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Effect of PPM1F in dorsal raphe 5-HT neurons in regulating methamphetamine-induced conditioned place preference
Yong Liu1, Min Wu2, Zongyue Sun3
1Department of Physiology, Binzhou Medical University, Shandong, China; Medical research center, Binzhou Medical University Hospital, Binzhou, Shandong, China; Institute for Metabolic & Neuropsychiatric Disorders, Binzhou Medical University Hospital, Binzhou, Shandong, China.
Abstract:
Methamphetamine (METH), a synthetically produced central nervous system stimulant, is one of the most illicit and addictive drugs worldwide. Protein phosphatase Mg2 + /Mn2 + -dependent 1F F (PPM1F) has been reported to exert multiple biological and cellular functions. Nevertheless, the effects of PPM1F and its neuronal substrates on METH addiction remain unclear. Herein, we first established a METH-induced conditioned place preference (CPP) mouse model. We showed that PPM1F is widely distributed in 5-HT neurons of the dorsal raphe nucleus (DRN), and METH treatment decreased the expression of PPM1F in DRN, which was negatively correlated with METH-induced CPP behaviors. Knockout of PPM1F mediated by adeno-associated virus (AAV) in DRN produced enhanced susceptibility to METH-induced CPP, whereas the overexpression of PPM1F in DRN attenuated METH-induced CPP phenotypes. The expression levels of Tryptophan hydroxylase2 (TPH2) and serotonin transporter (SERT) were down-regulated with a concurrent reduction in 5-hydroxytryptamine (5-HT), tryptophan hydroxylase2 (TPH2)-immunoreactivity neurons and 5-HT levels in DRN of PPM1F knockout mice. In the end, decreased expression levels of PPM1F were found in the blood of METH abusers and METH-taking mice. These results suggest that PPM1F in DRN 5-HT neurons regulates METH-induced CPP behaviors by modulating the key components of the 5-HT neurotransmitter system, which might be an important pathological gene and diagnostic marker for METH-induced addiction.
Insights
Protein phosphatase PPM1F in the brain
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Methamphetamine (METH) is a highly addictive stimulant.
- The role of Protein phosphatase Mg2+/Mn2+-dependent 1F (PPM1F) in METH addiction is unknown.
- PPM1F has diverse biological functions.
Purpose of the Study:
- To investigate the role of PPM1F in METH addiction.
- To explore PPM1F's neuronal substrates and their involvement in METH-induced behaviors.
Main Methods:
- Established a METH-induced conditioned place preference (CPP) mouse model.
- Utilized adeno-associated virus (AAV) for PPM1F knockout and overexpression in the dorsal raphe nucleus (DRN).
- Analyzed expression levels of PPM1F, TPH2, SERT, and 5-HT in mouse brains and blood samples.
Main Results:
- METH treatment decreased PPM1F expression in DRN 5-HT neurons, correlating with addiction severity.
- PPM1F knockout in DRN enhanced METH CPP, while overexpression attenuated it.
- PPM1F deficiency led to reduced TPH2, SERT, and 5-HT levels in the DRN.
- Lower PPM1F levels were observed in METH abusers' blood.
Conclusions:
- PPM1F in DRN 5-HT neurons modulates METH-induced CPP.
- PPM1F influences the 5-HT neurotransmitter system.
- PPM1F may serve as a biomarker and therapeutic target for METH addiction.
