A significant amount of evidence indicates that micro RNAs(mi RNAs) play an important role in drug addiction. The nucleus accumbens(NAc) is a critical part of the brain's reward circuit and is involved in a variet...A significant amount of evidence indicates that micro RNAs(mi RNAs) play an important role in drug addiction. The nucleus accumbens(NAc) is a critical part of the brain's reward circuit and is involved in a variety of psychiatric disorders, including depression, anxiety, and drug addiction. However, few studies have examined the expression of mi RNAs and their functional roles in the NAc under conditions of morphine addiction. In this study, mice were intravenously infused with morphine(0.01, 0.03, 0.3, 1 and 3 mg/kg/infusion) and showed inverted U-shaped response. After morphine self-administration, NAc was used to analyze the functional networks of altered mi RNAs and their putative target m RNAs in the NAc following intravenous self-administration of morphine. We utilized several bioinformatics tools, including Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway mapping and Cy Target Linker. We found that 62 mi RNAs were altered and exhibited differential expression patterns. The putative targets were related to diverse regulatory functions, such as neurogenesis, neurodegeneration, and synaptic plasticity, as well as the pharmacological effects of morphine(receptor internalization/endocytosis). The present findings provide novel insights into the regulatory mechanisms of accumbal molecules under conditions of morphine addiction and identify several novel biomarkers associated with morphine addiction.展开更多
Individual differences in behavioral characteristics or initial responses to abused drugs had been recently demonstrated to have predictive value in the propensity of later abuse. The research described here was initi...Individual differences in behavioral characteristics or initial responses to abused drugs had been recently demonstrated to have predictive value in the propensity of later abuse. The research described here was initiated to determine the initial response of rats to administration of morphine if the physiological response has predictive value for the propensity of the animals to later self-administration. The initial response of extracellular fluid levels of the biogenic monoamine neurotransmitters in the anterior cingulate cortex (aCC) was assessed in drug rats with in vivo microdialysis following administration of morphine. Rats that did not acquire morphine self-administration (NSA) had higher baseline levels of aCC extracellular fluid levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) than animals that developed stable morphine self-administration (SA). However, the response independent administration of morphine resulted in a dramatic increase in (DA) in aCC in the SA group, while the morphine injection in the NSA rats increased extracellular fluid levels of noradrenaline (NA). It is possible that these differences might be related to the development of physical dependence. Therefore, the development of physical dependence was observed in these animals. There was no relationship between the propensity to self-administration morphine and the development of physical dependence. Rats that showed the highest withdrawal scores had lower extracellular fluid levels of serotonin (5-HT) compared to rats showing low withdrawal scores. Thus, monoamine neuronal innervations of the aCC respond to an initial dose of morphine that is predictive of the later propensity to self-administration and the resistance and predisposition to the formation of opiate dependence, but there is no relationship between these two indices in individual animals. These data add to a growing body of evidence for the involvement of neuronal systems in the aCC in the actions of opiates.展开更多
OBJECTIVE Wide spread abuse of synthetic cathinones found in bath salts preparations has resulted in regulation of some cathinones internationally.Chemists skirt these laws by altering the chemical structures of first...OBJECTIVE Wide spread abuse of synthetic cathinones found in bath salts preparations has resulted in regulation of some cathinones internationally.Chemists skirt these laws by altering the chemical structures of first-generation cathinones(ie,MDPV,methylone,and mephedrone),resulting in second-generation cathinones(eg,α-PVP,α-PPP,MDPPP,and MDPBP).Although MDPV is a more effective reinforcer than cocaine,little is known about the reinforcing effectiveness of secondgeneration cathinones.To test the hypothesis that synthetic cathinones with higher selectivity for DAT relative to SERT are more effective reinforcers.METHODS Monoamine transporter inhibition was determined using synaptosomes prepared from rat brains.The relative reinforcing effectiveness of intravenously self-administered MDPV,MDPBP,MDPPP,α-PVP,α-PPP,and cocaine were directly compared through evaluations of (1)dose-response curves under a progressive ratio(PR)schedule of reinforcement and (2)demand curves obtained for each drug in male Sprague-Dawley rats.RESULTS Rank order selectivity for DAT/SERT wasα-PVP>MDPV>α-PPP≈MDPBP>MDPPP>cocaine.Comparisons of the maximum number of infusions obtained under a PR schedule of reinforcement(α-PVP>MDPV>α-PPP>MDPBP≈MDPPP>cocaine)and the essential value obtained for each drug in demand analyses(α-PVP>MDPV>α-PPP≈MDPBP≈MDPPP>cocaine)suggest relative reinforcing effectiveness is related to DAT/SERT selectivity.CONCLUSION These data provide evidence that DAT/SERT selectivity accounts for select synthetic cathinones functioning as more effective reinforcers than cocaine and may predict the abuse-related effects of novel synthetic cathinones in humans.展开更多
