Effect of Combined Administration of Afobazole and 5-HT2b/2c Receptor Antagonist SB-200646A on Neurochemical Profile of Brain Structures in C57Bl/6 and BALB/c Mice

Q4 · MEDICINE

Article

Author: Rayevsky, K. S. ; Kudrin, V. S. ; Klodt, P. M. ; Narkevich, V. B.

The effects of combined administration of afobazole and 5-HT(2b/2c)receptor antagonist SB-200646A on the content of monoamines and their metabolites in brain structures of C57Bl/6 and BALB/c mice were studied by the methods of HPLC with electrochemical detection. Combined administration of afobazole and SB-200646A increased the content of epinephrine in the striatum of BALB/c mice (to 230% of the control) and in the hippocampus of both mouse strains. The content of dihydroxyphenylacetic and homovanillic acids and parameters of dopamine metabolism in these structures were reduced. The content of dopamine in the hypothalamus and amygdala was elevated in C57Bl/6, but not in BALB/c mice. These findings attest to the involvement of monoamine systems of the brain in the mechanism of afobazole action and suggest that the enhanced anxiolytic effect of afobazole combination with SB-200646A can be interpreted as a positive modulation of the effect of anxiolytic determined by blockade of 5-HT(2)serotonin receptors.

01 Jan 2011·Eksperimental'naia i klinicheskaia farmakologiia

[Possible role of serotonin 5-HT2 receptors in mechanism of afobazole anxiolytic action: neurochemical study of inter-line differences in mice].

Article

Author: Klodt, P M ; Raevskiĭ, K S ; Kudrin, V S ; Narkevich, V B

Effects of separate and combined introduction of afobazole and SB-200646A (highly selective 5-HT2B/2C receptor antagonist) on the content of monoamines and their metabolites in brain structures of mice of C57/Bl/6 and BALB/C lines have been studied using neurochemical methods and high-performance liquid chromatography (HPLC). Afobazole (5 mg/kg, i.p.) significantly increased dopamine (DA) level in hypothalamus and amygdala of C57/Bl/6 mice, while no changes of DA content were observed in BALB/C mice. At the same time, the concentrations of DA metabolites dioxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the same structures as well as in striatum were decreased compared to control. Afobazole also led to a decrease in the content of 5-hydroxyindoleacetic acid (5-HIAA) and 5-HIAA/5-HT index in frontal cortex and amygdala of C57/Bl/6 mice; analogous decrease in the latter parameter was observed in striatum of BALB/C mice. The introduction of SB-200646A (10 mg/kg, i.p.) almost did not influence the neurochemical indices of the content and metabolism of monoamines, except for an increase in the HVA content in amygdala and the DOPAC and 5-HIAA concentrations in striatum of C57/Bl/6 mice. The joint introduction of afobazole and SB-200646A led to an increase in the content of norepinephrine (NE) in striatum of BALB/C mice and in hippocamp of mice of both lines. The data obtained may be indicative of the involvement of NE- and DA-ergic neurotransmitter systems in the mechanisms of afobazole action. Enhanced anxiolytic effect of the joint introduction of afobazole and SB-200646A can be interpreted as a positive modulation of the anxiolytic drug action related to the blocking of 5-HT2-type serortonin receptors. The results also reveal inter-line differences of neurochemical responses induced by combination of afobazole and selective antagonist of serotonin.

15 Jun 2006·SynapseQ4 · MEDICINE

The acute and chronic administration of the 5-HT2B/2C receptor antagonist SB-200646A significantly alters the activity of spontaneously active midbrain dopamine neurons in the rat: An in vivo extracellular single cell study

Q4 · MEDICINE

Article

Author: Blackburn, Thomas P. ; Ashby, Charles R. Jr. ; Suzuki, Katsuaki

This study examined the effect of the acute and chronic administration of the 5-HT(2B/2C) receptor antagonist N-(1-methyl-5-indolyl)-N'-(3-pyridyl) urea hydrochloride (SB-200646A) on the activity of spontaneously active DA cells in the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) in anesthetized, male Sprague-Dawley rats. This was accomplished using in vivo extracellular single cell recording. The i.v. administration of 4-16 mg/kg of SB-200646A significantly increased the firing rate and % events as bursts in spontaneously active VTA DA neurons and significantly increased the % events as burst in SNC DA neurons. The acute i.p. administration of 20 and 40 mg/kg of SB-200646A significantly increased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The acute administration of 10 mg/kg of SB-200646A significantly increased the coefficient of variation in spontaneously active SNC and DA neurons when compared with vehicle-treated controls. However, the acute i.p. administration of 20 mg/kg of SB-200646A significantly decreased the degree of bursting of VTA DA neurons. Similary, chronic i.p. administration of 10 mg/kg of SB-200646 did not significantly alter firing, whereas chronic administration of 20 mg/kg of SB-200646A or 20 mg/kg of clozapine significantly decreased the number of spontaneously active VTA DA neurons when compared with vehicle-treated controls. The SB-200646A-induced decrease in the number of spontaneously active VTA DA neurons was reversed by the i.v. administration of (+)-apomorphine or (-)-baclofen. The chronic i.p. administration of either 10 or 20 mg/kg of SB-200646A did not significantly alter the firing pattern of spontaneously active SNC DA neurons. However, the chronic administration of 20 mg/kg of SB-200646A significantly increased the degree of bursting in VTA DA neurons when compared with vehicle. Overall, the acute and chronic administration of SB-200646A produces in vivo electrophysiological effects, resembling that of atypical antipsychotic drugs.

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Anxiety Disorders	Discovery	GB	Smithkline Beecham Plc	-

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