The central dopamine system plays significant roles in motor activity and drug-induced behavioural sensitization. Our goal was to determine the significance of dopamine D3 receptors in the development of behavioural sensitization to methamphetamine, assessed with D3 receptor mutant mice. The absence of D3 receptors significantly increased the behavioural responses to acute methamphetamine and evoked a faster rate of behavioural sensitization to chronic methamphetamine. In addition, both D3 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 D3 mutants as compared with sensitized wild-type mice. Consistent with this finding, we observed higher levels of D1 receptor-evoked cAMP accumulation and basal phosphoDARPP-32/Thr34 in the limbic forebrain of D3 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 D3 mutants compared with wild-type mice after methamphetamine treatment. The convergent results implicate D3 receptors as a negative regulator of the development of methamphetamine sensitization. A compensatory up-regulation of D1 receptor-mediated signals, in addition to an altered Akt/GSK3 pathway, could contribute to the accelerated development of behavioural sensitization.
All Science Journal Classification (ASJC) codes
- Cellular and Molecular Neuroscience