A novel mechanism of cocaine to enhance dopamine d2-like receptor mediated neurochemical and behavioral effects. An in vivo and in vitro study

Neuropsychopharmacology. 2012 Jul;37(8):1856-66. doi: 10.1038/npp.2012.33. Epub 2012 Mar 28.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cocaine / administration & dosage
  • Cocaine / pharmacology*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Dopamine / pharmacology
  • Drug Synergism
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Glutamic Acid
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Locomotion / drug effects
  • Male
  • Microinjections
  • Nucleus Accumbens / drug effects
  • Nucleus Accumbens / metabolism
  • Piperazines / pharmacology
  • Quinpirole / administration & dosage
  • Quinpirole / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Dopamine D2 / agonists
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D2 / physiology*


  • Piperazines
  • Receptors, Dopamine D2
  • Quinpirole
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Glutamic Acid
  • 1-(2-(diphenylmethoxy)ethyl)-4-(3-phenyl-2-propenyl)piperazine
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Cocaine
  • Dopamine