PRECLINICAL STUDY: BRIEF REPORT: Epigenetic modulation at the CCR2 gene correlates with the maintenance of behavioral sensitization to methamphetamine

Ikegami, Daigo; Narita, Minoru; Imai, Shoichi; Miyashita, Kazuhiko; Tamura, Rie; Narita, Michiko; Takagi, Shigemi; Yokomizo, Akiko; Takeshima, Hideyuki; Ando, Takayuki; Igarashi, Katsuhide; Kanno, Jun; Kuzumaki, Naoko; Suzuki, Tsutomu

doi:10.1111/j.1369-1600.2010.00219.x

Cited by 22 publications

(20 citation statements)

References 7 publications

(7 reference statements)

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“…Though the role of CCL2/CCR2 in cocaine-induced addiction remains to be determined, the present results provide the first evidence for the implication of a chemokine receptor in neuroplasticity induced by cocaine. Similar results were recently observed for methamphetamine sensitization which was significantly decreased in CCR2 −/− mice (Ikegami et al 2010). Development of CCR2 antagonists could represent a new avenue in the therapeutic approach of addiction and weaning of drugs.…”

Section: Discussionsupporting

confidence: 87%

Implication of CCR2 Chemokine Receptor in Cocaine-Induced Sensitization

et al. 2011

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Cocaine-induced sensitization induces long-term neuroplastic changes in the striatum. Among these, extracellular signal-regulated kinase (ERK) is a fundamental component in striatal gene and epigenetic regulation and plays an important role in reward processes. As previous studies suggested that the chemokine CCL2 enhanced striatal dopamine release and as its cognate CCR2 receptor was located in brain structures implicated in cocaine reward, we tested the hypothesis that CCR2/CCL2 could be involved in cocaine-induced behavioral response. We used CCR2 knockout mice (CCR2(-/-)) and studied two crucial steps in cocaine sensitization: locomotor activity in sensitized mice and ERK activation in the striatum. We show that locomotor sensitization is significantly reduced in CCR2(-/-) mice as well as the dopamine transporter regulation and the cocaine-induced p-ERK striatal activation. Taken together, our results suggest that CCR2 receptor is involved in cocaine sensitization.

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Section: Discussionsupporting

confidence: 87%

Implication of CCR2 Chemokine Receptor in Cocaine-Induced Sensitization

et al. 2011

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“…There are several reports suggesting that CCL2-mediated neuroinflammation also underlies the pathogenesis of drug abuse (14). Moreover, upregulation of CC-chemokine receptor 2 (CCR2), a dominant receptor for CCL2, mediates behavioral sensitization to methamphetamine, which reflects a psychosis (15). Despite these lines of evidence, the pathophysiological roles of CCL2 in drug addiction remain unclear.…”

Section: Cc-chemokine Ligand 2 Facilitates Conditioned Place Preferenmentioning

confidence: 99%

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

et al. 2014

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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.

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“…Leukocytes can worsen inflammatory diseases, such as multiple sclerosis, through crosstalk with resident neurons or glial cells (16). Recent findings show that the CCL2/CCR2 pathway is involved in psychosis and psychic dependence to addictive drugs (17,23,24). Consequently, CCL2 is a potential therapeutic target for several disorders associated with nonresolving inflammation.…”

Section: Characteristics Of Ccl2mentioning

confidence: 99%

Epigenetic regulation of CC-chemokine ligand 2 in nonresolving inflammation

Kiguchi

Saika

Kobayashi

et al. 2014

Biomolecular Concepts

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Inflammation mediated by the crosstalk between leukocytes and resident tissue cells is crucial for the maintenance of homeostasis. Because chemokine ligands and receptors, which recruit a variety of leukocytes, are widely distributed among tissues, it is important to understand the mechanisms regulating inflammatory disease. Chemokines such as CC-chemokine ligand 2 (CCL2) amplify and maintain inflammation through chemokine-cytokine networks after the recruitment of circulating leukocytes. Chemokine-dependent nonresolving inflammation occurs in the peripheral and central nervous systems, and underlies several intractable diseases, including cancer and neuropathic pain. The chronic upregulation of chemokines is often mediated by epigenetic mechanisms consisting of DNA methylation, histone modification, and nucleosome positioning. In particular, histone acetylation and methylation have been shown to play important roles in the upregulation of chemokine expression. In addition to CCL2, several other chemokines strongly contribute to neuropathic pain through epigenetic induction. Consequently, targeting epigenetic changes may have therapeutic potential for nonresolving inflammatory diseases such as neuropathic pain. Further research into the epigenetics of inflammatory diseases should promote the development of novel and effective treatment strategies for intractable inflammatory diseases.

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PRECLINICAL STUDY: BRIEF REPORT: Epigenetic modulation at the CCR2 gene correlates with the maintenance of behavioral sensitization to methamphetamine

Cited by 22 publications

References 7 publications

Implication of CCR2 Chemokine Receptor in Cocaine-Induced Sensitization

Implication of CCR2 Chemokine Receptor in Cocaine-Induced Sensitization

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

Epigenetic regulation of CC-chemokine ligand 2 in nonresolving inflammation

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