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We characterized the effects of drugs on the uptake of [3H]neurotransmitter by and the binding of [125I](3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester ([125I]RTI-55) to the recombinant human dopamine (hDAT), serotonin (hSERT), or norepinephrine (hNET) transporters stably expressed in human embryonic kidney 293 cells. RTI-55 had similar affinity for the hDAT and hSERT and lower affinity for hNET (Kd = 1. 83, 0.98, and 12.1 nM, respectively). Kinetic analysis of [125I]RTI-55 binding indicated that the dissociation rate (k-1) was significantly lower for hSERT and the association rate (k+1) was significantly lower for hNET compared with the hDAT. The potency of drugs at blocking [3H]neurotransmitter uptake was highly correlated with potency at blocking radioligand binding for hDAT and hSERT. Substrates were more potent at the inhibition of [3H]neurotransmitter uptake than radioligand binding. The potency of drugs was highly correlated between displacement of [3H]nisoxetine (Kd = 6.0 nM) and [125I]RTI-55 from the hNET, suggesting that these radioligands recognize similar sites on the transporter protein. The correlation observed between inhibitory potency for uptake and binding of either ligand at the hNET was lower than correlations between uptake and binding for hDAT and hSERT. The present results indicate that the cocaine analog [125I]RTI-55 has unique binding properties at each of the transporters and that the use of recombinant transporters expressed by a single cell type can provide a powerful screening tool for drugs interacting with biogenic amine transporters, such as possible cocaine antagonists.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10215666&dopt=Abstract
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Synapse. 1998 Nov;30(3):318-28.
Cellular electrophysiological effects of chronic fluoxetine and duloxetine administration on serotonergic responses in the aging hippocampus.
Smith JE, Lakoski JM.
Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey 17033-0850, USA.
The pharmacological and physiological effects of chronic administration of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor (SSRI) fluoxetine and the dual 5-HT/norepinephrine (NE) reuptake inhibitor duloxetine were compared on 5-HT-mediated electrophysiological responses recorded in the hippocampus of young (3-5 months) and old (17-20 months) female Fischer 344 rats. Fluoxetine, duloxetine, or vehicle (saline) was administered once daily for 14 days (10 mg/kg, i.p.) and extracellular recordings of spontaneously firing CA1 and CA3 pyramidal neurons were conducted 24 h following the last injection using microiontophoretic drug application techniques in a chloral hydrate anesthetized preparation. The recovery times (RT50 values; sec) following 5-HT application on pyramidal neurons were significantly increased in the young and old chronic fluoxetine (FLX) treated groups (73% and 104%, respectively; P < 0.05), but not chronic duloxetine- (DLX) or vehicle- (VEH) treated groups. Following prolonged application of duloxetine (5-10 min), the 5-HT RT50 values were significantly increased in the young FLX groups as compared to the age-matched DLX- and VEH-treated groups. In contrast, a significant decline in the time to recovery produced by 5-HT (52%) was observed in the old vs. young FLX-treated group following the second co-application of 5-HT with duloxetine. Within each drug treatment and age group, co-application of duloxetine and 5-HT did not alter the inhibitory responses (IT50 values; nC) produced by the application of 5-HT alone. These results demonstrate cellular adaptive changes in serotonergic neuronal function occur following repeated exposure to 5-HT reuptake inhibitors in an age-dependent manner.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9776135&dopt=Abstract
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Epilepsia. 1998 Oct;39(10):1054-63.
Carbamazepine-induced release of serotonin from rat hippocampus in vitro.
Dailey JW, Reith ME, Steidley KR, Milbrandt JC, Jobe PC.
Department of Biomedical and Therapeutic Sciences, University of Illinois College of Medicine, Peoria 61656, USA.
PURPOSE: Carbamazepine is one of several antiepileptic drugs (AEDs) that release the inhibitory neurotransmitter serotonin as part of their pharmacodynamic action on brain neurons. We undertook this study to investigate the cellular processes by which carbamazepine (CBZ) releases serotonin from brain tissue. METHODS: Tissue slices were prepared from hippocampi of Sprague-Dawley rats. These hippocampal slices were preincubated in vitro in a buffer so that neurons within the slice would take up tritium-labeled serotonin. Subsequently the slices were superfused with buffer containing CBZ or other chemicals (or both) that increase the overflow of serotonin radioactivity. RESULTS: Carbamazepine produced a concentration-dependent (50, 125, 250, or 500 microM) increase in basal overflow of serotonin radioactivity from superfused rat hippocampal slices in vitro. In contrast, these concentrations did not alter potassium-stimulated release, suggesting that the CBZ-induced release does not depend on depolarization or exocytosis. Blockade of the neuronal membrane serotonin transporter by fluoxetine (1 microM) or citalopram (2 microM) did not alter overflow of serotonin radioactivity produced by 250 microM CBZ. p-chloramphetamine (10 microM) produced a substantial increase in overflow of serotonin radioactivity, and this effect appears to be antagonized by 250 microM CBZ. Uptake of [3H]-labeled serotonin into hippocampal synaptosomes was inhibited by CBZ with a median inhibitory concentration (IC50) of 511+/-33 microM and a Hill coefficient of 0.87+/-0.11, suggesting competitive inhibition of uptake by CBZ. CONCLUSIONS: We conclude that CBZ (a) releases serotonin from hippocampal slices independent of exocytosis and by a mechanism not involving the neuronal membrane serotonin transporter, and (b) at high enough concentration, blocks the neuronal serotonin transporter.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9776325&dopt=Abstract
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