The Role And Mechanism Of Metformin In Regulating Methamphetamine-induced Conditioned Place Preference Via Glucagon-like Peptide-1 Receptor

Methamphetamine(METH)is a psychostimulant,and its long-term abuse results in addiction.METH mainly acts on ventral tegmental area(VTA),nucleus accumbens(NAc)and prefrontal cortex(PFC)and other brain areas.Among them,the midbrain dopaminergic system projected from the VTA to the NAc and the PFC plays an important role in the reward effect of METH.The molecular mechanism on METH addcitiion is very complicated.METH causes a large amount of dopamine release in the VTA,as well as increases dopamine neuronal activity,activation of dopamine receptors,and alterations of downstream molecules.Adenosine 5’-monophosphate(AMP)-activated protein kinase(AMPK),cyclic adenosine monophosphate(c AMP)-responsive element-binding protein(CREB)play the important roles in METH induced conditioned place preference(CPP).Glucagon-like peptid-1(GLP-1)is an enterotropic hormone encoded by glucagon or the preglucagon gene(GCG).GLP-1 prevents the development of type 2 diabetes by regulating glucose homeostasis.GLP-1 acts on food intake centers in the VTA and NAc and suppresses the occurrence of obesity.In addition,GLP-1 is involved in addictive behavior associated with drugs such as cocaine,nicotine,alcohol,and amphetamines.GLP-1 plays various roles through the GLP-1 receptor.Our early results showed that GCG gene changed after the formation of METH-CPP in mice,which suggests that GLP-1 or GLP-1R may play an important role in the formation of METH-CPP.Metformin is a GLP-1R agonist and clinically used for the treatment of type 2 diabetes.It has been reported that metformin improves depression,anxiety,cognitive impairment,and neurodegenerative diseases induced by METH.However,whether metformin can resist the formation of METH-CPP and the molecular mechanism is still unclear.Thus,the main research objectives of this paper are: 1.To investigate the effect of metformin on the expression of METH-CPP.2.Using GLP-1R competitive antagonists Exendin-(9-39),explore the mechanism by which metformin resists METH-CPP formation by regulating GLP-1R expression.The results are as follows:(1)Metformin administration resisted the formation of METH-CPP in mice,and inhibited METH-induced GLP-1R,tyrosine hydroxylase(TH),and dopamine receptor 1(D1R)expression and phosphorylation levels of AMPKα and CREB,and significantly restored the decrease of thioredoxin-1(Trx-1)expression induced by METH in the VTA in mice.(2)Metformin pretreatment resisted the formation of METH-CPP in mice,while Exendin-(9-39)administration significantly inhibited the resistance of metformin to the formation of METH-CPP in mice.Western blot results showed that metformin pretreatment significantly inhibited the expressions of GLP-1R,TH and D1 R induced by METH in the VTA of mice and the increases of p-AMPKα and p-CREB,while the specific antagonism of GLP-1R,Exendin-(9-39)inhibited the effect of metformin on the expressions of GLP-1R,TH and D1 R induced by METH and the levels of p-AMPKα and p-CREB.In addition,metformin pretreatment restored the Trx-1 expression suppressed by METH,which was inhibited by Exendin-(9-39)administration.In summary,metformin resisted the formation of METH-CPP by regulating the expressions of GLP-1R,TH,D1 R,Trx-1,the levels of p-AMPKα and p-CREB.Therefore,metformin plays an important role in the resisting METH-CPP and is an important candidate drug for the treatment of METH addiction.This study provided the theoretical basis and had the significance for the treatment of METH addiction.