伏隔核壳区DA受体和NMDA受体对可卡因自身给药维持的影响
发布时间：2019-06-01 11:34
【摘要】：可卡因是天然强效的中枢神经兴奋剂,具有很强的成瘾性,滥用可卡因可造成身体的损害以及引发一系列社会问题,被世界禁毒组织列为禁止吸食的常见五大类毒品之一。可卡因抑制多巴胺的重摄取,提升胞外多巴胺水平,是可卡因成瘾的经典机制,尤其是伏隔核区(nucleus accumbens,NAc)胞外多巴胺水平的提升对于可卡因成瘾来说至关重要。大量实验表明,NAc内注射多巴胺受体拮抗剂可调节可卡因的成瘾行为,但由于给药途径、实验程序等的不一致,产生的结果也不尽相同,而且对多巴胺受体的处理也仅限于急性处理。此外,越来越多的研究发现,谷氨酸系统也参与了可卡因的成瘾过程,全身或是NAc内注射NMDA受体的非选择性拮抗剂可有效抑制可卡因的摄取,但因其严重的副作用而不能应用于临床。NMDA受体主要分为含NR2A亚基的NMDA受体和含NR2B亚基的NMDA受体两种亚型,每种亚型的受体都有各自独特的生物物理学及药理学特性,在可卡因成瘾中扮演不同的角色,而且目前所发现的含NR2B亚基的NMDA受体的选择性拮抗剂具有高效的神经保护作用,副作用小。因此,NMDA受体的亚型被认为是治疗可卡因成瘾可能的关键靶点。但是迄今为止,NMDA受体的两类亚型各自在可卡因成瘾中的具体作用还并不清楚。 本研究利用可卡因静脉自身给药模型,研究在自身给药模型的平台期向双侧NAc壳区分别长期(5天)注射多巴胺D1和D2受体拮抗剂对可卡因成瘾维持、消退及复吸的影响,以及向NAc壳区分别长期注射含NR2A亚基的NMDA受体和含NR2B亚基的NMDA受体的选择性拮抗剂对可卡因成瘾维持的影响。以期获得NAc壳区D1受体、D2受体、含NR2A亚基的NMDA受体及含NR2B亚基的NMDA受体在可卡因成瘾维持中的作用,为可卡因成瘾的治疗提供新思路。具体结果如下： (1)可卡因自身给药模型建立成功达到平台期后,向双侧NAc壳区预注射生理盐水(1μl/side),无论处理初期(第1天,急性作用)还是长期处理(随后的4天)都不影响大鼠可卡因自身给药行为及大鼠的体重。 (2)平台期向NAc壳区预注射D1受体拮抗剂SCH-23390(2μg/μl/side),处理初期可卡因摄取总量不变,但表现为前半程不进行可卡因自身给药,后半程以较高速率进行可卡因自身给药。随着处理次数的增加,可卡因摄取量进行性降低。长期处理后,大鼠的可卡因自身给药行为完全受到抑制。拮抗剂处理过程中不影响大鼠的体重。 (3)平台期向NAc壳区预注射D2受体拮抗剂sulpiride (2μg/μl/side),处理初期不影响大鼠可卡因自身给药行为,再次处理抑制大鼠可卡因的自身给药行为。拮抗剂处理过程中不影响大鼠的体重。 (4)平台期向NAc壳区预注射含NR2A亚基的NMDA受体选择性拮抗剂NVP-AAM077(1μg/μl/side),处理初期显著降低大鼠对可卡因的有效应答,并且使大鼠体重显著降低。随着处理次数的增加,对可卡因摄取和食欲的抑制效果逐渐降低。 (5)平台期向NAc壳区预注射含NR2B亚基的NMDA受体选择性拮抗剂Ro25-6981(5μg/μl/side)拮抗剂处理过程中不影响大鼠可卡因自身给药行为及大鼠的体重。 (6)平台期向NAc壳区注射D1或D2受体的拮抗剂,长期处理后以消退程序进行训练,整个消退过程内大鼠对可卡因的有效应答均保持在长期处理后的较低水平。 (7)平台期向NAc壳区长期注射D1或D2受体的拮抗剂,其对消退后可卡因引燃的复吸行为无影响。 以上结果表明,伏隔核壳区D1和D2受体均参与可卡因自身给药行为的维持,选择性阻断伏隔核壳区D1或D2受体可显著抑制可卡因的自身给药行为,而且大鼠对两种拮抗剂的响应略有差异,表现为对D1样受体拮抗剂更为敏感。平台期选择性阻断伏隔核壳区D1或D2受体可加快可卡因戒断,但不影响其复吸行为。可卡因自身给药行为的维持同样依赖含NR2A亚基的NMDA受体的活化,但并不依赖含NR2B亚基的NMDA受体。
[Abstract]:Cocaine is a natural and powerful central nervous system and has a strong addiction, the abuse of cocaine can cause physical damage and a range of social problems, and the world's anti-drug organization is one of the most common five-class drugs to ban smoking. Cocaine inhibits the re-uptake of dopamine, increases the level of extracellular dopamine, is a classic mechanism for cocaine addiction, especially the enhancement of extracellular dopamine levels in the nucleus accumbens (NAc) is essential for cocaine addiction. A large number of experiments show that the injection of dopamine receptor antagonist in NAc can regulate the addictive behavior of cocaine, but the result is different due to the inconformity of the route of administration, the experimental procedure and so on, and the treatment of the dopamine receptor is limited to the acute treatment. In addition, more and more studies have found that glutamate systems are also involved in the addictive process of cocaine, and the non-selective antagonists of the NMDA receptor in the whole body or in the NAc can effectively inhibit the uptake of cocaine, but cannot be applied to clinical use due to their severe side effects. The NMDA receptor is mainly divided into two subtypes of the NMDA receptor containing the NR2A subunit and the NMDA receptor containing the NR2B subunit, And the present invention has found that the selective antagonist of the NMDA receptor containing the NR2B subunit has the effect of high-efficiency neuroprotection and has little side effect. As a result, the subtype of the NMDA receptor is thought to be a key target for the treatment of cocaine addiction. To date, however, the specific role of the two subtypes of NMDA receptor in cocaine addiction is not clear. In this study, the effects of dopamine D1 and D2 receptor antagonists on the maintenance, regression and reabsorption of cocaine addiction were studied on the long-term (5-day) long-term (5-day) injection of dopamine D1 and D2 receptor antagonists on the two-sided NAc shell region by using the self-administration model of cocaine. and the long-term injection of the NMDA receptor containing the NR2A subunit and the selective antagonist of the NMDA receptor containing the NR2B subunit to the NAc shell region, In order to obtain the role of the NMDA receptor and the NMDA receptor containing the NR2B subunit in the maintenance of cocaine addiction, the NMDA receptor containing the NR2A subunit and the NMDA receptor containing the NR2B subunit are used to provide a new thought for the treatment of the cocaine addiction. Road. Specific results such as In the following: (1) After the model of the self-administration of the cocaine was established successfully, normal