group in the dorsal and median raphe as well as in all postsynaptic structures, with the exception of the hypothalamus. In contrast, after a 14-day treatment, the enhanced facilitated transport of Trp was no longer present, and the increase in the rate of 5-HT synthesis persisted only in the parietal and occipital cortex and the superior colliculus. These data suggest that flerobuterol, similar to other beta-adrenergic agonists, acutely increases 5-HT synthesis, in part, through an elevation of brain Trp availability.

01 Feb 1996·Human & Experimental ToxicologyQ4 · MEDICINE

Reduced survival after isoprenaline/ dopamine in d,l-propranolol intoxicated rats

Q4 · MEDICINE

Article

Author: Vleeming, W. ; Wemer, J. ; Meulenbelt, J. ; Toet, AE ; te Biesebeek, JD ; de Wildt, DJ

1 Respiratory and cardiovascular failure are principle toxic effects of β-blocker overdose. Respiratory arrest is the primary cause of death in β-blocker intoxicated rats. 2 The effect of β-adrenoceptor agonists on respiratory and cardiovascular failure in β-blocker overdose was investigated in a model of acute d,l-propranolol (30 mg kg -1 h-1) intoxication in spontaneously breathing rats. 3 Neither the aselective, hydrophilic β-agonist isoprena line (10, 25, 50 μg kg-1 min-1), nor the β 1-selective, lipophilic β-agonist flerobuterol (1,3,10 μ g kg-1 min-1) and the β2-selective, lipophilic β-agonist clenbuterol (10, 25, 50 μg kg-1 min-1) had any beneficial effect on cardiovascular and respiratory variables or survival time in d,l-propranolol intoxicated spontaneously breathing rats. 4 Isoprenaline (10 μg kg-1 min-1) had no favourable effect on haemodynamic and respiratory variables in artificially ventilated d,l -propranolol intoxicated rats either. 5 Addition of dopamine to isoprenaline resulted in a significant reduction of survival time, primarily caused by a decrease in mean arterial blood pressure, in artificially ventilated d,l-propranolol intoxicated rats. Addition of glucagon to isoprenaline did not affect survival time. 6 Artificial ventilation is the most important supportive measure in d,l-propranolol intoxication in the rat.

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Indication	Highest Phase	Country/Location	Organization	Date
Depressive Disorder, Major	Phase 2	-	Teva Pharmaceutical Industries Ltd.	-
Depressive Disorder, Major	Phase 2	FR	-	-

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