Drug addiction is a serious public health problem worldwide,for which there are currently no established therapeutic medications.Since the legalization of cannabis and the approval of cannabidiol(CBD)by the US Food and Drug Administration,its therapeutic potential for the treatment of substance abuse has been widely explored.Numerous studies have shown that CBD can reduce drug reward in animal models of addiction such as self-administration,conditioned positional preference,and intracranial self-stimulation.CBD can also reduce withdrawal symptoms from substances such as amphetamines,opioids,cocaine,marijuana,alcohol,and nicotine.The mechanisms by which CBD modulates drug addiction,however,are complex and understudied.Here we review studies of CBD related to addictive drugs to clarify the regulatory mechanisms of CBD in drug addiction and provide references for related studies on substance abuse.

Drug addiction is a serious public health problem worldwide,for which there are currently no established therapeutic medications.Since the legalization of cannabis and the approval of cannabidiol(CBD)by the US Food and Drug Administration,its therapeutic potential for the treatment of substance abuse has been widely explored.Numerous studies have shown that CBD can reduce drug reward in animal models of addiction such as self-administration,conditioned positional preference,and intracranial self-stimulation.CBD can also reduce withdrawal symptoms from substances such as amphetamines,opioids,cocaine,marijuana,alcohol,and nicotine.The mechanisms by which CBD modulates drug addiction,however,are complex and understudied.Here we review studies of CBD related to addictive drugs to clarify the regulatory mechanisms of CBD in drug addiction and provide references for related studies on substance abuse.

Methamphetamine (METH) is a highly addictive synthetic psychoactive drug that is often abused as a psychostimulant.Chronic exposure to METH induces neurotoxic effects through oxidative stress,impairment of mitochondrial function,activation of astrocytes and microglia,and amino acid excitability.METH abuse increases the chance of developing neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease,Huntington's disease.However,the mechanism behind METH-induced neurotoxicity remains incompletely understood.So far,there is no specific treatment for METH-induced neurotoxicity.This paper reviews some of the potential mechanisms of METH-induced neurotoxicity in recent years,such as neuroinflammation,glutamatergic excitotoxicity,oxidative stress,and mitochondrial toxicity,and discusses the current therapeutic strategies related to mitigating the neurotoxic effects of METH in the brain through different pathways.

Objective To investigate the regulatory role of nuclear factor erythroid 2-related factor 2(Nrf2)in the activation and polarization of microglia induced by methamphetamine(METH).Methods BV2 and HMC3 cells were studied in vitro and wild-type mice and Nrf2-knockout mice were studied in vivo.In vivo and in vitro toxicity models induced by METH were established,respectively.The activation and polarization of microglia in each group were examined using immunofluorescence and Western blot,respectively.Results METH treatment significantly increased the fluorescence level of inducible nitric oxide synthase(iNOS)in BV2 and HMC3 cells(P＜0.001),and significantly decreased the fluorescence level of Arginase1(Arg1)(P＜0.05,P＜0.01).METH exposure activated microglia in the cortex,increased expression levels of ionized calcium binding adaptor molecule-1(IBA1)and iNOS(P＜0.001,P＜0.05),and decreased the expression of Arg1(P＜0.01).The number of activated microglia was significantly increased after Nrf2 gene knockout(P＜0.01),compared with the WT METH group,while the expression levels of IBA1 and iNOS were also increased(P＜0.001,P＜0.01)and the expression level of Argl was decreased(P＜0.01).Conclusions Nrf2 plays an important role in regulating the activation and polarization of microglia induced by METH.Nrf2 may thus be a potential target for the treatment of neuroinflammation induced by METH.