saline (1. mu.l/ side) was pre-injected into the bilateral NAc shell region, regardless of the initial stage of treatment (1. mu.l/ side). The first day, the acute effect), or the long-term treatment (4 days later) did not affect the behavior of the rat's cocaine itself and the rats Body weight. (2) Pre-injection of D1 receptor antagonist SCH-23390 (2. mu.g/. mu.l/ side) to the NAc shell region during the platform period, and the total amount of cocaine intake in the initial stage of the treatment was not changed, but it showed that the first half-way did not carry out the self-administration of the cocaine, and the second half of the course was cacheable at a higher rate. Cocaine intake as the number of treatments increased Progressive reduction. After long-term treatment, the rat's cocaine itself is over. full inhibition. No effect in the treatment of the antagonist Rat body weight. (3) Pre-injection of D2 receptor antagonist, sulpiride (2.mu. g/. mu.l/ side) to the NAc shell region during the stage, did not affect the self-administration behavior of the rat's cocaine at the beginning of the treatment, and the inhibition of cocaine in the rat was re-treated. The self-administration behavior of the antagonist. The body weight of the rats was affected. (4) The NVP-AAM077 (1. mu.g/. mu.l/ side) of the NMDA receptor selective antagonist containing the NR2A subunit was pre-injected into the NAc shell region during the stage, and the effective response of the rat to the cocaine was significantly reduced at the beginning of the treatment, and The weight of rats was significantly reduced. Cocaine intake and appetite increased as the number of treatments increased. The inhibitory effect of NR2B-subunit-containing NMDA receptor-selective antagonist, Ro25-6981 (5. mu.g/. mu.l/ side), was pre-injected into the NAc shell region during the stage. the body weight of the rats and the weight of the rats. (6) an antagonist of the D1 or D2 receptor is injected into the NAc shell region on the platform stage, and the antagonist of the D1 or D2 receptor is injected after the long-term treatment, and the effective response of the rat to the cocaine in the whole regression process and (7) an antagonist for long-term injection of D1 or D2 receptors to the NAc shell region, The results showed that both the D1 and D2 receptors in the nucleus accumbens were involved in the self-administration of cocaine, and the selective blocking of the D1 or D2 receptors in the nucleus accumbens could significantly inhibit the self-administration of cocaine. In addition, the response of the rats to the two antagonists was slightly different And is shown to be more sensitive to the D1-like receptor antagonist. Cocaine withdrawal is accelerated without affecting its reabsorption. The maintenance of the cocaine itself is also dependent on the activation of the NMDA receptor containing the NR2A subunit, but it does not
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.61
本文编号：2490242
[Abstract]:Cocaine is a natural and powerful central nervous system and has a strong addiction, the abuse of cocaine can cause physical damage and a range of social problems, and the world's anti-drug organization is one of the most common five-class drugs to ban smoking. Cocaine inhibits the re-uptake of dopamine, increases the level of extracellular dopamine, is a classic mechanism for cocaine addiction, especially the enhancement of extracellular dopamine levels in the nucleus accumbens (NAc) is essential for cocaine addiction. A large number of experiments show that the injection of dopamine receptor antagonist in NAc can regulate the addictive behavior of cocaine, but the result is different due to the inconformity of the route of administration, the experimental procedure and so on, and the treatment of the dopamine receptor is limited to the acute treatment. In addition, more and more studies have found that glutamate systems are also involved in the addictive process of cocaine, and the non-selective antagonists of the NMDA receptor in the whole body or in the NAc can effectively inhibit the uptake of cocaine, but cannot be applied to clinical use due to their severe side effects. The NMDA receptor is mainly divided into two subtypes of the NMDA receptor containing the NR2A subunit and the NMDA receptor containing the NR2B subunit, And the present invention has found that the selective antagonist of the NMDA