健康与遗传心理学研究室知识库

自然奖赏与成瘾药物奖赏神经生物学机制的比较研究是药物成瘾研究中的一个重要领域，以往研究主要关注二者共同神经机制的比较，以自然奖赏为切入点探索药物成瘾的神经生物学基础。近年来，基于成瘾研究的治疗意义，自然奖赏与成瘾药物奖赏存在哪些分离的神经机制逐渐受到关注，以期找到成瘾药物特异性作用的神经机制，然后进行选择性干预，为临床治疗提供依据。病理性渴求是成瘾长期存在的根本原因。如何抑制渴求是治疗药物成瘾的关键;并且，研究自然奖赏物渴求产生与终止的负反馈机制能为成瘾药物渴求的研究提供参考。本研究以吗啡为成瘾药物、食物为自然奖赏物，采用条件位置偏爱的表达与反应恢复作为渴求模型比较成瘾药物渴求与自然奖赏物渴求神经机制的异同，分别考察腹腔注射，及外侧下丘脑、伏隔核微量注射NMDA受体拮抗剂M K-801对吗啡与食物渴求表达的影响，重点考察外侧下丘脑及伏隔核注射黑色素浓集素
(MCH)对吗啡、食物渴求的影响。主要结果如下:
(1)腹腔注射M K-801显著抑制吗啡CPP的表达，但促进食物CPP的表达;
(2)外侧下丘脑注射M K801对吗啡CPP的表达无明显的影响，但显著促进食物CPP的表达;
(3)伏隔核注射M K801抑制吗啡CPP的表达，但相同剂量的M K801对食物CPP表达无显著影响;
(4)伏隔核注射MC日对吗啡与食物CPP的表达存在相反的作用，抑制吗啡CPP表达，促进食物CPP表达。
(5)伏隔核注射MCH抑制吗啡诱发的吗啡CPP反应恢复，对食物诱发的食物CPP反应恢复无明显影响;
(6)外侧下丘脑注射MCH对吗啡诱发的吗啡CPP反应恢复无明显影响，但抑制食物诱发的食物CPP反应恢复。
以上结果表明，外侧下丘脑与伏隔核的NMDA及MCH受体在自然奖赏物与成瘾药物渴求表达过程起不同的作用。外侧下丘脑主要参与食物渴求的调节，伏隔核主要参与吗啡渴求的调节。伏隔核的MCH受体对吗啡和食物渴求的表达存在相反的作用。外侧下丘脑的MCH神经元投射可能是食物渴求发动与终止负反馈环路的重要环节，并参与成瘾药物渴求的表达。上述结果提示，MCH在治疗阿片类药物成瘾及肥胖症方面可能具有一定的应用潜力。

Drug dependence has been considered as a reoccurred brain disease characterized by persistent abnormal craving for addictive drug. It is a major worldwide public health problem. In addicts, one of the main unsolved challenges is eradicating the pathological craving for the drug without impairing the general affective state of the subjects and their motivation for natural reinforcers. Therefore, comparison of the neurobiological mechanisms of natural reward and drug reward has been one of the most important fields in drug addiction researches recently. The comparison studies aims to obtain some dissociations in neurobiological substrates between drug of abuse and natural reward, and then provide insights to clinic treatment of drug addiction.
Pathological craving for the drug is the fundamental characters of drug addiction, and it persists long after the discontinuation of drug use. How to inhibit the abnormal craving is critical to the clinic treatment of drug addiction.In the present series of studies, aimed to elucidating the differential neural substrates of the craving for natural reinforcers and addictive drugs, the roles of NMDA and MCH receptors of lateral hypothalamus and nucleus accumbens on the expression of morphine and food craving were investigated in conditioned place preference (CPP) paradigm. The main results are as follows:
1 .The expression of morphine CPP was inhibited but food CPP was potentiated after system injection of MK801，one of the NMDA antagonists.
2. MK801 enhanced the expression of food CPP, but had no obvious effect on the expression of morphine CPP after microinjecting it into lateral hypothalamus
3. Antagonization of NMDA receptor with MK801 in nucleus accumbens impaired the expression of morphine CPP, and food CPP in high dose (5.0 u g), but no effect in low dose(1.0,2.0 u g).
4. Opposite effect of MCH on the expression of food and morphine CPP was observed after microinjecting it into the shell of nucleus accumbens, with food craving increased and morphine craving depressed.
5. In the shell of nucleus accumbens, MCH prevented the reinstatement of morphine CPP; no effect was observed on the reinstatement of food CPP.
6. In the lateral hypothalamus, MCH prevented the reinstatement of food CPP but had no effect on the reinstatement of morphine CPP.
These results suggest there are differential roles of the NDMA and MCH receptors of lateral hypothalamus and nucleus accumbens on the morphine and food craving in rats. It indicates that MCH receptor in the nucleus accumbens may be a potential target for developing special and efficient treatments of drug addiction and obesity.