In the brain, D₁-receptor-containing medium spiny neurons (D₁-MSNs) functionally interact with D₂-MSNs to exhibit abused drug-induced behaviors. In our previous study, Δ-fosB induction was prominently observed in not only D₁-, but also non-D₁-receptor-containing MSNs after repeated administration of methamphetamine (METH), suggesting that D₂-MSNs may be partly involved in METH-induced sensitization. It has been well documented that the endogenous δ-opioid enkephalin, δ-opioid receptors and adenosine A_2A receptors are mostly expressed in D₂-MSNs. In the present study, we investigated the distinct role of δ-opioid and adenosine A_2A receptors in METH-induced behavioral sensitization. We found that cross-sensitization to the locomotor-enhancing effect of METH was observed by repeated treatment with both the selective δ-opioid receptor agonist SNC80 and the adenosine A_2A receptor antagonist istradefylline in mice. On the other hand, hyperlocomotion produced by SNC80, but not METH or istradefylline, was dramatically reduced in preproenkephalin knockout mice. These findings indicate that heterogeneously expressed receptors on D₂-MSNs may reciprocally regulate the function of D₂-MSNs through different mechanisms to induce behavioral sensitization of METH. To prove this hypothesis, we will perform the genetic recombination approach.