Drugs online research references
J Neurochem. 1998 Aug;71(2):653-65.
Voltammetric studies on mechanisms of dopamine efflux in the presence of substrates and cocaine from cells expressing human norepinephrine transporter.
Chen N, Trowbridge CG, Justice JB Jr.
Department of Pharmacology, Nanjing Medical University, PRC.
The effects of substrates m-tyramine and beta-phenethylamine, as well as cocaine, on the DA efflux from a cell line stably expressing the human norepinephrine transporter (hNET) were investigated by using rotating disk electrode voltammetry. Both the substrates and cocaine induced apparent DA efflux in a concentration-dependent manner. Their EC50 values for inducing DA efflux were similar to their IC50 values for inhibiting DA uptake. The substrate-induced DA efflux was inhibited by various NET blockers, enhanced by raising the internal [Na+] with Na+,K+-ATPase inhibition, but was insensitive to membrane potential-altering agents valinomycin, veratridine, and high [K+]. The initial rate of m-tyramine-induced DA efflux was related to preloaded [DA] in a manner defined by a Michaelis-Menten expression. In contrast, DA efflux in the presence of cocaine displayed a much slower efflux rate, lower efficacy, was not stimulated by elevated internal [Na+], and was nonsaturable with preloaded [DA]. Single exponential kinetic analysis of the entire time course of the DA efflux showed that the apparent first-order rate constant for m-tyramine-induced DA efflux declined with increased preloaded [DA], whereas that for the DA efflux in the presence of cocaine was unchanged with varying preloaded [DA]. These results suggest that the substrates stimulate the NET-dependent DA efflux by increasing the accessibility of the NET to internal DA, whereas cocaine "uncovers" NET-independent DA efflux by reducing the accessibility of diffused/leaked external DA to the NET.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9681456&dopt=Abstract
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Neuroreport. 1999 Feb 25;10(3):553-5.
Effects of acute and chronic fluoxetine treatment of CRH-induced anxiety.
To CT, Anheuer ZE, Bagdy G.
Laboratory of Neurochemistry and Experimental Medicine, National Institute of Psychiatry and Neurology, Budapest, Hungary.
The effects of acute and chronic fluoxetine treatment on anxiogenic effect of corticotropin-releasing hormone (CRH) were studied in the social interaction test in male Sprague-Dawley rats. Injection of CRH (100 ng, i.c.v.), fluoxetine (5 mg/kg, i.p.) or their combination had significant anxiogenic effects (decrease in total interaction time and increase in self-grooming) in the social interaction test. The effects of CRH and fluoxetine in combination were not additive. Fluoxetine, but not CRH significantly inhibited locomotor activity. After chronic fluoxetine treatment (5 mg/kg/day, 21 days) the acute anxiogenic effects of either CRH or fluoxetine were abolished. Our studies provide evidence for a 5-HT/CRH interaction in the regulation of anxiety.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10208588&dopt=Abstract
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rug.ac.be
OBJECTIVE: Biotransformation of metoprolol to alpha-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) is mediated by CYP2D6. The selective serotonin reuptake inhibitors (SSRIs) are known to inhibit CYP2D6. The aim was to study in vitro the potential inhibitory effect of SSRIs on metoprolol biotransformation. METHODS: Using microsomes from two human livers, biotransformation of metoprolol to alpha-hydroxymetoprolol (HM) and O-demethylmetoprolol (ODM) as a function of the concentrations of the SSRIs and of some of their metabolites was studied. RESULTS: The kinetics of the formation of both metabolites are best described by a biphasic enzyme model. The estimated values of Vmax and kM for the high affinity site are for the alpha-hydroxylation in human liver HL-1 32 pmol mg(-1) min(-1) and 75 micromol x l(-1) respectively, and in human liver HL-9 39 pmol mg(-1) x min(-1) and 70 micromol x l(-1) respectively; for the O-demethylation in HL-1 131 pmol mg(-1) min(-1) and 95 micromol x l(-1) respectively, and in HL-9 145 pmol mg(-1) min(-1) and 94 micromol x l(-1) respectively. Quinidine is for both pathways a potent inhibitor of the high-affinity site, with K(i) values ranging from 0.03 to 0.18 micromol x l(-1). Fluoxetine, norfluoxetine and paroxetine are likewise potent inhibitors, with Ki values ranging from 0.30 to 2.1 micromol x l(-1) fluvoxamine, sertraline, desmethylsertraline, citalopram and desmethylcitalopram are less potent inhibitors, with K(i) values above 10 micromol x l(-1). CONCLUSION: The rank order of the SSRIs for inhibition of metoprolol metabolism is comparable to that reported in the literature for other CYP2D6 substrates, with fluoxetine, norfluoxetine and paroxetine being the most potent. These findings need further investigation to determine their clinical relevance.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9681670&dopt=Abstract
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