健康与遗传心理学研究室知识库

药物成瘾行为习惯化是从娱乐性用药向强迫性用药转化的关键阶段。据报道，背侧纹状体(Dorsal striatum, DS)的多巴胺(Dopamine, DA)系统在药物成瘾习惯化中发挥关键作用。另外，L型电压门控钙离子通道(L-type voltage dependent calcium channels, LTCCs)作为DA受体的靶向调节分子参与调控成瘾行为。但是，LTCCs在可卡因习惯化行为中发挥的作用及其机制还尚不清楚。此外，树鼩的 DS脑区结构与近灵长类动物十分接近，可明确区分为两个不同的功能亚区：尾状核(Nucleus caudaatus, Cd)和壳核(Putamen, Put)，且树鼩善于完成操作性条件反射行为训练。因此，本研究利用树鼩作为模式动物，采用可变的固定间隔(Fixed interval, FI)自身给药程序进行可卡因习惯化行为训练，选取Cd和  Put 作为关键脑区，比较研究 LTCCs 的两种重要亚型 Cav1.2和Cav1.3在可卡因成瘾行为习惯化中的作用及亚型特异性。结果显示，FI训练后约 60%的树鼩形成可卡因习惯化觅药行为，且与未形成习惯化行为的动物相比，其 Put脑区内的Cav1.2、D1R蛋白含量显著增加，Cav1.3、D2R蛋白含量则显著降低；而其 Cd 脑区内的上述蛋白均无显著变化。提示，参与调控树鼩习惯化行为的脑区是 Put 脑区，Cav1.2与D1R和 Cav1.3 与D2R分别以正向和负向调控这一行为过程。为进一步探索上述关键分子参与调控习惯化是否具有种属特异性，我们利用大鼠进行比对研究，经过同样的FI程序训练，仅有 40%左右的大鼠形成可卡因习惯化行为，且与未形成习惯化行为的动物相比，其 DLS脑区内的 Cav1.2、D1R蛋白含量显著增加，而 DMS 脑区内的Cav1.3、D2R蛋白含量则显著降低。上述结果提示，DLS与DMS 脑区分别以正向和负向协同参与调控大鼠的习惯化行为，而 Put脑区则专一性调控树鼩的可卡因习惯化，说明DS脑区参与调控可卡因习惯化行为具有种属特异性。此外，Cav1.2与D1R、Cav1.3与 D2R蛋白表达的变化趋势始终一致，表明 D1R和D2R可能是通过分别调节下游靶分子Cav1.2和 Cav1.3 从而参与调控可卡因习惯化，这就为进一步深入探索成瘾习惯化行为的调控机制奠定了初步的理论基础。

Habitual drug seeking is the pivot phase in the transition from recreational drug use to compulsive drug use. It is reported that the DA(dopamine) system in the DS(dorsal striatum) plays an important role in the habitual drug seeking. Moreover, LTCCs(L-type voltage dependent calcium channels) plays its part in addictive behaviors working as the downstream targets of DA receptors. However, the function of LTCCs in habitual drug seeking behavior is still unknown. Additionally, the DS of tree shrews can be divided into two function subregions, the Cd(Nucleus caudaatus) and the Put(Putamen) which is similar to human beings and tree shrews are good at conditioni learning. Therefore, this research chooses tree shrew as the model animal and uses changeable FI(Fixed interval) self-administration program in cocaine habitual seeking behavior training. And this study considers the Cd and Put as key regions, comparing the different functions of Cav1.2 and Cav1.3 in the habitual drug seeking. The results show that about 60% of tree shrews form cocaine habitual seeking behavior after FI training and the protein expression levels of Cav1.2 and D1R in the Put are higher, Cav1.3 and D2R are lower in habitual than non-habitual group, whereas there is no differences in the Cd. These results indicate that the Put instead of the Cd is involved in the cocaine habitual seeking behavior and Cav1.2, D1R and Cav1.3, D2R mediate this process in the positive and negative ways respectively. In order to explore further on the species specialty in habitual behaviors, we use rats to compare with and we find that only 40% rats can establish cocaine habitual seeking behavior after the same training process and the protein expression levels of Cav1.2 and D1R of the DLS are higher and Cav1.3 and D2R of the DMS are lower in the habitual than non-habitual group. These results imply that the DLS and DMS mediate this process in the positive and negative ways respectively in rats, but the Put is involved in cocaine habitual behavior in tree shrew specifically, indicating that the DS has species specialty in cocaine habitual seeking behavior. What’s more, Cav1.2 and D1R as well as Cav1.3 and D2R exhibit the same changing tendency in habitual drug seeking behavior in rats and tree shrews, implying that D1R and D2R may mediate Cav1.2 and Cav1.3 respectively in cocaine habitual behaviors which form a preliminary theoretical basis in exploring the mechanism of habitual drug seeking behaviors.