Methamphetamine(METH)is a new type of abused drug with a strong central stimulant effect.Its excitatory pathway involves a series of central higher-level functions,including drug-related rewards and motivation,learning and memory,decision-making,and execution.METH not only causes neurotoxicity,but its long-term use may also cause cognitive dysfunction,loss of personality,and may lead to serious social violence in addicts.Exosomes,as a novel cell-to-cell carrier,are involved in the occurrence and development of drug addiction,and exosome microRNAs are important biomarkers for METH addiction and are also involved in various aspects of METH-induced neurotoxicity.Eoxosmes may thus be useful therapeutic carriers providing a new approach for the diagnosis and treatment of METH abuse.

Objective To investigate the regulatory role of nuclear factor erythroid 2-related factor 2(Nrf2)in the activation and polarization of microglia induced by methamphetamine(METH).Methods BV2 and HMC3 cells were studied in vitro and wild-type mice and Nrf2-knockout mice were studied in vivo.In vivo and in vitro toxicity models induced by METH were established,respectively.The activation and polarization of microglia in each group were examined using immunofluorescence and Western blot,respectively.Results METH treatment significantly increased the fluorescence level of inducible nitric oxide synthase(iNOS)in BV2 and HMC3 cells(P＜0.001),and significantly decreased the fluorescence level of Arginase1(Arg1)(P＜0.05,P＜0.01).METH exposure activated microglia in the cortex,increased expression levels of ionized calcium binding adaptor molecule-1(IBA1)and iNOS(P＜0.001,P＜0.05),and decreased the expression of Arg1(P＜0.01).The number of activated microglia was significantly increased after Nrf2 gene knockout(P＜0.01),compared with the WT METH group,while the expression levels of IBA1 and iNOS were also increased(P＜0.001,P＜0.01)and the expression level of Argl was decreased(P＜0.01).Conclusions Nrf2 plays an important role in regulating the activation and polarization of microglia induced by METH.Nrf2 may thus be a potential target for the treatment of neuroinflammation induced by METH.

Methamphetamine(METH)is a new type of abused drug with a strong central stimulant effect.Its excitatory pathway involves a series of central higher-level functions,including drug-related rewards and motivation,learning and memory,decision-making,and execution.METH not only causes neurotoxicity,but its long-term use may also cause cognitive dysfunction,loss of personality,and may lead to serious social violence in addicts.Exosomes,as a novel cell-to-cell carrier,are involved in the occurrence and development of drug addiction,and exosome microRNAs are important biomarkers for METH addiction and are also involved in various aspects of METH-induced neurotoxicity.Eoxosmes may thus be useful therapeutic carriers providing a new approach for the diagnosis and treatment of METH abuse.

Methamphetamine (METH) is a highly addictive synthetic psychoactive drug that is often abused as a psychostimulant.Chronic exposure to METH induces neurotoxic effects through oxidative stress,impairment of mitochondrial function,activation of astrocytes and microglia,and amino acid excitability.METH abuse increases the chance of developing neurodegenerative diseases such as Alzheimer's disease,Parkinson's disease,Huntington's disease.However,the mechanism behind METH-induced neurotoxicity remains incompletely understood.So far,there is no specific treatment for METH-induced neurotoxicity.This paper reviews some of the potential mechanisms of METH-induced neurotoxicity in recent years,such as neuroinflammation,glutamatergic excitotoxicity,oxidative stress,and mitochondrial toxicity,and discusses the current therapeutic strategies related to mitigating the neurotoxic effects of METH in the brain through different pathways.

