OBJECTIVE To examine the effects of aquaporin 4(AQP4) on opioid addiction and underlie the mechanism behind it. METHODS(1) In the heroin-induced self-administration(SA) experiment,we explored the role of AQP4 on heroi...OBJECTIVE To examine the effects of aquaporin 4(AQP4) on opioid addiction and underlie the mechanism behind it. METHODS(1) In the heroin-induced self-administration(SA) experiment,we explored the role of AQP4 on heroin-induced psychological addiction. After the mice were trained to learn heroin-induced SA under a fixedratio1(FR1) reinforcement program for 7 d,we randomly switched the heroin doses to 0.00625,0.0125,0.025,0.05 or 0.1 mg·kg^(-1)per infusion to counterbalance assignment design. In the end,all mice underwent extinction training and reinstatement testing.(2) In oral sucrose self-administration,5% sucrose solution was used for the mice and the procedures were similar to heroin SA.(3) In morphine-induced hyperactivity test,mice were habituated in the test apparatus for 30 min and then were given saline(10 mL·kg^(-1),sc) or morphine(10 or 20 mg·kg^(-1),sc) to record the locomotion for 1.5 h.(4) For the in vivo microdialysis experiment,mice were surgically implanted with intracranial guide cannula into nucleus accumbens(AP +1.4 mm,ML ±0.9 mm,DV-3.8 mm from bregma). After 5 d of recovery from surgery,the mice were challenged by saline(10 mL·kg^(-1),sc)or morphine(10 mg·kg^(-1),sc),and then samples were collected every 20 min. RESULTS We found that AQP4 deletion had no effects on sucrose-seeking and sucrose-taking,but it significantly attenuated heroin-taking and heroin-seeking behaviors in heroin self-administration. Besides these,AQP4 deletion had no effects on basal level of locomotion,but dramatically decreased morphine-induced hyperactivity.Furthermore,the in vivo microdialysis studies showed that AQP4 deficiency inhibited morphine(10mg · kg^(-1),sc)-induced elevation of extracellular dopamine levels in nucleus accumbens in mice.CONCLUSION Our present findings demonstrate that AQP4 was potentially involved in the properties of opioid rewarding by inhibiting dopamine release in nucleus accumbens(NAc).展开更多
Time：December 7-10,2017 Venue：San Diego,California,USA Website：www.aaap.org/annual-meeting The Annual Meeting of American Academy of Addiction Psychiatry 2017 will be held on December 7-10,2017 in San Diego,Califor...Time：December 7-10,2017 Venue：San Diego,California,USA Website：www.aaap.org/annual-meeting The Annual Meeting of American Academy of Addiction Psychiatry 2017 will be held on December 7-10,2017 in San Diego,California,USA.The Annual Meeting and Scientific Symposium provide the latest scientific developments in addiction psychiatry for physicians and allied health professionals who treat patients with substance use disorders（SUD）and mental health disorders.展开更多
Time:December 7-10,2017Venue:San Diego,California,USA Website:www.aaap.org/annual-meeting The Annual Meeting of American Academy of Addiction Psychiatry 2017 will be held on December 7-10,2017 in San Diego,California,...Time:December 7-10,2017Venue:San Diego,California,USA Website:www.aaap.org/annual-meeting The Annual Meeting of American Academy of Addiction Psychiatry 2017 will be held on December 7-10,2017 in San Diego,California,USA.The Annual Meeting and Scientific Symposium provide the latest scientific developments in addiction展开更多
Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system. These phenomena are usually referred as ′drug-induced neuroplasticity′ and depend on c...Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system. These phenomena are usually referred as ′drug-induced neuroplasticity′ and depend on changes in gene expression. The cAMP response element binding protein(CREB),as a downstream molecule in mediating the actions of cAMP is an important transcriptional factor in establishing and maintaining addiction to drugs of abuse. Application of a PDE4 inhibitor attenuates the rewarding properties of cocaine and morphine. Given the fact that PDE10A is specifically located in striatum,an important structure involved in the reward circuit,we thus investigated the PDE10A inhibitormodulated the behavioral reinforcement exerted by morphine. The results show that MP-10 2.5 mg·kg^(-1),administered subcutaneously,significantly inhibited the acquisition