Regulations of methamphetamine reward by extracellular signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors

Hiroyuki Mizoguchi, Kiyofumi Yamada, Makoto Mizuno, Tomoko Mizuno, Atsumi Nitta, Yukihiro Noda, Toshitaka Nabeshima

研究成果: Article

101 引用 (Scopus)


Little is known about molecular mechanisms for long-lasting neuroadaptation related to the rewarding effects of methamphetamine (MAP). In the present study, we examined the intracellular signaling that is associated with the expression of conditioned place preference (CPP) induced by MAP in rats. Rats were given MAP or saline (control group) for conditioning to the CPP test. MAP-treated and control animals were killed immediately after the CPP test [CPP+]. Some of the MAP-treated rats were killed without the CPP test [CPP-]. Hyperphosphorylation of mitogen-activated protein kinase (MAPK) ERK1/2, but not p38 and c-Jun N-terminal kinase/stress-activated protein kinase, was found in the nucleus accumbens (NAc) and striatum but not in other brain areas of MAP-treated CPP+ animals. No such phosphorylation was seen in control and MAP-treated CPP- animals. Moreover, the transcription factor ets-like gene-1 (Elk-1), but not cAMP response element-binding protein, also showed a similar hyperphosphorylation in the same regions of MAP-treated CPP+. Tyrosine kinase receptors, including tyrosine kinase B, were not activated in any brain regions examined in all groups. Both the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3- methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) and the D2 receptor antagonist raclopride inhibited the expression of CPP as well as the activation of ERK1/2 in MAP-treated CPP+ animals, when they were injected before the CPP test. The microinjection of 2′-amino-3′- methoxyflavone (PD98059), a selective MAPK kinase inhibitor, into the NAc before the test, abolished the MAP-induced ERK1/2 activation and decreased the expression of MAP-induced CPP. These results suggest the importance of the ERK1/2 signaling pathway through activation of dopamine D1 and D2 receptors in the expression of CPP induced by MAP.

ジャーナルMolecular Pharmacology
出版物ステータスPublished - 01-05-2004


All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology