| BACKGROUND:Methamphetamine(METH)is the main component of "ice" and one of the main abuse drugs in our country.Relapse refers to a drug addiction person who reawakens the desire to crave drugs due to certain factors after withdrawal,and then takes drugs again.At present,the neural circuit and its mechanisms of METH relapse are unclear,inducing clinical lack of effective medicine and intervention methods.Lateral parabrachial nuclei(LPB)and central amygdala(CeA)are key brain areas that regulate rewards,food intake,and emotions,and are also important brain targets involved in drug addiction.LPB sends out a large number of nerve projections to CeA,forming the LPB—CeA pathway.Early research on this pathway focused on glutamatergic neurons(GluN)in LPB and GABAergic neurons(GAB Aergic neurons,GN)in CeA.In 2020,a study found that there are cholinergic neurons(ChN)in the brain area of LPB.But is there a projection between the ChN of LPB(LPBchAT)and the GN of CeA(CeAGABA)?What is the physiological function?Is it a key target for participating in the relapse of METH?These problems have yet to be resolved.Gegen Qinlian Decoction(GQD)comes from Zhang Zhongjing’s"Treatise On Febrile Caused by Cold(Shang Han Lun)".It is a classic compound composed of Pueraria lobata,Scutellaria baicalensis Georgi,Coptis and Roast radix glycyrrhizae.GQD can relieve the evil influence outside the body and remove the harmful energy inside the body.It is recorded in "Compendium of Materia Medica" and other books that Pueraria lobata,Scutellaria baicalensis Georgi and Coptis Coptidis all have the effects of clearing harmful energy and relieving fidgetness,such as,Pueraria lobata can treat harmful heat in the body’s thoracic and diaphragm;Scutellaria baicalensis Georgi is an essential medicine for the treatment of Shaoyang syndrome;Coptis relieves confusion and delirium.Therefore,the combined use of Pueraria lobata,Scutellaria baicalensis Georgi and Coptis Coptidis can increase the effect of purging harmful energy and detoxification,and has a significant inhibitory effect on the mental symptoms of irritable brain.The therapeutic effect of GQD is consistent with the symptoms of METH patients,and can be used as a candidate drug for the prevention and treatment of relapse in METH.AIMS:In this paper,the METH-primed reinstatement mice model is used to explore(1)the physiological structure and function of the LPBChAT—CeAGABA pathway;(2)the role of the LPBChAT—CeA pathway on the METH-primed reinstatement behavior in mice;(3)interventional effect of GQD on the METH-primed reinstatement behavior in mice.METHODS:Use conditioned place preference(CPP)method to construct a METH-primed reinstatement mice model;Using immunofluorescence technology,in vivo optical fiber recording,and brain slice patch clamp technology,to observe the physiological structure and function of eLPBChAT—CeAGABA pathway,and detect the activities of eLPBChATand CeA in METH-primed reinstatement model mice.Using chemical genetic technology,to observe the regulatory effect of eLPBChAT—CeA pathway on the METH-primed reinstatement behavior in mice.GQD was used to observe the intervention effect on the METH-primed reinstatement in mice.RESULTS:(1)LPBChAT is concentrated in the external lateral parabrachial nucleus(eLPB),and sends fiber projection to CeAGABA.(2)Under physiological conditions,activation of eLPBChAT can simultaneously enhance the activity of CeAGABA.(3)eLPBChAT and CeA are highly activated in METH primed mice.(4)Specific activation of eLPBChAT or specific activation of eLPBChAT—CeA pathway can block METH-primed reinstatement behavior in mice.(5)GQD effectively reduces METH-primed reinstatement behavior and activates the eLPBChAT and CeA in mice.CONCLUSION:(1)There is a direct fiber projection between eLPBChAT and CeAGABA,and activation of eLPBChAT can simultaneously enhance the activity of CeAGABA.(2)The eLPBChAT-CeA pathway is esscential for the METH-primed reinstatement behavior in mice.(3)GQD can reduce the METH-primed reinstatement behavior in mice. |
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