of morphine-induced CPP. Moreover,MP-10 did not alter the expression of morphine-induced CPP,but did accelerate the extinction of morphine-induced CPP. Additionally,chronic treatment with MP-10 2.5 mg·kg^(-1)decreased expression of phosphorylated CREB(pC REB) in dorsomedial striatum,in shell of NAc,and in anterior cingulate cortex(ACC) as well as decreased expression of ΔFos B in the shell of NAc and ACC. These data indicate that PDE10A inhibition may have a potential therapeutic effect on addiction. Since the MP-10 has relative short metabolic Stability,we also developed a few novel potent new PDE10A selective inhibitor with improved stability and brain exposure. The new compound exhibited promising potential in schizophrenia and addiction treatment.展开更多
Opioids have been used for treated pain for thousands of years. Meanwhile, opioids induce drug addic- tion, which causes serious medical and social problems. Most opioids research have been concentrated on neurons i...Opioids have been used for treated pain for thousands of years. Meanwhile, opioids induce drug addic- tion, which causes serious medical and social problems. Most opioids research have been concentrated on neurons in the central nerve system （CNS） , however, the action of glia, which accounts for 90% cells in CNS have been long neglected. Unlike the classical opioid-neuron stereoselective interaction opioids were found to non-stereose- lectively bind the accessory protein myeloid differentiation factor 2 （MD-2） of innate immune Toll- like receptor 4 （TLR4） , which induces glial activation and pro-inflammatory factors production, therefore contributing to opioid hyper-analgesia, drug tolerance, dependence and addiction. A series of TLR4 antagonists have been discovered by multiple drug discovery strategies for inhibiting the opioids＇ side effects and treating drug abuse, among which （ ＋ ）-naltrexone and T-5342126 have been transferred to Xalud and BioLineRx respectively, for further pre-clini- cal/clinical drug development.展开更多
OBJECTIVE Individuals vary in sensitivity to the behavioral effects of nicotine,resulting in differences in their vulnerability to addiction.The role of rearing environment in determining individual sensitivity to nic...OBJECTIVE Individuals vary in sensitivity to the behavioral effects of nicotine,resulting in differences in their vulnerability to addiction.The role of rearing environment in determining individual sensitivity to nicotine is unclear.The neuropharmacological mechanisms mediating the effect of rearing environment on the actions of nicotine are also understood.Thus,the contribution of rearing environment in determining the sensitivity to the locomotor effects of nicotine and regulating α4β2*-and α7-nicotinic acetylcholine(n ACh) receptor expressionwas determined in rats reared in isolated(IC) or enriched(EC) conditions.METHODS To measure locomotor activity,adolescent rats(postnatal day 21-51)were injected with saline(1 mL·kg^(-1)) or nicotine(0.3 mg·kg^(-1)) subcutaneously,then placed in chamberswhere ambulatory activity was monitored for 30-min by computer for 14 daily sessions.α4β2*-andα7-n ACh receptor expression in the mesolimbic dopamine pathway was determined by quantitative autoradiography of [125 I]-epibatidine and [125 I]-bungarotoxinbinding,respectively,in 16 μmol·L^(-1) coronal sections.Values for receptor expression in fmol are ±s of 8 brains and compared by two-tailed,unpaired t-test with P<0.05 considered significant.RESULTS EC-rats are similarly sensitive as IC-rats to the locomotor effects of nicotine.[125 I]-epibatidine binding in the ventral tegmental area of EC-rats was reduced(2.8±0.3 fmo L) compared to IC-rats(4.0±0.4 fmo L);there was no difference in the nucleus accumbens.There was no difference between EC-and IC-rats in α7-n ACh receptor expression in the mesolimbic dopamine pathway.CONCLUSION Rearing environment differentially regulates n ACh receptor subtypes in EC and IC rats.These data suggest regulation of n ACh receptors by environmental factors may be a mechanism for the protective effect of enrichment against altered sensitivity to nicotine in genetically vulnerable individuals.The characterization of these mechanisms will aid in development of novel pharmacological tools mimicking the protection afforded by environmental enrichment in nicotine-sensitive individuals.展开更多
