title: Effects of long-term biogenic amine transporter blockade on receptor/G-protein coupling in rat brain.
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 (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 1mg/kg WF-23, injected i.p. every two days. Receptor activation of G-proteins was determined by [35S]GTPgammaS autoradiography in brain sections for D2, 5-HT1A and alpha2-adrenergic receptors, as well as mu opioid receptors as a non-monoamine receptor control. Chronic treatment with WF-23 produced significant reductions in D2, 5-HT1A, and alpha2-adrenergic receptor-stimulated [35S]GTPgammaS binding in caudate/putamen, hippocampus and amygdala, respectively. There were no effects of WF-23 treatment on mu opioid-stimulated [35S]GTPgammaS binding. Additionally, there was no effect of WF-23 treatment on D2 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.
authors.affiliation: Wake Forest University Health Sciences, Physiology and Pharmacology Department, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
authors.forename: Kerry Ann
authors.initials: KA
authors.lastname: O'Connor
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Gregg
authors.forename: Huw M L
authors.initials: HM
authors.lastname: Davies
authors.forename: Steven R
authors.initials: SR
authors.lastname: Childers
mesh_terms: D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000493:pharmacokinetics; D004334:Drug Administration Schedule; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D007554:Isotopes / Q000493:pharmacokinetics; D008297:Male; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013134:Spiperone / Q000493:pharmacokinetics; D013995:Time
chemical_list: C425777:10,11-dihydroxy-N-n-propylnorapomorphine; C112780:2-propanoyl-3-(2-naphthyl)-tropane; D015306:Biogenic Monoamines; D018492:Dopamine Antagonists; D007554:Isotopes; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D043562:Receptors, G-Protein-Coupled; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013134:Spiperone; D003042:Cocaine; D001058:Apomorphine