title: 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 ligand 2 (CCL2) participates in the methamphetamine dependence using mice. Upregulation of CCL2 but not CC-chemokine receptor 2 (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 immunohistochemistry, 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.
authors.affiliation: Department of Pharmacology, Wakayama Medical University, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Wakida
authors.forename: Norikazu
authors.initials: N
authors.lastname: Kiguchi
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Saika
authors.forename: Hideki
authors.initials: H
authors.lastname: Nishiue
authors.forename: Yuka
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Shiroh
authors.initials: S
authors.lastname: Kishioka
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology / Q000627:therapeutic use; D000697:Central Nervous System Stimulants / Q000009:adverse effects*; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000166:cytology; D017397:Prefrontal Cortex / Q000166:cytology; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use; D015813:Substance Abuse Detection / Q000379:methods; D019966:Substance-Related Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000201:enzymology
chemical_list: D048588:Benzoxazines; D000697:Central Nervous System Stimulants; D018932:Chemokine CCL2; C579117:RS 504393; D054390:Receptors, CCR2; D013141:Spiro Compounds; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase