The International Journal of Neuropsychopharmacology

Research Article

Role of convergent activation of glutamatergic and dopaminergic systems in the nucleus accumbens in the development of methamphetamine psychosis and dependence

Masayuki Miyazakia1, Yukihiro Nodaa1a2, Akihiro Mouria1a2, Kazuto Kobayashia3, Masayoshi Mishinaa4a5, Toshitaka Nabeshimaa6 and Kiyofumi Yamadaa1 c1

a1 Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University, Graduate School of Medicine, Nagoya, Japan

a2 Division of Clinical Science and Neuropsychopharmacology, Meijo University, Graduate School of Pharmacy, Nagoya, Japan

a3 Department of Molecular Genetics, Fukushima Medical University School of Medicine, Fukushima, Japan

a4 Department of Molecular Neurobiology and Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

a5 The Research Organization of Science and Technology, Ritsumeikan University, Shiga, Japan

a6 Department of Regional Pharmaceutical Care and Sciences, Faculty of Pharmacy, Meijo University, Nagoya, Japan


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.

(Received July 22 2012)

(Reviewed August 21 2012)

(Revised September 25 2012)

(Accepted October 01 2012)

(Online publication November 30 2012)

Key words

  • Dopaminergic;
  • glutamatergic;
  • methamphetamine;
  • N-methyl-d-aspartate receptor;
  • nucleus accumbens


c1 Address for correspondence: Dr K. Yamada, 65 Turumacho, Showa-ku, Nagoya 466-8560, Japan. Tel.: +81 52 741 2111 Fax: +81 52 744 2685 Email: