Reduction of methamphetamine-induced sensitization and reward in matrix metalloproteinase-2 and -9-deficient mice Hiroyuki Mizoguchi,* ,  Kiyofumi Yamada,* ,  Minae Niwa,* Akihiro Mouri,* Tomoko Mizuno,* Yukihiro Noda,* , à Atsumi Nitta,* Shigeyoshi Itohara,§ Yoshiko Banno¶ and Toshitaka Nabeshima* *Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Nagoya, Japan  Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan àDivision of Clinical Science in Clinical Pharmacy Practice, Management and Research, Faculty of Pharmacy, Meijo University, Nagoya, Japan §Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, Japan ¶Department of Cell Signaling, Gifu University Graduate School of Medicine, Gifu, Japan Abstract Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) function to remodel the pericellular environment. Their acti- vation and regulation are associated with synaptic physiology and pathology. Here, we investigated whether MMP-2 and MMP-9 are involved in the rewarding effects of and sensiti- zation to methamphetamine (METH) in animals, in which the remodelling of neural circuits may play a crucial role. Repea- ted METH treatment induced behavioural sensitization, which was accompanied by an increase in MMP-2 and MMP-9 activity in the brain. In MMP-2- and MMP-9-deficient mice [MMP-2-(–/–) and MMP-9-(–/–)], METH-induced behavioural sensitization and conditioned place preference, a measure of the rewarding effect, as well as METH-increased dopamine release in the nucleus accumbens (NAc) were attenuated compared with those in wild-type mice. In contrast, infusion of purified human MMP-2 into the NAc significantly potentiated the METH-increased dopamine release. The [ 3 H]dopamine uptake into striatal synaptosomes was reduced in wild-type mice after repeated METH treatment, but METH-induced changes in [ 3 H]dopamine uptake were significantly attenuated in MMP-2-(–/–) and MMP-9-(–/–) mice. These results suggest that both MMP-2 and MMP-9 play a crucial role in METH- induced behavioural sensitization and reward by regulating METH-induced dopamine release and uptake in the NAc. Keywords: dopamine, drug dependence, matrix metallopro- teinases, methamphetamine. J. Neurochem. (2007) 100, 1579–1588. Drug dependence is a complex phenomenon with important psychological and social causes and consequences, which result from adaptations in specific brain circuits caused by repeated exposure to drugs of abuse (Berke and Hyman 2000; Yamada et al. 2005). It has been proposed that cellular and molecular mechanisms for drug dependence involve processes similar to those operating in other forms of synaptic plasticity such as learning and memory (Shippen- berg and Heidbreder 1995; Mizoguchi et al. 2004). Meth- amphetamine (METH), a typical drug of abuse, has both acute and long-lasting effects on psychomotor behaviours. The effects of METH are associated with an increase in extracellular dopamine levels in the brain through redistri- Received September 2, 2006; revised manuscript received September 21, 2006; accepted October 16, 2006. Address correspondence and reprint requests to Toshitaka Nabeshima PhD, Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466–8560, Japan. E-mail: tnabeshi@med.nagoya-u.ac.jp or Kiyofumi Yamada PhD, Laboratory of Neuropsychopharmacology, Division of Life Science, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan. E-mail: kyamada@p.kanazawa-u.ac.jp Abbreviations used: DAT, dopamine transporter; ECM, extracellular matrix; Fc, frontal cortex; GFAP, glial fibrillary acidic protein; METH, methamphetamine; MMP, matrix metalloproteinase; NAc, nucleus accumbens; NeuN, neuron-specific nuclear antigen; SDS–PAGE, sodium dodecyl sulfate – polyacrylamide gel electrophoresis; TIMP, tissue inhibitors of MMP; tPA, tissue plasminogen activator. Journal of Neurochemistry , 2007, 100, 1579–1588 doi:10.1111/j.1471-4159.2006.04288.x Ó 2006 The Authors Journal Compilation Ó 2006 International Society for Neurochemistry, J. Neurochem. (2007) 100, 1579–1588 1579