文摘OBJECTIVE To examine the effects of aquaporin 4(AQP4) on opioid addiction and underlie the mechanism behind it. METHODS(1) In the heroin-induced self-administration(SA) experiment,we explored the role of AQP4 on heroin-induced psychological addiction. After the mice were trained to learn heroin-induced SA under a fixedratio1(FR1) reinforcement program for 7 d,we randomly switched the heroin doses to 0.00625,0.0125,0.025,0.05 or 0.1 mg·kg^(-1)per infusion to counterbalance assignment design. In the end,all mice underwent extinction training and reinstatement testing.(2) In oral sucrose self-administration,5% sucrose solution was used for the mice and the procedures were similar to heroin SA.(3) In morphine-induced hyperactivity test,mice were habituated in the test apparatus for 30 min and then were given saline(10 mL·kg^(-1),sc) or morphine(10 or 20 mg·kg^(-1),sc) to record the locomotion for 1.5 h.(4) For the in vivo microdialysis experiment,mice were surgically implanted with intracranial guide cannula into nucleus accumbens(AP +1.4 mm,ML ±0.9 mm,DV-3.8 mm from bregma). After 5 d of recovery from surgery,the mice were challenged by saline(10 mL·kg^(-1),sc)or morphine(10 mg·kg^(-1),sc),and then samples were collected every 20 min. RESULTS We found that AQP4 deletion had no effects on sucrose-seeking and sucrose-taking,but it significantly attenuated heroin-taking and heroin-seeking behaviors in heroin self-administration. Besides these,AQP4 deletion had no effects on basal level of locomotion,but dramatically decreased morphine-induced hyperactivity.Furthermore,the in vivo microdialysis studies showed that AQP4 deficiency inhibited morphine(10mg · kg^(-1),sc)-induced elevation of extracellular dopamine levels in nucleus accumbens in mice.CONCLUSION Our present findings demonstrate that AQP4 was potentially involved in the properties of opioid rewarding by inhibiting dopamine release in nucleus accumbens(NAc).
文摘Time：December 7-10,2017 Venue：San Diego,California,USA Website：www.aaap.org/annual-meeting The Annual Meeting of American Academy of Addiction Psychiatry 2017 will be held on December 7-10,2017 in San Diego,California,USA.The Annual Meeting and Scientific Symposium provide the latest scientific developments in addiction psychiatry for physicians and allied health professionals who treat patients with substance use disorders（SUD）and mental health disorders.
文摘Time:December 7-10,2017Venue:San Diego,California,USA Website:www.aaap.org/annual-meeting The Annual Meeting of American Academy of Addiction Psychiatry 2017 will be held on December 7-10,2017 in San Diego,California,USA.The Annual Meeting and Scientific Symposium provide the latest scientific developments in addiction
文摘Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system. These phenomena are usually referred as ′drug-induced neuroplasticity′ and depend on changes in gene expression. The cAMP response element binding protein(CREB),as a downstream molecule in mediating the actions of cAMP is an important transcriptional factor in establishing and maintaining addiction to drugs of abuse. Application of a PDE4 inhibitor attenuates the rewarding properties of cocaine and morphine. Given the fact that PDE10A is specifically located in striatum,an important structure involved in the reward circuit,we thus investigated the PDE10A inhibitormodulated the behavioral reinforcement exerted by morphine. The results show that MP-10 2.5 mg·kg^(-1),administered subcutaneously,significantly inhibited the acquisition of morphine-induced CPP. Moreover,MP-10 did not alter the expression of morphine-induced CPP,but did accelerate the extinction of morphine-induced CPP. Additionally,chronic treatment with MP-10 2.5 mg·kg^(-1)decreased expression of phosphorylated CREB(pC REB) in dorsomedial striatum,in shell of NAc,and in anterior cingulate cortex(ACC) as well as decreased expression of ΔFos B in the shell of NAc and ACC. These data indicate that PDE10A inhibition may have a potential therapeutic effect on addiction. Since the MP-10 has relative short metabolic Stability,we also developed a few novel potent new PDE10A selective inhibitor with improved stability and brain exposure. The new compound exhibited promising potential in schizophrenia and addiction treatment.
