Upregulation of CCL7 and CCL2 in reward system mediated through dopamine D1 receptor signaling underlies methamphetamine-induced place preference in mice

We previously showed that the CC-chemokine ligand 2 (CCL2)-CC-chemokine receptor 2 (CCR2) system is responsible for conditioned place preference (CPP) by methamphetamine (Meth). In this study, we investigated the roles for other chemokines mediating Meth-induced CPP and the upstream factors upregulating chemokines in mice. We found that CCL7 mRNA level was upregulated in the prefrontal cortex (PFC) after Meth administration (3 mg/kg, subcutaneous), and increased CCL7 immunoreactivity was localized to the PFC NeuN-positive neurons. Meth-induced CPP was blocked by the dopamine D1 receptor antagonist SCH 23390 but not by the D2 receptor antagonists raclopride or haloperidol. The D1 receptor agonist SKF 81297 alone elicited CPP, suggesting a critical role of D1 receptor signaling in Meth-induced reward. Consistent with these results, the Meth-induced upregulation of CCL7 and CCL2 were attenuated by SCH 23390, and a single administration of SKF 81297 upregulated mRNA expression levels of CCL7 and CCL2 in the PFC. Furthermore, Meth-induced CPP was prevented by INCB 3284, a selective antagonist of CCR2, a receptor that binds both CCL7 and CCL2. Collectively, we identified two CC-chemokines (i.e., CCL7 and CCL2) as key regulatory factors in Meth-induced reward. Pharmacological inhibitors of these chemokines may warrant development as novel therapeutics for ameliorating Meth addiction.