【摘要】：可卡因是天然強效的中樞神經(jīng)興奮劑,具有很強的成癮性,濫用可卡因可造成身體的損害以及引發(fā)一系列社會問題,被世界禁毒組織列為禁止吸食的常見五大類毒品之一。可卡因抑制多巴胺的重攝取,提升胞外多巴胺水平,是可卡因成癮的經(jīng)典機制,尤其是伏隔核區(qū)(nucleus accumbens,NAc)胞外多巴胺水平的提升對于可卡因成癮來說至關重要。大量實驗表明,NAc內(nèi)注射多巴胺受體拮抗劑可調(diào)節(jié)可卡因的成癮行為,但由于給藥途徑、實驗程序等的不一致,產(chǎn)生的結果也不盡相同,而且對多巴胺受體的處理也僅限于急性處理。此外,越來越多的研究發(fā)現(xiàn),谷氨酸系統(tǒng)也參與了可卡因的成癮過程,全身或是NAc內(nèi)注射NMDA受體的非選擇性拮抗劑可有效抑制可卡因的攝取,但因其嚴重的副作用而不能應用于臨床。NMDA受體主要分為含NR2A亞基的NMDA受體和含NR2B亞基的NMDA受體兩種亞型,每種亞型的受體都有各自獨特的生物物理學及藥理學特性,在可卡因成癮中扮演不同的角色,而且目前所發(fā)現(xiàn)的含NR2B亞基的NMDA受體的選擇性拮抗劑具有高效的神經(jīng)保護作用,副作用小。因此,NMDA受體的亞型被認為是治療可卡因成癮可能的關鍵靶點。但是迄今為止,NMDA受體的兩類亞型各自在可卡因成癮中的具體作用還并不清楚。 本研究利用可卡因靜脈自身給藥模型,研究在自身給藥模型的平臺期向雙側NAc殼區(qū)分別長期(5天)注射多巴胺D1和D2受體拮抗劑對可卡因成癮維持、消退及復吸的影響,以及向NAc殼區(qū)分別長期注射含NR2A亞基的NMDA受體和含NR2B亞基的NMDA受體的選擇性拮抗劑對可卡因成癮維持的影響。以期獲得NAc殼區(qū)D1受體、D2受體、含NR2A亞基的NMDA受體及含NR2B亞基的NMDA受體在可卡因成癮維持中的作用,為可卡因成癮的治療提供新思路。具體結果如下： (1)可卡因自身給藥模型建立成功達到平臺期后,向雙側NAc殼區(qū)預注射生理鹽水(1μl/side),無論處理初期(第1天,急性作用)還是長期處理(隨后的4天)都不影響大鼠可卡因自身給藥行為及大鼠的體重。 (2)平臺期向NAc殼區(qū)預注射D1受體拮抗劑SCH-23390(2μg/μl/side),處理初期可卡因攝取總量不變,但表現(xiàn)為前半程不進行可卡因自身給藥,后半程以較高速率進行可卡因自身給藥。隨著處理次數(shù)的增加,可卡因攝取量進行性降低。長期處理后,大鼠的可卡因自身給藥行為完全受到抑制。拮抗劑處理過程中不影響大鼠的體重。 (3)平臺期向NAc殼區(qū)預注射D2受體拮抗劑sulpiride (2μg/μl/side),處理初期不影響大鼠可卡因自身給藥行為,再次處理抑制大鼠可卡因的自身給藥行為。拮抗劑處理過程中不影響大鼠的體重。 (4)平臺期向NAc殼區(qū)預注射含NR2A亞基的NMDA受體選擇性拮抗劑NVP-AAM077(1μg/μl/side),處理初期顯著降低大鼠對可卡因的有效應答,并且使大鼠體重顯著降低。隨著處理次數(shù)的增加,對可卡因攝取和食欲的抑制效果逐漸降低。 (5)平臺期向NAc殼區(qū)預注射含NR2B亞基的NMDA受體選擇性拮抗劑Ro25-6981(5μg/μl/side)拮抗劑處理過程中不影響大鼠可卡因自身給藥行為及大鼠的體重。 (6)平臺期向NAc殼區(qū)注射D1或D2受體的拮抗劑,長期處理后以消退程序進行訓練,整個消退過程內(nèi)大鼠對可卡因的有效應答均保持在長期處理后的較低水平。 (7)平臺期向NAc殼區(qū)長期注射D1或D2受體的拮抗劑,其對消退后可卡因引燃的復吸行為無影響。 以上結果表明,伏隔核殼區(qū)D1和D2受體均參與可卡因自身給藥行為的維持,選擇性阻斷伏隔核殼區(qū)D1或D2受體可顯著抑制可卡因的自身給藥行為,而且大鼠對兩種拮抗劑的響應略有差異,表現(xiàn)為對D1樣受體拮抗劑更為敏感。平臺期選擇性阻斷伏隔核殼區(qū)D1或D2受體可加快可卡因戒斷,但不影響其復吸行為。可卡因自身給藥行為的維持同樣依賴含NR2A亞基的NMDA受體的活化,但并不依賴含NR2B亞基的NMDA受體。
[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
【學位授予單位】：陜西師范大學
【學位級別】：碩士
【學位授予年份】：2013
【分類號】：R749.61

【參考文獻】

相關期刊論文 前1條

1 王小波;葉能勝;王繼芬;谷學新;;可卡因及代謝物的分析檢測研究進展[J];化學通報;2010年02期

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本文編號：2490242