receptor containing the NR2B subunit has the effect of high-efficiency neuroprotection and has little side effect. As a result, the subtype of the NMDA receptor is thought to be a key target for the treatment of cocaine addiction. To date, however, the specific role of the two subtypes of NMDA receptor in cocaine addiction is not clear. In this study, the effects of dopamine D1 and D2 receptor antagonists on the maintenance, regression and reabsorption of cocaine addiction were studied on the long-term (5-day) long-term (5-day) injection of dopamine D1 and D2 receptor antagonists on the two-sided NAc shell region by using the self-administration model of cocaine. and the long-term injection of the NMDA receptor containing the NR2A subunit and the selective antagonist of the NMDA receptor containing the NR2B subunit to the NAc shell region, In order to obtain the role of the NMDA receptor and the NMDA receptor containing the NR2B subunit in the maintenance of cocaine addiction, the NMDA receptor containing the NR2A subunit and the NMDA receptor containing the NR2B subunit are used to provide a new thought for the treatment of the cocaine addiction. Road. Specific results such as In the following: (1) After the model of the self-administration of the cocaine was established successfully, normal saline (1. mu.l/ side) was pre-injected into the bilateral NAc shell region, regardless of the initial stage of treatment (1. mu.l/ side). The first day, the acute effect), or the long-term treatment (4 days later) did not affect the behavior of the rat's cocaine itself and the rats Body weight. (2) Pre-injection of D1 receptor antagonist SCH-23390 (2. mu.g/. mu.l/ side) to the NAc shell region during the platform period, and the total amount of cocaine intake in the initial stage of the treatment was not changed, but it showed that the first half-way did not carry out the self-administration of the cocaine, and the second half of the course was cacheable at a higher rate. Cocaine intake as the number of treatments increased Progressive reduction. After long-term treatment, the rat's cocaine itself is over. full inhibition. No effect in the treatment of the antagonist Rat body weight. (3) Pre-injection of D2 receptor antagonist, sulpiride (2.mu. g/. mu.l/ side) to the NAc shell region during the stage, did not affect the self-administration behavior of the rat's cocaine at the beginning of the treatment, and the inhibition of cocaine in the rat was re-treated. The self-administration behavior of the antagonist. The body weight of the rats was affected. (4) The NVP-AAM077 (1. mu.g/. mu.l/ side) of the NMDA receptor selective antagonist containing the NR2A subunit was pre-injected into the NAc shell region during the stage, and the effective response of the rat to the cocaine was significantly reduced at the beginning of the treatment, and The weight of rats was significantly reduced. Cocaine intake and appetite increased as the number of treatments increased. The inhibitory effect of NR2B-subunit-containing NMDA receptor-selective antagonist, Ro25-6981 (5. mu.g/. mu.l/ side), was pre-injected into the NAc shell region during the stage. the body weight of the rats and the weight of the rats. (6) an antagonist of the D1 or D2 receptor is injected into the NAc shell region on the platform stage, and the antagonist of the D1 or D2 receptor is injected after the long-term treatment, and the effective response of the rat to the cocaine in the whole regression process and (7) an antagonist for long-term injection of D1 or D2 receptors to the NAc shell region, The results showed that both the D1 and D2 receptors in the nucleus accumbens were involved in the self-administration of cocaine, and the selective blocking of the D1 or D2 receptors in the nucleus accumbens could significantly inhibit the self-administration of cocaine. In addition, the response of the rats to the two antagonists was slightly different And is shown to be more sensitive to the D1-like receptor antagonist. Cocaine withdrawal is accelerated without affecting its reabsorption. The maintenance of the cocaine itself is also dependent on the activation of the NMDA receptor containing the NR2A subunit, but it does not
【学位授予单位】：陕西师范大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.61
【参考文献】
相关期刊论文 前1条
1 王小波;叶能胜;王继芬;谷学新;;可卡因及代谢物的分析检测研究进展[J];化学通报;2010年02期
，本文编号：2490242
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