Effects of long-term biogenic amine transporter blockade on receptor/G-protein coupling in rat brain

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 (2beta-propanoyl-3beta-(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 [S-35]GTPgammaS autoradiography in brain sections for D,, 5-HT1A and alpha(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-HT1A, and alpha(2)-adrenergic receptor-stimulated [S-35]GTPgammaS binding in caudate/putamen, hippocampus and amygdala, respectively. There were no effects of WF-23 treatment on mu opioid-stimulated [S-35]GTPgammaS bindin-g. Additionally, there was no effect of WF-23 treatment on D, receptor binding, as determined by [H-3]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. (C) 2004 Elsevier Ltd. All rights reserved.