Growth hormone deficiency(GHD)has become a serious healthcare burden,and presents a huge impact on the physical and mental health of patients.Here,we developed an actively separated microneedle patch(PAA/NaHCO_(3)^(-)...Growth hormone deficiency(GHD)has become a serious healthcare burden,and presents a huge impact on the physical and mental health of patients.Here,we developed an actively separated microneedle patch(PAA/NaHCO_(3)^(-)Silk MN)based on silk protein for sustained release of recombinant human growth hormone(rhGH).Silk protein,as a friendly carrier material for proteins,could be constructed in mild full-water conditions and ensure the activity of rhGH.After manually pressing PAA/NaHCO_(3)^(-)Silk MN patch to skin for 1 min,active separation is achieved by absorbing the interstitial fluid(ISF)to trigger HCO_(3)^(-)in the active backing layer to produce carbon dioxide gas(CO_(2)).In rats,the MN patch could maintain the sustained release of rhGH for more than 7 days,and produce similar effects as daily subcutaneous(S.C.)injections of rhGH in promoting height and weight with well tolerated.Moreover,the PAA/NaHCO_(3)^(-)Silk MN patch with the potential of painless self-administration,does not require cold chain transportation and storage possess great economic benefits.Overall,the PAA/NaHCO_(3)^(-)Silk MN patch can significantly improve patient compliance and increase the availability of drugs,meet current unmet clinical needs,improve clinical treatment effects of GHD patients.展开更多
Opioid use disorder(OUD)has become a considerable global public health challenge;however,potential medications for the management of OUD that are effective,safe,and nonaddictive are not available.Accumulating preclini...Opioid use disorder(OUD)has become a considerable global public health challenge;however,potential medications for the management of OUD that are effective,safe,and nonaddictive are not available.Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor(D3R)have effects on addiction in different animal models.We have previously reported that YQA14,a D3R antagonist,exhibits very high affinity and selectivity for D3Rs over D2Rs,and is able to inhibit cocaine-or methamphetamine-induced reinforcement and reinstatement in self-administration tests.In the present study,our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats,also attenuated heroin-induced reinstatement of drug-seeking behavior.On the other hand,YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice.Moreover,we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system.These findings suggest that D3R might play a very important role in opioid addiction,and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.展开更多
China has adopted a dual urban-rural administration system for many years which gives far more attention to cities than to rural areas. Designated as a National Comprehensive Reform Experiment Area for Coordinated Urb...China has adopted a dual urban-rural administration system for many years which gives far more attention to cities than to rural areas. Designated as a National Comprehensive Reform Experiment Area for Coordinated Urban-Rural Development, Chengdu is one of several areas in China where the practice of rural planning was fi rstly carried out. After the earthquakes in Wenchuan in 2008 and Lushan in 2013, the post-disaster reconstruction further enriched the local capabilities of rural planning and management. The practice of Chengdu demonstrates that the success of rural planning and management depends on two aspects, a well-organized and well-developed legal systems and institutions and bottom-up selfadministration of local residents which incorporates the social relationships of local communities based on clan and blood kinships. This paper introduces the positive experience of Chengdu in rural planning and management that could be benefi cial for other areas in the country.展开更多
基金funded by the National Research Council of Science & Technology(NST)grant by the Korean government(MSIP)(No.CRC-15-04-KIST)the National Research Foundation of Korea under the grant(No.NRF-2017R1A2B200399Mid-career Researcher Program)
