TY - JOUR
T1 - Mice deficient in protein tyrosine phosphatase receptor type Z (PTPRZ) show reduced responsivity to methamphetamine despite an enhanced response to novelty
AU - Fujikawa, Akihiro
AU - Noda, Yukihiro
AU - Yamamoto, Hideko
AU - Tanga, Naomi
AU - Sakaguchi, Gaku
AU - Hattori, Satoko
AU - Song, Wen Jie
AU - Sora, Ichiro
AU - Nabeshima, Toshitaka
AU - Katsuura, Goro
AU - Noda, Masaharu
N1 - Funding Information:
The analyses were supported by JSPS KAKENHI Grant Numbers 21700416, 24500390, and 17K07069 for AF, and 16209008 and 08458187 for MN. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. SHIONOGI & CO. LTD provided support in the form of salary for author GS, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of the authors are articulated in the ?author contributions? section.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85070894919&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070894919&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0221205
DO - 10.1371/journal.pone.0221205
M3 - Article
C2 - 31430310
AN - SCOPUS:85070894919
VL - 14
JO - PLoS One
JF - PLoS One
SN - 1932-6203
IS - 8
M1 - e0221205
ER -