Abstract

This study examines the effect of long-term elevation of brain monoamine levels on receptor/G-protein coupling by chronic administration of a highly potent tropane analog, WF-23 (2β-propanoyl-3β-(2-naphthyl) tropane). WF-23 blocks dopamine, serotonin and norepinephrine transporters with high affinity in vitro, and blocks transporters for at least two days following a single in vivo administration. Rats were chronically treated for 15 days with 1 mg/kg WF-23, injected i.p. every two days. Receptor activation of G-proteins was determined by [ 35S]GTPγS autoradiography in brain sections for D 2, 5-HT 1A and α 2-adrenergic receptors, as well as mu opioid receptors as a non-monoamine receptor control. Chronic treatment with WF-23 produced significant reductions in D 2, 5-HT 1A, and α 2-adrenergic receptor-stimulated [ 35S]GTPγS binding in caudate/putamen, hippocampus and amygdala, respectively. There were no effects of WF-23 treatment on mu opioid-stimulated [ 35S]GTPγS binding. Additionally, there was no effect of WF-23 treatment on D 2 receptor binding, as determined by [ 3H]spiperone autoradiography. These data show that chronic blockade of monoamine transporters produces specific uncoupling of receptors and G-proteins in specific brain regions in the absence of receptor downregulation.

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