CC-Chemokine Ligand 2 Facilitates Conditioned Place Preference to Methamphetamine Through the Activation of Dopamine Systems

Abstract. Methamphetamine addiction is characterized by drug craving caused by stimulation of the reward system. Because neuroinflammation underlies several neurological disorders, we investigated whether CC-chemokine ligand2 (CCL2) participates in the methamphetamine dependence using mice. Upregulation of CCL2 but not CC-chemokine receptor2 (CCR2), a dominant receptor for CCL2, mRNA in both the prefrontal cortex (PFC) and nucleus accumbens (NAC) was observed after methamphetamine (3 mg/kg, s.c.) administration. Using immuno-histochemistry, high CCL2 protein levels localized to neurons in the PFC and NAC. In the conditioned place preference (CPP) test, methamphetamine (0.3– 3 mg/kg, s.c.) induced a CPP, reflecting psychic dependence on methamphetamine, in a dose-dependent manner. The CPP to methamphetamine was attenuated by RS504393 (1 mg/kg, s.c.), a CCR2 antagonist. Moreover, methamphetamine increased phosphorylated tyrosine hydroxylase (pTH) levels in the ventral tegmental area (VTA). Increased levels of pTH in the VTA by methamphetamine was also suppressed by RS504393. Furthermore, intracerebroventricular injection of recombinant CCL2 increased pTH levels in the VTA. Taken together, we demonstrate that activation of dopamine neurons, which enhances reward-system activity, via the CCL2-CCR2 axis plays a crucial role in psychic dependence on methamphetamine. Novel treatments targeting this machinery may be effective for drug addiction.