[3H]cocaine labels a binding site associated with the serotonin transporter in guinea pig brain: Allosteric modulation by paroxetine |
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Authors: | Hyacinth C Akunne Brian R de Costa Arthur E Jacobson Kenner C Rice Richard B Rothman |
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Institution: | (1) Laboratory of Clinical Psychopharmacology, NIDA Addiction Research Center, PO BOX 5180, 21224 Baltimore, MD;(2) Section on Drug Design and Synthesis, Laboratory of Medicinal Chemistry, NIDDK, 20892 Bethesda, MD |
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Abstract: | We studied the characteristics of 3H]cocaine binding to membranes prepared from whole guinea pig brain. Cocaine binding was specific and saturable. A one-site binding model fit the data adequately: the Kd value of 3H]cocaine was 44 nM with a Bmax value of 280 fmol/mg protein. The rank order of potency for the 3H]cocaine binding site was paroxetine > clomipramine > (–)-cocaine > fluoxetine > mazindol > desipramine > GBR12909 > phencyclidine > benztropine > GBR12935 > (+)-cocaine. The IC50 values of these drugs for inhibition of 3H]cocaine binding were highly correlated with their IC50 values for inhibition of 3H]5-HT uptake into synaptosomes prepared from whole guinea pig brain. High affinity 5-HT uptake inhibitors produced dose-dependent wash-resistant (pseudoirreversible) inhibition of 3H]cocaine binding. The wash-resistant inhibition produced by paroxetine was due to an increase in the Kd of 3H]cocaine binding sites, and was accompanied by an increase in the dissociation rate, consistent with an allosteric mechanism. These studies suggest that, using membranes prepared from whole guinea pig brain, 3H]cocaine labels a binding site associated with serotonin transporter and that paroxetine and cocaine bind to different sites on the serotonin transporter.Abbreviations GBR12909
1-(2-{bis(4-fluorophenyl)methoxy}ethyl)-4-{3-phenylpropyl}piperazine
- TCP
1-{1-(2-thienyl)cyclohexyl}piperidine
- BTCP
N-{1-(2-benzo(b)thiophenyl)cyclohexyl}piperidine
- PCP
1-(1-phenylcyclohexyl)piperidine
- GBR12935
(1-2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine)
- CMI
clomipramine |
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Keywords: | Cocaine paroxetine serotonin serotonin uptake GBR12909 |
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