Recent in vitro results suggest that cocaine may exert direct and/or indirect allosteric enhancing actions at dopamine (DA) D 2 receptors (D 2Rs). 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 2Rs 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. © 2012 American College of Neuropsychopharmacology. All rights reserved.

A novel mechanism of cocaine to enhance dopamine D 2-like receptor mediated neurochemical and behavioral effects. An in vivo and in vitro study

FERRARO, Luca Nicola;BEGGIATO, Sarah;TOMASINI, Maria Cristina;ANTONELLI, Tiziana;TANGANELLI, Sergio;
2012

Abstract

Recent in vitro results suggest that cocaine may exert direct and/or indirect allosteric enhancing actions at dopamine (DA) D 2 receptors (D 2Rs). 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 2Rs 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. © 2012 American College of Neuropsychopharmacology. All rights reserved.
2012
Ferraro, Luca Nicola; Frankowska, M; Marcellino, D; Zaniewska, M; Beggiato, Sarah; Filip, M; Tomasini, Maria Cristina; Antonelli, Tiziana; Tanganelli,...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/1674278
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