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Time-Dependent Changes in Receptor/G-Protein Coupling in Rat Brain following Chronic Monoamine Transporter Blockade

The potent tropane analog, WF-23 [2β-propanoyl-3β-(2-naphthyl) tropane], blocks dopamine, serotonin, and norepinephrine transporters with high affinity in vitro and blocks transporters for at least 2 days following a single in vivo administration. Previous studies demonstrated desensitization of monoamine receptor-coupled G-proteins in brain following chronic treatment of rats with WF-23. The current study sought to determine the time course of this desensitization and the behavioral effects of receptor desensitization. Rats were treated with 1 mg/kg WF-23 and injected i.p. every 48 h for 1 to 21 days. Receptor activation of G-proteins was determined by guanosine 5′-O-(3-[35S]thiotriphosphate) ([35S]GTPγS) binding in brain sections for monoamine receptors, as well as μ opioid receptors as a nonmonoamine receptor control. Chronic treatment with WF-23 produced significant reductions in D2, 5-hydroxytryptamine 1A, and α2-adrenergic receptor-stimulated [35S]GTPγS binding; however, the time course of desensitization varied with different receptors. There was no effect of WF-23 treatment on μ opioid-stimulated [35S]GTPγS binding at any time point. Consistent with previous studies, there was no effect of WF-23 treatment on D2 receptor binding, as determined by [3H]spiperone autoradiography. Locomotor activity was significantly increased for up to 48 h following acute administration of WF-23, demonstrated by increased photocell beam interruptions. WF-23-induced increases in locomotor activity occurred following repeated administration, as above, for up to 7 days. Following 7 days of treatment, there was a significant decrease in WF-23-increased locomotor activity. This reduction occurred at the same time point as the decrease in D2 receptor/G-protein coupling, suggesting a role of D2 desensitization in producing tolerance to WF-23-mediated behavior.