Data Sheet 1_Higher levels of D2R and D3R in the frontal–striatal regions are associated with reduced perseverative reward seeking after opioid abstinence.xlsx

IntroductionThe lower levels of dopamine D2 receptor (D2R) in the striatum and the heightened levels of dopamine D2 receptor (D3R) in the midbrain have been linked to impulsive behavior and risky decision-making associated with drug dependence. While D3R has been considered a potential target for treating drug dependence, the connection between D3R in the prefrontal-striatal regions and maladaptive drug-related behaviors remains poorly understood.
MethodsThis study utilized two high-cost tasks to investigate perseverative reward seeking, specifically conflict-based approaching behavior and persistent responding behavior under a progesterone receptor (PR) procedure. Additionally, D2R and D3R levels in the medial prefrontal cortex (mPFC) and striatum were examined through Western blotting.
ResultsAfter each task, male rats were divided into two subpopulations: high-approaching vs. low-approaching and high-responding vs. low-responding. Rats treated with morphine (MOR) exhibited a 3 fold increase in the likelihood of developing high-approaching or high-responding behaviors compared to drug-naïve rats. D2R expression was higher in the ventral striatum of morphine-treated, low-approaching rats than high-approaching rats, negatively correlating with approaching behaviors within the morphine-exposed group. After six consecutive PR sessions, D3R levels in the dorsal striatum differed significantly between morphine-treated, low-responding rats and morphine-treated, high-responding rats, negatively correlating with responding behaviors within the morphine-exposed group. An intriguing finding was the non-linear relationships, resembling an inverted U shape, observed between the level of D3R in the mPFC and reward-seeking behaviors, as revealed by both tasks.
DiscussionThe elevated or relatively higher levels of D2R and D3R in the frontal-striatal regions may serve as protective factors for individuals abstaining from opioids, enabling them to control their reward-seeking behavior better.

引言
纹状体中的多巴胺D2受体（dopamine D2 receptor, D2R）水平降低、中脑内的多巴胺D3受体（dopamine D3 receptor, D3R）水平升高，均与药物依赖相关的冲动行为及风险决策存在关联。尽管D3R已被视为治疗药物依赖的潜在靶点，但前额叶-纹状体区域的D3R与适应不良的药物相关行为之间的关联仍有待阐明。

方法
本研究采用两项高代价任务，探究持续性奖赏寻求行为，具体包括基于冲突的趋近行为以及孕激素受体（progesterone receptor, PR）实验范式下的持续性反应行为。此外，通过蛋白质印迹法（Western blotting）检测内侧前额叶皮层（medial prefrontal cortex, mPFC）与纹状体中的D2R及D3R表达水平。

结果
每项任务结束后，将雄性大鼠分为两个亚群：高趋近组与低趋近组，以及高反应组与低反应组。与未暴露于药物的大鼠相比，吗啡（MOR）处理组大鼠出现高趋近或高反应行为的概率升高3倍。在吗啡处理组中，低趋近大鼠的腹侧纹状体D2R表达水平高于高趋近大鼠，且该表达水平与该给药组内的趋近行为呈负相关。连续完成6次PR实验回合后，吗啡处理的低反应大鼠与高反应大鼠的背侧纹状体D3R水平存在显著差异，且该水平与该给药组内的反应行为呈负相关。两项任务均显示，内侧前额叶皮层的D3R水平与奖赏寻求行为之间存在类似倒U型的非线性关联，这一发现颇具研究价值。

讨论
前额叶-纹状体区域中D2R与D3R的升高或相对较高水平，或可成为戒断阿片类药物个体的保护因子，使其能够更好地控制奖赏寻求行为。