健康与遗传心理学研究室知识库

临床研究发现，药物成瘾个体除了对成瘾药物表现出强迫性觅药行为外，还对自然奖赏物表现出强迫样症状，如物质滥用与神经性暴食症、贪食症和强迫性性行为有很高的共病率，并且强迫样行为与强迫性用药行为相似的临床症状进一步提示他们之间可能存在相同的神经基础。课题组前期研究表明在吗啡短程戒断期动物对多种自然奖赏物表现为快感缺失样症状，而在长程戒断时快感缺失症状消失，表现为对自然奖赏物渴求增强。但是短程戒断期，快感缺失样症状与对高奖赏价值的奖赏物的渴求是并存的。也就是说，尽管短程戒断的动物在 PR 程序下分别诱发对2.5%、4%、15%、30%、40%糖水的消耗性和动机性快感缺失样症状，却表现出对60%糖水反应增强，同时在冒险性性奖赏行为测试中也表现出对性刺激反应增强，并且这种高动机、高冒险性行为只有在面对高诱因价值的奖赏时才会表现出来。而高诱因价值奖赏物需要较强的抑制控制能力，本文认为物质滥用导致的抑制控制功能障碍有可能是强迫样行为控制能力减弱的原因之一。而且临床实验证实强迫样行为患者表现出与物质滥用者同样的抑制控制能力受损。
在综合考虑上述因素和前期实验的基础上，本研究采用冲突模型，即在获得奖赏(60%糖水和性接触)的同时伴随足部电击作为惩罚，用来反应动物的抑制控制能力，评估大剂量吗啡前处理动物短程戒断期对高诱因价值奖赏物的渴求动机，并进一步采用行为药理学方法激活与失活参与抑制控制的目标脑区及通路，探讨强迫样行为的神经机制，以期能够为临床干预和治疗物质成瘾及并发的进食障碍和强迫性性行为提供相应的实验依据。通过本文的研究发现：
(1)实验一和实验二的结果显示，与盐水组动物相比，吗啡组动物产生了明显的强迫样行为，表现为在有电击情况下吗啡组动物对 60% 糖水的渴求动机不但没有减弱，反而有所增加，同时也表现出了对发情期雌鼠较强的趋近行为以及更短的潜伏期，因此我们认为吗啡戒断大鼠对自然奖赏物的强迫样行为可能与吗啡前处理导致的抑制控制能力受损有关。
(2)前额叶皮层的 ACC 脑区被认为是抑制控制的重要结构，实验三也得到相似结果。ACC 脑区受损诱发盐水组动物的强迫样行为，而对脑区功能已经损伤的吗啡组动物并无影响，反之，ACC 脑区功能修复则显著降低了吗啡组动物对奖赏的强迫样动机(实验 4与实验 5)，进一步证实 ACC 脑区受损是诱发强迫样行为的重要因素，改善 ACC 脑区的功能有助于减轻以上症状。
(3)ACC 与 Amy之间通路参与成本-收益的评估，阻断 ACC 与 Amy 的联系会产生决策异常。实验六与实验八交叉失活 ACC 与 BLA 之间通路，结果与双侧失活 ACC脑区结果一致，盐水组动物表现为对 60% 糖水和性接触的强迫样行为的增强，对吗啡组无影响。实验七和实验九交叉失活 ACC 与 CeA 通路后，两组都没有明显变化。这说明对于盐水组来说，ACC 与 Amy 两个亚区之间的通路负责不同行为调控。对于吗啡组而言，由于吗啡前处理使包括 ACC 在内的某些脑区受损，所以对于 ACC 与 Amy 通路的作用需采用激活的方式进一步验证。

It is well established that exposure to drugs not only leads to the development of compulsive drug seeking/taking behaviors in humans as well as in animals but also causes a compulsive-like behaviors for natural rewards (sex, food, social et al) in abused drug users. Clinical research has found high rate of comorbidity between substance use disorder and eating disorders as well as compulsive sexual behaviorone. Moreover, substance use and compulsive-like behaviors show similar phenomenological features, such as craving, dependence, loss of control, and abstinence, perhaps they share a common possible pathophysiology.
One of our previous studies has demonstrated that morphine exposure-induced diminished consummatory and motivational behaviors for natural rewards (anhedonia-like behaviors) after acute or short-, but not long-term withdrawal(1-week), and developed motivational sensitization to natural rewards after protracted withdrawal period. More notably, the anhedonia-like behaviors coexisted with heightened craving for the high-incentive reward following short-term withdrawal, i.e., despite the consummatory and motivational anhedonia-like responses to multiple rewarding stimuli (less than 60% sucrose solution and sexual performance ), the PR responding for 60% sucrose solution and the risky appetitive behavior for sexual stimulus was markedly increased. And the appetitive motivational behaviors persist only when the morphine-treated rats are facing the high-value rewards (i.e., 60% sucrose and sexual reward). Thus we regard that morphine-induced maladaptive behavior at least partially differ from the reward incentive motivation. In fact, there is another component, i.e., the dysfunction of top-down inhibitory control caused by repeated drug use that may contribute to the high comorbidity rates of pathological pursuit of natural rewards in drug abusers. Several studies demonstrate that deficits in inhibitory control/executive control could be implicated in these disorders (eating disorder and compulsive sexual behavior).
Therefore, this study aimed to use a conflict task, which can reflect the ability of inhibitory control, to assess compulsive-like appetitive behaviors for natural rewards (i.e., 60% sucrose solution and a sexual partner) under punishment after short-term withdrawal from morphine. Then its probable neural mechanisms are discussed by behavior pharmacological methods based on the conflict model, in order to attain a better understanding of the neurobiological underpinnings of compulsive-like behaviors and also to aide in the development of new therapeutic interventions that could be effective in these disorders. And we found:
1. The results of experiment 1 and 2 showed that, compared to the saline-treated rats, the morphine-treated rats displayed a significantly higher performance for 60% sucrose solution under the foot-shock punishment. The sexually experienced male rats pretreated with morphine displayed more appetitive behaviors and the shorter latency to approach the sexual stimulus despite the foot shock as a punishment, which indicated that the morphine-treated rats displayed compulsive-like behaviors for nature rewards suggesting impairment in inhibitory control which may contribute to the comorbidities between drug abuse and other compulsive-like behaviors.
2. A multitude of studies had suggested that deficits in prefrontal cortical function (including ACC) and consequential impaired performance with inhibitory control could be crucial in promoting compulsive drug use, which is consistent with our study. In experiment 3, bilateral inactivation of ACC impaired the inhibitory control and induced compulsive-like behavior in saline-treated rats, while didn’t influence morphine-treated rats’ performance. On the contrary, morphine-treated induced impairment of inhibitory control was rescued by bilateral activation of ACC(experiment 4-5). The study further strengthened the evidence dysfunction in ACC played critical role in compulsive-like motivational behaviors.
3. As for saline-treated group, disconnection between ACC and BLA evoked compulsive-like behavior on Sal + Cont group, inactivation of ACC-CeA have no significant effect on it. For morphine-treated group, it seemed to make no different at all after disconnection of ACC and Amy. This suggested that BLA-ACC and ACC-CeA were responsible for different behavior regulation in Sal-treated group, and the role of the pathways between ACC and Amy need to be validated prospectively using activation methods owing to morphine pretreatment had destroyed some certain brain function including the ACC.