Ginsenosides attenuate methamphetamine-induced behavioral side effects in mice via activation of adenosine A2A receptors: possible involvements of the striatal reduction in AP-1 DNA binding activity and proenkephalin gene expression.
Current evidence suggests that ginsenosides inhibit methamphetamine (MA)-induced changes in behavior, but the precise mechanisms that underlie this effect are yet to be determined. We examined the role of adenosine receptors in the ginsenoside-induced changes in hyperlocomotion and conditioned place preference (CPP) in mice that occurred in response to administration of MA (2 mg/kg, i.p. x 1 or 2 mg/kg, i.p. x 6). Changes in circling behavior paralleled changes in CPP in the presence of MA. Pre-treatment with ginsenosides (50 or 150 mg/kg, i.p.) attenuated the MA-induced circling behavior and CPP. This attenuation was reversed by the adenosine A2A receptor antagonist 1,3,7-trimethyl-8-(3-chrostyryl)xanthine (CSC; 0.5 and 1.0 mg/kg) in a dose-dependent manner, but neither the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 0.5 and 1.0 mg/kg) nor the A2B receptor antagonist alloxazine (ALX; 1.5 and 3.0 mg/kg) had any such effect. MA-induced increases in activator protein (AP)-1 DNA binding activity, Fos-related antigen immunoreactivity (FRA-IR), proenkephalin mRNA expression, and proenkephalin-like immunoreactivity were reduced consistently in the striatum of animals that were pretreated with ginsenosides. These reductions were largely prevented by CSC, but not by CPT or ALX. Our results suggest that the stimulation of A2A receptors by ginsenosides attenuates the changes in behavior and the increases in AP-1 DNA binding activity, FRA-IR, and proenkephalin gene expression in mouse striatum that are induced by MA.
Shin
Eun-Joo
EJ
Neurotoxicology Program, Department of Pharmacy, College of Pharmacy, Korea Institute of Drug Abuse, Kangwon National University, Chunchon 200-701, Republic of Korea.
Nabeshima
Toshitaka
T
Suh
Hong-Won
HW
Jhoo
Wang-Kee
WK
Oh
Ki-Wan
KW
Lim
Yong-Kwang
YK
Kim
Dong Sup
DS
Choi
Ki Hwan
KH
Kim
Hyoung-Chun
HC
D058917:Adenosine A2 Receptor Antagonists; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D015152:Blotting, Northern / Q000379:methods; D002452:Cell Count / Q000379:methods; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D036145:Ginsenosides / Q000494:pharmacology*; D007150:Immunohistochemistry / Q000379:methods; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016761:Oncogene Proteins v-fos / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D013239:Stereotyped Behavior / Q000187:drug effects; D013722:Teprotide / Q000494:pharmacology; D013997:Time Factors; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D058917:Adenosine A2 Receptor Antagonists; D000697:Central Nervous System Stimulants; D004745:Enkephalins; D036145:Ginsenosides; D016761:Oncogene Proteins v-fos; D011498:Protein Precursors; D012333:RNA, Messenger; D043705:Receptor, Adenosine A2A; D018808:Transcription Factor AP-1; C029992:proenkephalin; D008694:Methamphetamine; D013722:Teprotide