文摘Opioids have been used for treated pain for thousands of years. Meanwhile, opioids induce drug addic- tion, which causes serious medical and social problems. Most opioids research have been concentrated on neurons in the central nerve system （CNS） , however, the action of glia, which accounts for 90% cells in CNS have been long neglected. Unlike the classical opioid-neuron stereoselective interaction opioids were found to non-stereose- lectively bind the accessory protein myeloid differentiation factor 2 （MD-2） of innate immune Toll- like receptor 4 （TLR4） , which induces glial activation and pro-inflammatory factors production, therefore contributing to opioid hyper-analgesia, drug tolerance, dependence and addiction. A series of TLR4 antagonists have been discovered by multiple drug discovery strategies for inhibiting the opioids＇ side effects and treating drug abuse, among which （ ＋ ）-naltrexone and T-5342126 have been transferred to Xalud and BioLineRx respectively, for further pre-clini- cal/clinical drug development.
基金supported by Nebraska Cancer and Smoking Disease Research Programs LB506and LB595 to CS BOCKMAN and DJ STAIRS
文摘OBJECTIVE Individuals vary in sensitivity to the behavioral effects of nicotine,resulting in differences in their vulnerability to addiction.The role of rearing environment in determining individual sensitivity to nicotine is unclear.The neuropharmacological mechanisms mediating the effect of rearing environment on the actions of nicotine are also understood.Thus,the contribution of rearing environment in determining the sensitivity to the locomotor effects of nicotine and regulating α4β2*-and α7-nicotinic acetylcholine(n ACh) receptor expressionwas determined in rats reared in isolated(IC) or enriched(EC) conditions.METHODS To measure locomotor activity,adolescent rats(postnatal day 21-51)were injected with saline(1 mL·kg^(-1)) or nicotine(0.3 mg·kg^(-1)) subcutaneously,then placed in chamberswhere ambulatory activity was monitored for 30-min by computer for 14 daily sessions.α4β2*-andα7-n ACh receptor expression in the mesolimbic dopamine pathway was determined by quantitative autoradiography of [125 I]-epibatidine and [125 I]-bungarotoxinbinding,respectively,in 16 μmol·L^(-1) coronal sections.Values for receptor expression in fmol are ±s of 8 brains and compared by two-tailed,unpaired t-test with P<0.05 considered significant.RESULTS EC-rats are similarly sensitive as IC-rats to the locomotor effects of nicotine.[125 I]-epibatidine binding in the ventral tegmental area of EC-rats was reduced(2.8±0.3 fmo L) compared to IC-rats(4.0±0.4 fmo L);there was no difference in the nucleus accumbens.There was no difference between EC-and IC-rats in α7-n ACh receptor expression in the mesolimbic dopamine pathway.CONCLUSION Rearing environment differentially regulates n ACh receptor subtypes in EC and IC rats.These data suggest regulation of n ACh receptors by environmental factors may be a mechanism for the protective effect of enrichment against altered sensitivity to nicotine in genetically vulnerable individuals.The characterization of these mechanisms will aid in development of novel pharmacological tools mimicking the protection afforded by environmental enrichment in nicotine-sensitive individuals.
