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. 2022 Jun 22;27(10):4009–4022. doi: 10.1038/s41380-022-01662-z

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 6 — A Timeline of phaclofen or baclofen pretreatment for the syn-NICD-shRNA or syn-NICD-OE METH group in the locomotor activity test. B, C Phaclofen pretreatment reversed the significant decrease in locomotion and increase in centre time evoked by inhibition of NICD in the mPFC on day 1 and day 23. B Mixed-design ANOVA followed by post hoc multiple LSD test showed significant main effects of phaclofen [F _{(1, 23)} = 17.61, P < 0.001]; AAV [F _{(1, 23)} = 5.10_, P < 0.05]; and AAV × phaclofen [F _{(1, 23)} = 4.06, P < 0.05] on locomotor activity. C Mixed-design ANOVA followed by post hoc multiple LSD test showed the significant main effect of phaclofen [F _{(1, 24)} = 8.52, P < 0.01]; AAV [F_{(1, 24)} = 4.84, P < 0.05]; and AAV×phaclofen [F _{(1, 24)} = 7.61, P < 0.05] on centre time. D, E Baclofen pretreatment reversed the significant increase in locomotion and decrease in centre time evoked by overexpression of NICD in the mPFC on day 1 and day 23. 6D. Mixed-design ANOVA with LSD post hoc multiple comparison was performed. There were significant main effects of baclofen [F _{(1, 20)} = 11.31, P < 0.01]; AAV [F _{(1, 20)} = 5.11, P < 0.05]; and AAV × baclofen [F _{(1, 20)} = 4.34, P < 0.05] on locomotor activity. E Mixed-design ANOVA followed by post hoc multiple LSD test showed significant main effect of baclofen [F _{(1, 22)} = 11.46, P < 0.01]; AAV [F _{(1, 22)} = 11.12, P < 0.01]; but not the AAV × baclofen [F _{(1, 22)} = 2_.86, P > 0.05] on centre time. *P < 0.05, **P < 0.01 vs. the vehicle control group. ###P < 0.001 vs. the same group on day1. n.s. means no significant changes. The results are expressed as the mean ± SEM, n = 6–8. F Working model of Notch1 signalling pathway–mediated regulation of the GABA_B1 receptor as a protective factor against METH-induced behaviour sensitization. We show that the baseline levels of Notch1 signalling in the mPFC as a consequence of ligand (Jagged1) and receptor (Notch1) interaction maintain the status quo of the baseline state (left). In the MIP model, Notch1 signalling downregulation in the mPFC results in an increase in the GABA_B1 receptor, thereby creating an environment that attenuates mPFC neural activity and METH-induced locomotor sensitization.