文摘A significant amount of evidence indicates that micro RNAs(mi RNAs) play an important role in drug addiction. The nucleus accumbens(NAc) is a critical part of the brain's reward circuit and is involved in a variety of psychiatric disorders, including depression, anxiety, and drug addiction. However, few studies have examined the expression of mi RNAs and their functional roles in the NAc under conditions of morphine addiction. In this study, mice were intravenously infused with morphine(0.01, 0.03, 0.3, 1 and 3 mg/kg/infusion) and showed inverted U-shaped response. After morphine self-administration, NAc was used to analyze the functional networks of altered mi RNAs and their putative target m RNAs in the NAc following intravenous self-administration of morphine. We utilized several bioinformatics tools, including Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway mapping and Cy Target Linker. We found that 62 mi RNAs were altered and exhibited differential expression patterns. The putative targets were related to diverse regulatory functions, such as neurogenesis, neurodegeneration, and synaptic plasticity, as well as the pharmacological effects of morphine(receptor internalization/endocytosis). The present findings provide novel insights into the regulatory mechanisms of accumbal molecules under conditions of morphine addiction and identify several novel biomarkers associated with morphine addiction.
文摘Individual differences in behavioral characteristics or initial responses to abused drugs had been recently demonstrated to have predictive value in the propensity of later abuse. The research described here was initiated to determine the initial response of rats to administration of morphine if the physiological response has predictive value for the propensity of the animals to later self-administration. The initial response of extracellular fluid levels of the biogenic monoamine neurotransmitters in the anterior cingulate cortex (aCC) was assessed in drug rats with in vivo microdialysis following administration of morphine. Rats that did not acquire morphine self-administration (NSA) had higher baseline levels of aCC extracellular fluid levels of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) than animals that developed stable morphine self-administration (SA). However, the response independent administration of morphine resulted in a dramatic increase in (DA) in aCC in the SA group, while the morphine injection in the NSA rats increased extracellular fluid levels of noradrenaline (NA). It is possible that these differences might be related to the development of physical dependence. Therefore, the development of physical dependence was observed in these animals. There was no relationship between the propensity to self-administration morphine and the development of physical dependence. Rats that showed the highest withdrawal scores had lower extracellular fluid levels of serotonin (5-HT) compared to rats showing low withdrawal scores. Thus, monoamine neuronal innervations of the aCC respond to an initial dose of morphine that is predictive of the later propensity to self-administration and the resistance and predisposition to the formation of opiate dependence, but there is no relationship between these two indices in individual animals. These data add to a growing body of evidence for the involvement of neuronal systems in the aCC in the actions of opiates.
基金supported by NIH and NIDA(R01DA039146T32DA031115)NIH Intramural Research Programs
文摘OBJECTIVE Wide spread abuse of synthetic cathinones found in bath salts preparations has resulted in regulation of some cathinones internationally.Chemists skirt these laws by altering the chemical structures of first-generation cathinones(ie,MDPV,methylone,and mephedrone),resulting in second-generation cathinones(eg,α-PVP,α-PPP,MDPPP,and MDPBP).Although MDPV is a more effective reinforcer than cocaine,little is known about the reinforcing effectiveness of secondgeneration cathinones.To test the hypothesis that synthetic cathinones with higher selectivity for DAT relative to SERT are more effective reinforcers.METHODS Monoamine transporter inhibition was determined using synaptosomes prepared from rat brains.The relative reinforcing effectiveness of intravenously self-administered MDPV,MDPBP,MDPPP,α-PVP,α-PPP,and cocaine were directly compared through evaluations of (1)dose-response curves under a progressive ratio(PR)schedule of reinforcement and (2)demand curves obtained for each drug in male Sprague-Dawley rats.RESULTS Rank order selectivity for DAT/SERT wasα-PVP>MDPV>α-PPP≈MDPBP>MDPPP>cocaine.Comparisons of the maximum number of infusions obtained under a PR schedule of reinforcement(α-PVP>MDPV>α-PPP>MDPBP≈MDPPP>cocaine)and the essential value obtained for each drug in demand analyses(α-PVP>MDPV>α-PPP≈MDPBP≈MDPPP>cocaine)suggest relative reinforcing effectiveness is related to DAT/SERT selectivity.CONCLUSION These data provide evidence that DAT/SERT selectivity accounts for select synthetic cathinones functioning as more effective reinforcers than cocaine and may predict the abuse-related effects of novel synthetic cathinones in humans.
