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Dual alteration of limbic dopamine D 1 receptor‐mediated signalling and the Akt/GSK3 pathway in dopamine D 3 receptor mutants during the development of methamphetamine sensitization
Author(s) -
Chen PeiChun,
Lao ChuLan,
Chen JinChung
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04203.x
Subject(s) - methamphetamine , sensitization , dopamine receptor d2 , dopamine , receptor , endocrinology , forebrain , medicine , biology , neuroscience , pharmacology , central nervous system
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)‐α/β 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.