Siegesbeckiae Herba Alleviates Abnormal Emotion-Associated Behaviors In Methamphetamine Withdrawal Mice

BACKGROUND:Methamphetamine(METH),as the most abused drug type in China,seriously threatens our country’s economy,health care and safety,and causes an immeasurable social burden.METH is a powerful central nervous system stimulant.It has short-term excitement and anti-fatigue effects when used in small doses,but it produces strong hallucinogenic and neurostimulator effects when used repeatedly in large doses.This leads to dependence and addiction and can increase the risk of mental illnesses such as anxiety,depression,and schizophrenia.At present,the neurotoxic biological mechanism of meth,especially the key brain areas and neural circuit targets,is still unclear,which leads to the lack of effective drugs and intervention methods for the prevention and treatment of addiction and comorbidity.Interpeduncular nucleus(IPN)is an ovoid nucleus located at the posterior end of the ventral midline of the midbrain.It has a large number of fiber connections with the forebrain and brain stem,and also serves as a bridge between Habenular(Hb)and monoaminergic system in the brain.IPN is involved in the regulation of many physiological functions,such as emotion control,reward,learning and memory,sleep and so on.It is one of the information integration centers of brain function expression,suggesting that IPN may be the key brain area of mental disorders caused by excitatory drugs like METH.Traditional Chinese medicine has a long history of treatment for drug addiction and mental disorders.Siegesbeckiae Herba is a kind of composite plant,which has the functions of anti-inflammation,lowering blood pressure,resistance to pathogenic microorganisms and regulating body immunity.In the clinical practice of modern Chinese medicine,Siegesbeckiae Herba can be used to treat patients with chronic pain and ischemic stroke,and studies have confirmed the unique efficacy of Siegesbeckiae Herba in anti-inflammatory analgesia,sedation and hypnosis,suggesting that Siegesbeckiae Herba may help alleviate neurotoxic effects such as emotional abnormalities caused by METH.AIMS:In this paper,METH withdrawal mouse model was adopted to explore:(1)Emotion-associated behaviors of mice in METH withdrawal period;(2)The regulatory role of IPNGABA in the abnormal emotion-associated behaviors of METH withdrawal mice and its loop target;(3)Intervention effect of Siegesbeckiae Herba on abnormal emotion-associated behaviors in METH withdrawal mice and the mechanism of IPN.METHODS:By using METH withdrawal mouse model,elevated plus maze(EPM),open field test(OFT)and marble-burying test(MBT)were used to assess anxiety-like behaviors.Tail suspension test(TST)and the forced swimming test(FST)were used to assess depression-like behaviors.Methods such as immunofluorescence,optical fiber recording,and patch clamp recording were used to detect neuronal changes in the vMHb and IPN and look for key functional neuronal targets.Chemical genetics and optogenetic techniques were used to observe the role of specific neuronal targets in the vMHb-IPN pathway in the formation of abnormal emotion-related behaviors in METH withdrawal mice.Intragastric administration method was adopted to test the curative effect of Siegesbeckiae Herba on emotion-related abnormal behaviors in METH withdrawal mice and its correlation with vMHb-IPN pathway.RESULTS:(1)The METH withdrawal mice showed obvious anxiety like behavior;(2)The expression of c-Fos in GABAergic neurons in IPN of METH withdrawal mice was enhanced,the evoked threshold of action potential was increased,and the number of spontaneous action potential was increased significantly;(3)Conditional inhibition of GABAergic neurons in IPN of METH withdrawal mice in vivo could significantly reduce anxiety like behavior;(4)The intragastric administration of Siegesbeckiae Herba can reduce the anxiety like behavior of METH withdrawal mice;(5)Siegesbeckiae Herba can reduce the excitability of GABAergic neurons in IPN of METH withdrawal mice.CONCLUSION:(1)The abnormal activation of GABAergic neurons in IPN is the key brain mechanism of anxiety and other abnormal behaviors in METH withdrawal mice;(2)Siegesbeckiae Herba can effectively alleviate anxiety and other abnormal emotional behaviors in METH withdrawal mice by regulating the activation homeostasis of GABAergic neurons in IPN.