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 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.