@article{c3bc6c9c8e744068854e6cc24b8817d5,
title = "Adolescent psychosocial stress enhances sensitization to cocaine exposure in genetically vulnerable mice",
abstract = "Development of drug addictive behaviors is modulated by both genetic and environmental risk factors. However, the molecular mechanisms remain unknown. To address the role of adolescent stress in the development of drug addiction, we combined a transgenic mouse model in which a putative dominant-negative form of DISC1 under expressional control of the prion protein promoter is used as a genetic risk factor and adolescent social isolation stress as a gene-environmental interaction (GXE). Repeated cocaine exposure induced greater locomotion in the GXE group than in the other groups. In a conditioned place preference (CPP) test, GXE mice exhibited a significant place preference to the cocaine-conditioned area compared with the other groups. In the nucleus accumbens (NAc) of GXE mice, we found increased enzyme activity of phosphodiesterase-4 (PDE4), predominantly located in NAc D2-receptor-expressing neurons, and enhanced effects of the PDE4 inhibitor rolipram, but not the D1 agonist SKF81297, on the phosphorylation of DARPP-32 and GluA1 at PKA sites. Rolipram injection before cocaine exposure completely inhibited cocaine-induced hyperlocomotion and CPP in the GXE group. These results indicate that GXE enhances sensitivity to repeated cocaine exposure via an increase in PDE4 activity in NAc D2-recptor-expressing neurons, leading to the development of cocaine addictive behaviors.",
keywords = "Addiction, Adolescent stress, DISC1, Gene-environmental interaction, Nucleus accumbens, Phosphodiesterase",
author = "Takatoshi Hikida and Makiko Morita and Mahomi Kuroiwa and Tom Macpherson and Takahide Shuto and Naoki Sotogaku and Minae Niwa and Akira Sawa and Akinori Nishi",
note = "Funding Information: The authors declare that there are no conflicts of interest regarding this article. This work was supported by the Japan Society for the Promotion of Science KAKENHI grants ( JP16H06568 , JP16K14579 and JP18H02542 to TH; JP16K10198 to MK; JP16H05135 to AN), the Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology program ( JPJPR14M6 to MN), Takeda Science Foundation , Smoking Research Foundation , Hyogo Science and Technology Association , Uehara Memorial Foundation of Life Science (TH) , Stanley , S-R , RUSK , NARSAD , Maryland Stem Cell Research Fund (AS) and the National Institute of Health ( MH-094268 Silvio O. Conte Center, and MH-105660 to AS; DA-040127 to AS and MN). This work was performed, in part, under the International Collaborative Research Program of Institute for Protein Research, Osaka University, ICRa-18-03. Funding Information: The authors declare that there are no conflicts of interest regarding this article. This work was supported by the Japan Society for the Promotion of Science KAKENHI grants (JP16H06568, JP16K14579 and JP18H02542 to TH; JP16K10198 to MK; JP16H05135 to AN), the Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology program (JPJPR14M6 to MN), Takeda Science Foundation, Smoking Research Foundation, Hyogo Science and Technology Association, Uehara Memorial Foundation of Life Science (TH), Stanley, S-R, RUSK, NARSAD, Maryland Stem Cell Research Fund (AS) and the National Institute of Health (MH-094268 Silvio O. Conte Center, and MH-105660 to AS; DA-040127 to AS and MN). This work was performed, in part, under the International Collaborative Research Program of Institute for Protein Research, Osaka University, ICRa-18-03. Publisher Copyright: {\textcopyright} 2019 Elsevier B.V. and Japan Neuroscience Society",
year = "2020",
month = feb,
doi = "10.1016/j.neures.2019.02.007",
language = "English (US)",
volume = "151",
pages = "38--45",
journal = "Neuroscience Research",
issn = "0168-0102",
publisher = "Elsevier Ireland Ltd",
}