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.
Chen
Pei-Chun
PC
Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Chang-Gung University, Kwei-Shan, Tao-Yuan, Taiwan.
Lao
Chu-Lan
CL
Chen
Jin-Chung
JC
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western / Q000379:methods; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D008032:Limbic System / Q000187:drug effects* / Q000502:physiology; D008694:Methamphetamine / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D050505:Mutant Proteins / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*; D013239:Stereotyped Behavior / Q000187:drug effects; D013997:Time Factors
D000697:Central Nervous System Stimulants; D050505:Mutant Proteins; D017447:Receptors, Dopamine D1; D050637:Receptors, Dopamine D3; D008694:Methamphetamine; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3