title: Time-dependent changes in receptor/G-protein coupling in rat brain following chronic monoamine transporter blockade.
abstract: The potent tropane analog, WF-23 [2beta-propanoyl-3beta-(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-[(35)S]thiotriphosphate) ([(35)S]GTPgammaS) binding in brain sections for monoamine receptors, as well as mu opioid receptors as a nonmonoamine receptor control. Chronic treatment with WF-23 produced significant reductions in D(2), 5-hydroxytryptamine 1A, and alpha(2)-adrenergic receptor-stimulated [(35)S]GTPgammaS binding; however, the time course of desensitization varied with different receptors. There was no effect of WF-23 treatment on mu opioid-stimulated [(35)S]GTPgammaS binding at any time point. Consistent with previous studies, there was no effect of WF-23 treatment on D(2) receptor binding, as determined by [(3)H]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 D(2) receptor/G-protein coupling, suggesting a role of D(2) desensitization in producing tolerance to WF-23-mediated behavior.
authors.affiliation: Department of Physiology/Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: O'Connor
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Porrino
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; D015306:Biogenic Monoamines / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D003042:Cocaine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008297:Male; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013997:Time Factors
chemical_list: C112780:2-propanoyl-3-(2-naphthyl)-tropane; D015306:Biogenic Monoamines; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D043562:Receptors, G-Protein-Coupled; D019204:GTP-Binding Proteins; D003042:Cocaine