基金financial support from the National Natural Science Foundation of China(32071342 and 31922042)Guangdong Special Support Program(2019TQ05Y209)+2 种基金the Natural Science Foundation of Guangdong Province(2021A1515010431)the Fundamental Research Funds for the Central Universities(Nos.2021-RC310-005,2020-RC320-002 and 2019PT320028)Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2021-I2M-1-058)。
文摘Growth hormone deficiency(GHD)has become a serious healthcare burden,and presents a huge impact on the physical and mental health of patients.Here,we developed an actively separated microneedle patch(PAA/NaHCO_(3)^(-)Silk MN)based on silk protein for sustained release of recombinant human growth hormone(rhGH).Silk protein,as a friendly carrier material for proteins,could be constructed in mild full-water conditions and ensure the activity of rhGH.After manually pressing PAA/NaHCO_(3)^(-)Silk MN patch to skin for 1 min,active separation is achieved by absorbing the interstitial fluid(ISF)to trigger HCO_(3)^(-)in the active backing layer to produce carbon dioxide gas(CO_(2)).In rats,the MN patch could maintain the sustained release of rhGH for more than 7 days,and produce similar effects as daily subcutaneous(S.C.)injections of rhGH in promoting height and weight with well tolerated.Moreover,the PAA/NaHCO_(3)^(-)Silk MN patch with the potential of painless self-administration,does not require cold chain transportation and storage possess great economic benefits.Overall,the PAA/NaHCO_(3)^(-)Silk MN patch can significantly improve patient compliance and increase the availability of drugs,meet current unmet clinical needs,improve clinical treatment effects of GHD patients.
文摘Opioid use disorder(OUD)has become a considerable global public health challenge;however,potential medications for the management of OUD that are effective,safe,and nonaddictive are not available.Accumulating preclinical evidence indicates that antagonists of the dopamine D3 receptor(D3R)have effects on addiction in different animal models.We have previously reported that YQA14,a D3R antagonist,exhibits very high affinity and selectivity for D3Rs over D2Rs,and is able to inhibit cocaine-or methamphetamine-induced reinforcement and reinstatement in self-administration tests.In the present study,our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats,also attenuated heroin-induced reinstatement of drug-seeking behavior.On the other hand,YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice.Moreover,we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system.These findings suggest that D3R might play a very important role in opioid addiction,and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
基金sponsored by the Science and Technology Support Project Funding of Sichuan Province (No. 2013FZ0009)the National Natural Science Foundation of China (No. 51278421 No.51678487)
文摘China has adopted a dual urban-rural administration system for many years which gives far more attention to cities than to rural areas. Designated as a National Comprehensive Reform Experiment Area for Coordinated Urban-Rural Development, Chengdu is one of several areas in China where the practice of rural planning was fi rstly carried out. After the earthquakes in Wenchuan in 2008 and Lushan in 2013, the post-disaster reconstruction further enriched the local capabilities of rural planning and management. The practice of Chengdu demonstrates that the success of rural planning and management depends on two aspects, a well-organized and well-developed legal systems and institutions and bottom-up selfadministration of local residents which incorporates the social relationships of local communities based on clan and blood kinships. This paper introduces the positive experience of Chengdu in rural planning and management that could be benefi cial for other areas in the country.
