Mice deficient in protein tyrosine phosphatase receptor type Z (PTPRZ) show reduced responsivity to methamphetamine despite an enhanced response to novelty

• Published in: PloS one Vol. 14; no. 8; p. e0221205
• Main Authors: Fujikawa, Akihiro, Noda, Yukihiro, Yamamoto, Hideko, Tanga, Naomi, Sakaguchi, Gaku, Hattori, Satoko, Song, Wen-Jie, Sora, Ichiro, Nabeshima, Toshitaka, Katsuura, Goro, Noda, Masaharu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 20.08.2019; Public Library of Science (PLoS)
• Subjects: Amino acids; Animal models; Animals; Behavior, Animal - drug effects; Biocompatibility; Biology; Biology and Life Sciences; Body weight; Brain; Brain research; Cell surface; Central Nervous System Stimulants - pharmacology; Dopamine; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine receptors; Dopamine transporter; Dopaminergic Neurons - drug effects; Dopaminergic Neurons - metabolism; Dosage; Drug abuse; Drugs; EDTA; Efflux; Exploratory Behavior; Kinases; Life sciences; Locomotion - drug effects; Locomotion - genetics; Male; Medicine and Health Sciences; Mesencephalon; Mesolimbic system; Methamphetamine; Methamphetamine - pharmacology; Mice; Mice, Knockout; Microdialysis; Models, Animal; Neostriatum; Neurobiology; Neurons; Neurophysiology; Neurosciences; Nucleus accumbens; Phenols (Class of compounds); Phenotypes; Phosphatase; Phosphatases; Phosphorylation; Polymerase chain reaction; Potassium; Protein-tyrosine-phosphatase; Proteins; Psychiatry; Receptor-Like Protein Tyrosine Phosphatases, Class 5 - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 5 - metabolism; Research and Analysis Methods; Rodents; Social Sciences; Studies; Synaptosomes; Tyrosine; University graduates; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0221205

Methamphetamine (METH), a commonly abused drug, elevates extracellular dopamine (DA) levels by inducing DA efflux through the DA transporter (DAT). Emerging evidence in rodent models suggests that locomotor responses to a novel inescapable open field may predict behavioral responses to abused drugs; METH produces more potent stimulant effects in high responders to novelty than in low responders. We herein found that mice deficient in protein tyrosine phosphatase receptor type Z (Ptprz-KO) exhibited an enhanced behavioral response to novelty; however, METH-induced hyperlocomotion was significantly lower in Ptprz-KO than in wild-type mice when METH was administered at a non-toxic dose of 1 mg per kg body weight (bdw). Single-cell RT-PCR revealed that the majority of midbrain DA neurons expressed PTPRZ. No histological alterations were observed in the mesolimbic or nigrostriatal dopaminergic pathways in Ptprz-KO brains; however, a significant decrease was noted in brain DA turnover, suggesting functional alterations. In vivo microdialysis experiments revealed that METH-evoked DA release in the nucleus accumbens was significantly lower in Ptprz-KO mice than in wild-type mice. Consistent with this result, Ptprz-KO mice showed significantly fewer cell surface DAT as well as weaker DA uptake activity in striatal synaptosomes prepared 1 hr after the administration of METH than wild-type mice, while no significant differences were observed in the two groups treated with saline. These results indicate that the high response phenotype of Ptprz-KO mice to novelty may not be simply attributed to hyper-dopaminergic activity, and that deficits in PTPRZ reduce the effects of METH by reducing DAT activity.