Evaluation of dependence liability of emerging psychoactive substances

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수의과대학 수의학과
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서울대학교 대학원
물질 의존성
학위논문 (박사)-- 서울대학교 대학원 : 수의학과, 2015. 2. 유한상.
It has become a social problem that people who abuse narcotics such as central nervous acting medicinal drugs and new psychoactive substances have been increasing in Korea. As the center for evaluation of psychoactive substances in order to control them, the Ministry of Food and Drug Safety (MFDS) have two big categories of evaluating principles according to the purposes for uses of the substances. In the case of medicinal drugs, evaluating dependence potential through conventional in vivo experiment is essential because it is used to humans for medical purposes. However, in the case of synthetic psychoactive substances not for medicinal purposes, it is not only unnecessary to evaluate every individual substances through animal behavioral experiments but also impossible to do so. In this regard, it is important to establish rapid methods for prediction of dependence potential of numerous new psychoactive substances which are not intended for medical uses.
In the present study, physical dependence, psychological dependence, and dopaminergic/serotonergic effects were evaluated in various medicinal drugs and some of synthetic cannabinoids in the behavioral pharmacological approach. Jumping test was used to evaluate physical dependence liability and climbing behavior test and head twitch response were evaluated to check the substances‟ dopaminiergic and serotonergic effects, respectively. The psychological dependence liability was evaluated with a conditioned place preference test and self-administration test. Each animal behavioral test has been validated by many scientists, and is generally used in the field of substance dependence liability.
Three medicinal drugs that are abusable (propofol, quetiapine, and tramadol) and three synthetic cannabinoids (JWH-073, JWH-081, and JWH-210) were selected in order to evaluate their abuse liabilities. Propofol produced negative responses in the climbing and jumping tests, but presented positive results in conditioned place preference and self-administration tests. The results suggested that propofol does not activate the dopaminiergic system nor lead to physical dependence, but does have a psychological dependence liability. In the case of quetiapine, climbing and jumping behavior tests were negative, but the head twitch, conditioned place preference, and self-administration tests were positive. From these results quetiapine was suggested to have effect on the serotonergic system, and may have a psychological dependence liability. The results were coincident with the expression level changes of related genes and proteins. Tramadol showed negative responses in the climbing test, but yielded positive results in the jumping, head twitch, conditioned place preference, and self-administration tests, which suggests that tramadol might affect the serotonergic system and induce physical and psychological dependence.
In the current situation of flooding circulation of psychoactive substances, it is requested to develop rapid dependence evaluating methods for screening the unknown substances effectively. In MFDS, various in vitro, in silico, and ex vivo techniques are applied to meet the necessities of rapid controlling system. In the policy making part, the 꼝emporary narcotics act. was established in 2011 to control new psychoactive substances immediately without evaluating dependence and effect on central nervous system. To back up the policy scientifically, a dependence prediction method should be developed based on various techniques such as receptor binding assay, QSAR/QSPR modeling, neurotransmitter analysis using HPLC, and so forth.
Psychological dependence liability of three synthetic cannabinoids (JWH-073, JWH-081, and JWH-210) which are known to show different binding affinities to the CB1 receptor was evaluated using conditioned place preference and self-administration techniques. And the results from the in vivo study were compared with those of receptor binding assay to determine whether there is a relationship between dependence potential and receptor binding affinity or not. Although the tested synthetic cannabinoids showed negative results in the self-administration test, the conditioned place preference of the drugs increased significantly, and the increase coincided with the results of the CB1 receptor binding assay performed in vitro using over-expressed protein membrane.
To maintain Korea as 꼋rug free. state, and keep Korean people from drug abuse problem, it is needed to sustainable effort on monitoring abusable substances through scientific evaluation. And developing a simple and rapid method for the evaluation will provide an utmost tool for those efforts.
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College of Veterinary Medicine (수의과대학)Dept. of Veterinary Medicine (수의학과)Theses (Ph.D. / Sc.D._수의학과)
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