Dual alteration of limbic dopamine D1 receptor-mediated signalling and the Akt/GSK3 pathway in dopamine D3 receptor mutants during the development of methamphetamine sensitization

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.