title: A novel mechanism of cocaine to enhance dopamine d2-like receptor mediated neurochemical and behavioral effects. An in vivo and in vitro study.
abstract: Recent in vitro results suggest that cocaine may exert direct and/or indirect allosteric enhancing actions at dopamine (DA) D(2) receptors (D(2)Rs). In the present paper we tested the hypothesis that cocaine in vivo can enhance the effects of the D(2)-likeR agonist quinpirole in rats by using microdialysis and pharmacological behavioral studies. Furthermore, in vitro D(2)-likeR binding characteristics and Gα(i/o)-protein coupling, in the absence and in the presence of cocaine, have been investigated in rat striatal membranes. Intra-nucleus accumbens perfusion of the D(2)-likeR agonist quinpirole (10 μM) reduced local dialysate glutamate levels, whereas cocaine (10 and 100 nM) was ineffective. At a low concentration (100 nM), cocaine significantly enhanced quinpirole-induced reduction of accumbal extracellular glutamate levels. The behavioral experiments showed that cocaine (0.625 mg/kg), but not the DA uptake blocker GBR 12783 (1.25 mg/kg), enhanced quinpirole (1 mg/kg)-induced hyperlocomotion. Finally, cocaine (100 nM), but not GBR 12783 (200 nM), produced a small, but significant increase in the efficacy of DA to stimulate binding of GTPγS to striatal D(2)-likeRs, whereas the D(2)-likeR binding characteristics were unchanged in striatal membranes by cocaine in the nM range. The significant increase in the maximal response to DA-stimulated GTPγS binding to D(2)-likeRs by 100 nM cocaine remained in the presence of GBR 12783. The observed cocaine-induced enhancement of the Gα(i/o)-protein coupling of D(2)Rs may be in part because of allosteric direct and/or indirect enhancing effects of cocaine at these receptors. These novel actions of cocaine may have relevance for understanding the actions of cocaine upon accumbal DA, and/or glutamate transmission and thus its rewarding as well as relapsing effects.
authors.affiliation: Department of Clinical and Experimental Medicine, Pharmacology Section and LTTA Centre, University of Ferrara, Ferrara, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Ferraro
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Frankowska
authors.forename: Daniel
authors.initials: D
authors.lastname: Marcellino
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zaniewska
authors.forename: Sarah
authors.initials: S
authors.lastname: Beggiato
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Filip
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Tomasini
authors.forename: Tiziana
authors.initials: T
authors.lastname: Antonelli
authors.forename: Sergio
authors.initials: S
authors.lastname: Tanganelli
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
mesh_terms: D000818:Animals; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000494:pharmacology; D004357:Drug Synergism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D018698:Glutamic Acid; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008845:Microinjections; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D019257:Quinpirole / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism / Q000502:physiology*
chemical_list: D010879:Piperazines; D017448:Receptors, Dopamine D2; D019257:Quinpirole; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018698:Glutamic Acid; C039737:1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D003042:Cocaine; D004298:Dopamine