OBJECTIVE：To stu dy the mechanism of improvement effects of Gastrodin injection on methamphetamine induced neurotoxic damage in rats via nNOS pathway. METHODS ：SD rats were randomly divided into control group ，methamphetamine group，regular-dose of gastrodin group ，double-dose of gastrodin group ，negative control （NC）adenovirus group ，NC adenovirus+ methamphetamine group ，NC adenovirus+gastrodin group and nNOS adenovirus+gastrodin group ，with 10 rats in each group. Control group was given normal saline intraperitoneally ，twice a day. Methamphetamine group was given methamphetamine intraperitoneally（7.5 mg/kg），twice a day. Regular-dose and double-dose of gastrodin groups were respectively given different doses of Gastrodin injection （10，20 mg/kg）intraperitoneally 30 min earlier ，once a day ，and then given methamphetamine intraperitoneally by the same way as methamphetamine group. NC adenovirus group was given NC adenovirus （4.8×107 PFU）3 μL once in the striatum and normal saline intraperitoneally ，twice a day. NC adenovirus+methamphetamine group was given NC adenovirus by the same way and methamphetamine （7.5 mg/kg）intraperitoneally，twice a day. NC adenovirus+gastrodin group was given NC adenovirus+methamphetamine by the same way ，meanwhile given Gastrodin injection intraperitoneally （20 mg/kg）30 min before methamphetamine ，once a day. nNOS adenovirus+gastrodin group was given nNOS adenovirus and methamphetamine by the same way ，meanwhile given Gastrodin injection intraperitoneally （20 mg/kg）30 min before methamphetamine ，once a day. Each group was given relevant medicine intraperitoneally 1 mL/100 g，for consecutive 3 days. The stereotyped behavior of rats were observed and scored ；the apoptotic rate ，the protein expression of apoptotic factors （Bcl-2，Bax，Cleaved caspase- 3），the levels of oxidative stress factors （MDA，SOD，GPx） and NO ，the protein expression of nNOS were detected. RESULTS ： Compared with control group ，stereotyped behavior score ，cell apoptosis rate of striatum ，protein expression of Bax ，Cleaved caspase-3 and nNOS ，the levels of MDA and NO were increased significantly in methamphetamine group ；while the protein expression of Bcl- 2 and the levels of SOD and GPx were decreased significantly （P＜0.05 or P＜0.01）. Compared with methamphetamine group ，stereotyped behavior score ，cell apoptosis rate of striatum ，protein expression of Bax ，Cleaved caspase- 3 and nNOS ，the levels of MDA and NO were decreased significantly in regular-dose and double-dose of gastrodin groups ；while the protein expression of Bcl- 2，the levels of SOD and GPx were increased significantly ，and most above indexes in double-dose of gastradin group were better than regular-dose of gastrodin group （P＜0.05 or P＜0.01）. Compared with NC adenovirus group ，cell apoptosis rate of striatum ，protein expression of Bax ，Cleaved caspase- 3 and nNOS ，the levels of MDA and NO were increased significantly in NC adenovirus+methamphetamine group ；while the protein expression of Bcl- 2，the levels of SOD and GPx were decreased significantly （P＜0.01）. Compared with NC adenovirus+methamphetamine group ，cell apoptosis rate of striatum ，protein expression of Bax ，Cleaved caspase- 3 and nNOS ，the levels of MDA and NO were decreased significantly in NC adenovirus+ gastrodin group ；while the protein expression of Bcl- 2，the levels of SOD and GPx were increased significantly （P＜0.01）. Compared with NC adenovirus+gastrodin group ，cell apoptosis rate of striatum ，protein expression of Bax ，Cleaved caspase- 3 and nNOS，the levels of MDA and NO were increased significantly in nNOS adenovirus+gastrodin group ；while the protein expression of Bcl- 2，the levels of SOD and GPx were decreased significantly （P＜0.01）. CONCLUSIONS ：Gastrodin injection can protect rats against neurotoxic damage induced by methamphetamine ，and the effect is related to the inhibition of nNOS-mediated apoptosis and oxidative stress.

Objective To introduce a single person operation procedure for tail vein injection in conscious tree shrews,and to improve the success rate of injection. Methods The tree shrew was fixed by a canvas glove and a clamp. The tail of the tree shrew was fixed by the operator's left hand, and the drug was injected by the right hand with a 1 mL disposable syringe. Results This method had the advantages of simple operation,economy and practicality,good fixation effect,high matching degree of animals and high success rate of drug administration. Conclusions Compared with other methods,this method has obvious advantages such as single person operation, convenient, time-saving and labor-saving. The cost is low and the effect is good,thus significantly improving the success rate of injection.