期刊
JOURNAL OF NEUROCHEMISTRY
卷 100, 期 1, 页码 225-241出版社
WILEY
DOI: 10.1111/j.1471-4159.2006.04203.x
关键词
behavioural sensitization; cyclin-dependent kinase 5; dopamine and cAMP-regulated phosphoprotein of M-r 32,000; dopamine D-1; receptor; dopamine D-3; receptor mutant; methamphetamine
The central dopamine system plays significant roles in motor activity and drug-induced behavioural sensitization. Our goal was to determine the significance of dopamine D-3 receptors in the development of behavioural sensitization to methamphetamine, assessed with D-3 receptor mutant mice. The absence of D-3 receptors significantly increased the behavioural responses to acute methamphetamine and evoked a faster rate of behavioural sensitization to chronic methamphetamine. In addition, both D-3 receptor protein and mRNA levels in the limbic forebrain decreased in sensitized wild-type mice. Further analyses indicated that D-1-dependent behavioural sensitization and the number of limbic D-1 receptors increased in sensitized D-3 mutants as compared with sensitized wild-type mice. Consistent with this finding, we observed higher levels of D-1 receptor-evoked cAMP accumulation and basal phosphoDARPP-32/Thr34 in the limbic forebrain of D-3 mutants than wild-type mice and the difference was more pronounced after chronic methamphetamine treatment. We also observed an increase in phospho-extracellular signal-regulated kinase 2 but a decrease in phosphoAkt/Ser473 and phosphoglycogen synthase kinase 3 (GSK3)-alpha/beta in the limbic forebrain of D-3 mutants compared with wild-type mice after methamphetamine treatment. The convergent results implicate D-3 receptors as a negative regulator of the development of methamphetamine sensitization. A compensatory up-regulation of D-1 receptor-mediated signals, in addition to an altered Akt/GSK3 pathway, could contribute to the accelerated development of behavioural sensitization.
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