Cocaine modulates allosteric D₂-σ₁ receptor-receptor interactions on dopamine and glutamate nerve terminals from rat...

The effects of nanomolar cocaine concentrations, possibly not blocking the dopamine transporter activity, on striatal D₂-σ₁ 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 D_2LR HEK293T cells, quinpirole had a reduced potency to inhibit the CREB signal versus D_2LR singly transfected cells. In the presence of cocaine (100nM), the potency of quinpirole to inhibit the CREB signal was restored. In D_2L 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 D₂-σ₁R complexes on the rat striatal DA and glutamate nerve terminals and functional D₂-σ₁R-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.