title: Role of convergent activation of glutamatergic and dopaminergic systems in the nucleus accumbens in the development of methamphetamine psychosis and dependence.
abstract: Methamphetamine (Meth) abuse can result in long-lasting psychosis and dependence. The nucleus accumbens (NAc), which controls psychomotor and reward behaviours, is an important interface between the limbic system and receives convergent projections from dopaminergic and glutamatergic terminals. This study investigated the involvements of dopaminergic and glutamatergic transmission in the development of Meth psychosis and dependence by using tyrosine hydroxylase heterozygous mutant (TH+/-) mice and N-methyl-d-aspartate receptor knockout (NR2A-/-) mice. Repeated treatment with Meth (1 mg/kg s.c.) for 7 d in wild-type mice led to the development of behavioural abnormalities such as hyperactivity, sensory motor gating deficits and place preference. Associated with the behavioural changes, repeated treatment with Meth led to protein kinase A activation and phosphorylation of Ca2+/calmodulin kinase II and cyclic AMP response element binding protein in the NAc. In contrast, TH+/- and NR2A-/- mice displayed neither behavioural abnormalities nor activation of intracellular signalling pathways in the NAc. These results suggest that both dopaminergic and glutamatergic transmission play a crucial role in the development of Meth psychosis and dependence, which are associated with convergent activation of intracellular signalling pathways in the NAc.
authors.affiliation: Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University, Graduate School of Medicine, Nagoya, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Noda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Mouri
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Mishina
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Nabeshima
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000704:Analysis of Variance; D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism*; D007266:Inhibition, Psychological; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation / Q000235:genetics; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011618:Psychotic Disorders / Q000209:etiology* / Q000473:pathology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics; D013216:Reflex, Startle / Q000187:drug effects / Q000235:genetics; D014446:Tyrosine 3-Monooxygenase / Q000172:deficiency
chemical_list: D015259:Dopamine Agents; C120997:NR2A NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D008694:Methamphetamine; D014446:Tyrosine 3-Monooxygenase; D017868:Cyclic AMP-Dependent Protein Kinases; D004298:Dopamine