title: A conjugate vaccine attenuates morphine- and heroin-induced behavior in rats.
abstract: BACKGROUND
  Currently approved medications for opioid addiction have shown clinical efficacy, but undesired side effects, dependence induced by the medications themselves, and low treatment compliance necessitate the need for novel therapies.
  
  
  METHODS
  A novel morphine-keyhole limpet hemocyanin conjugate vaccine was synthesized with 6-glutarylmorphine as the hapten and a lengthened linker of 6 carbon atoms. The titer and specificity of the triggered antibody were assessed by enzyme-linked immunosorbent assay. The effects of the vaccine on the morphine-induced elevation of dopamine levels in the nucleus accumbens were determined by high-performance liquid chromatography. The effects of the vaccine on morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin self-administration were also assessed.
  
  
  RESULTS
  After subcutaneous administration in rats, the vaccine triggered a high antibody titer, with comparable specificity for morphine, 6-acetylmorphine, and heroin, but no interaction with dissimilar therapeutic opioid compounds, including buprenorphine, naloxone, and nalorphine, was observed. The vaccine significantly prevented the elevation of dopamine levels in the nucleus accumbens induced by a single morphine challenge. Moreover, the vaccine prevented the expression of morphine-induced locomotor sensitization and heroin-primed reinstatement of heroin seeking, suggesting its potential for preventing relapse.
  
  
  CONCLUSIONS
  These results demonstrate that active immunization with the present vaccine induces a robust morphine/heroin-specific antibody response in rats and attenuates the behavioral effects of morphine and heroin.
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Li
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Cheng-Yu
authors.initials: CY
authors.lastname: Sun
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Yi-Xiao
authors.initials: YX
authors.lastname: Luo
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Yan-Xue
authors.initials: YX
authors.lastname: Xue
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Shi-Qiu
authors.initials: SQ
authors.lastname: Meng
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Ling-Zhi
authors.initials: LZ
authors.lastname: Xu
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Na
authors.initials: N
authors.lastname: Chen
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Jia-Hui
authors.initials: JH
authors.lastname: Deng
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Zhai
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Kosten
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten).
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten) linlu@bjmu.edu.cn sunhq@bjmu.edu.cn.
authors.forename: Lin
authors.initials: L
authors.lastname: Lu
authors.affiliation: Peking University Sixth Hospital/Institute of Mental Health (Dr Li, Ms C.-Y. Sun, Dr Luo, Ms Meng, Mr Xu, Ms Deng, Drs Lu, and H.-Q. Sun), and National Institute on Drug Dependence, Peking University, Beijing, China (Drs Dr Li, Ms C.-Y. Sun, Dr Luo, Dr Xue, Ms Meng, Mr Xu, Ms Chen, Ms Deng, Drs Zhai, Shi, and Lu); Institute for Food and Drug Safety Evaluation, National Institutes for Food and Drug Control, Beijing, China (Dr Li); Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China (Drs Lu and H.-Q. Sun); Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, Texas (Dr Kosten) linlu@bjmu.edu.cn sunhq@bjmu.edu.cn.
authors.forename: Hong-Qiang
authors.initials: HQ
authors.lastname: Sun
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage* / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000097:blood*; D058999:Drug-Seeking Behavior / Q000187:drug effects; D003932:Heroin / Q000008:administration & dosage / Q000009:adverse effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D009022:Morphine Derivatives / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012054:Reinforcement, Psychology; D012646:Self Administration; D016896:Treatment Outcome; D018074:Vaccines, Conjugate / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000701:Analgesics, Opioid; D000906:Antibodies; D009022:Morphine Derivatives; D018074:Vaccines, Conjugate; D003932:Heroin; D009020:Morphine; C026979:6-O-monoacetylmorphine; D004298:Dopamine
keywords: drug addiction; heroin; immunization; morphine; vaccine