Activation of D₂-like receptors in rat ventral tegmental area inhibits cocaine-reinstated drug-seeking behavior.

Relapse is a hallmark of cocaine addiction. Cocaine-induced neuroplastic changes in the mesocorticolimbic circuits critically contribute to this phenomenon. Pre-clinical evidence indicates that relapse to cocaine-seeking behavior depends on activation of dopamine neurons in the ventral tegmental area. Thus, blocking such activation may inhibit relapse. Because the activity of dopamine neurons is regulated by D₂-like autoreceptors expressed on somatodendritic sites, this study, using the reinstatement model, aimed to determine whether activation of D₂-like receptors in the ventral tegmental area can inhibit cocaine-induced reinstatement of extinguished cocaine-seeking behavior. Rats were trained to self-administer i.v. cocaine (0.25 mg/infusion) under a modified fixed-ratio 5 schedule. After such behavior was well learned, rats went through extinction training to extinguish cocaine-seeking behavior. The effect of quinpirole, a selective D₂-like receptor agonist microinjected into the ventral tegmental area, on cocaine-induced reinstatement was then assessed. Quinpirole (0-3.2 μg/side) dose-dependently decreased cocaine-induced reinstatement and such effects were reversed by the selective D₂-like receptor antagonist eticlopride when co-microinjected with quinpirole into the ventral tegmental area. The effect appeared to be specific to the ventral tegmental area because quinpirole microinjected into the substantia nigra had no effect. Because D₂-like receptors are expressed on rat ventral tegmental area dopamine neurons projecting to the pre-frontal cortex and nucleus accumbens, our data suggest that these dopamine circuits may play a critical role in cocaine-induced reinstatement. The role of potential changes in D₂-like receptors and related signaling molecules of dopamine neurons in the vulnerability to relapse was discussed.