Cocaine modulates allosteric D21 receptor-receptor interactions on dopamine and glutamate nerve terminals from rat striatum

Cell Signal. 2017 Dec;40:116-124. doi: 10.1016/j.cellsig.2017.09.007. Epub 2017 Sep 18.


The effects of nanomolar cocaine concentrations, possibly not blocking the dopamine transporter activity, on striatal D21 heteroreceptor complexes and their inhibitory signaling over Gi/o, have been tested in rat striatal synaptosomes and HEK293T cells. Furthermore, the possible role of σ1 receptors (σ1Rs) in the cocaine-provoked amplification of D2 receptor (D2R)-induced reduction of K+-evoked [3H]-DA and glutamate release from rat striatal synaptosomes, has also been investigated. The dopamine D2-likeR agonist quinpirole (10nM-1μM), concentration-dependently reduced K+-evoked [3H]-DA and glutamate release from rat striatal synaptosomes. The σ1R antagonist BD1063 (100nM), amplified the effects of quinpirole (10 and 100nM) on K+-evoked [3H]-DA, but not glutamate, release. Nanomolar cocaine concentrations significantly enhanced the quinpirole (100nM)-induced decrease of K+-evoked [3H]-DA and glutamate release from rat striatal synaptosomes. In the presence of BD1063 (10nM), cocaine failed to amplify the quinpirole (100nM)-induced effects. In cotransfected σ1R and D2LR HEK293T cells, quinpirole had a reduced potency to inhibit the CREB signal versus D2LR singly transfected cells. In the presence of cocaine (100nM), the potency of quinpirole to inhibit the CREB signal was restored. In D2L singly transfected cells cocaine (100nM and 10μM) exerted no modulatory effects on the inhibitory potency of quinpirole to bring down the CREB signal. These results led us to hypothesize the existence of functional D21R complexes on the rat striatal DA and glutamate nerve terminals and functional D21R-DA transporter complexes on the striatal DA terminals. Nanomolar cocaine concentrations appear to alter the allosteric receptor-receptor interactions in such complexes leading to enhancement of Gi/o mediated D2R signaling.

Keywords: BD1063; HEK293T cells; Quinpirole; Receptor heteromers; Release; Synaptosomes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cocaine / administration & dosage*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism*
  • Cyclic AMP Response Element-Binding Protein / genetics
  • Dopamine / metabolism
  • Dopamine Agonists / administration & dosage
  • Dopamine Plasma Membrane Transport Proteins / genetics
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Glutamic Acid / metabolism
  • HEK293 Cells
  • Humans
  • Multiprotein Complexes / drug effects
  • Multiprotein Complexes / genetics
  • Nerve Endings / drug effects
  • Nerve Endings / metabolism
  • Quinpirole / administration & dosage
  • Rats
  • Receptors, Dopamine D2 / chemistry
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, sigma / chemistry
  • Receptors, sigma / genetics
  • Receptors, sigma / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Synaptosomes / drug effects
  • Synaptosomes / metabolism


  • Cyclic AMP Response Element-Binding Protein
  • Dopamine Agonists
  • Dopamine Plasma Membrane Transport Proteins
  • Multiprotein Complexes
  • Receptors, Dopamine D2
  • Receptors, sigma
  • sigma-1 receptor
  • Quinpirole
  • Glutamic Acid
  • Cocaine
  • Dopamine