Dopamine D4 receptor activation decreases the expression of -opioid receptors in the rat striatum

The dopaminergic and opioid peptide systems interact in many nuclei of the brain. In the striatum, dopamine/opioid peptide interactions modulate locomotor and motivated behaviors as well as reward, motivational, and tolerance processes in opiate dependence. Dopamine D4 receptors (D4 R) and -opioid receptors (MOR) are highly concentrated in the striosomes (islands) of the striatum, suggesting the existence of receptor-receptor interactions between them. In the present work we studied the role of D4 R in modulating MOR expression in the islands by using immunohistochemistry and image analysis. The activation of D4 R by the agonist PD168,077 (1 mg/kg) decreased MOR immunoreactivity (IR) in the striosomes 6 hours after drug treatment. MOR IR levels had recovered 12 hours later. Treatment with a D4 R antagonist (L745,870, 1mg/kg) blocked downregulation of MOR IR, showing that the D4 R agonist effects observed were specific. Furthermore, treatment with the D2/D3 receptor agonist quinpirol (1 mg/kg) and D2/D3 receptor antagonist raclopride (1 mg/kg) had no effect in MOR IR, suggesting that D4 R is the only D2-like receptor producing an MOR downregulation in the islands. The decreases of MOR IR in the striosomes suggest that D4 R activation may reduce MOR signaling. Increasing evidence has demonstrated that the islands in the striatum play a critical role in habit acquisition during drug addiction. D4 R/MOR interactions could be crucial in such processes.