化学遗传学失活眶额皮层可减少雄性和雌性 Wistar 大鼠线索诱导的乙醇和蔗糖觅药复吸。
Chemogenetic Inactivation of Orbitofrontal Cortex Decreases Cue-induced Reinstatement of Ethanol and Sucrose Seeking in Male and Female Wistar Rats.
机构信息
From the, Neuroscience and Behavior Graduate Program (JSH, DEM), University of Massachusetts Amherst, Amherst, Massachusetts, USA.
Department of Psychological and Brain Sciences (ANB, TR, JDT, DEM), University of Massachusetts Amherst, Amherst, Massachusetts, USA.
出版信息
Alcohol Clin Exp Res. 2020 Sep;44(9):1769-1782. doi: 10.1111/acer.14407. Epub 2020 Jul 26.
BACKGROUND
The orbitofrontal cortex (OFC) encodes internal representations of outcomes and subjective value to facilitate flexible reward seeking. OFC activation is associated with drug seeking in both human subjects and animal models. OFC plays a role in alcohol use, but studies in animal models have produced conflicting results with some showing decreased seeking after OFC inactivation but others showing increased seeking or no changes. In part, this may be due to the different measures of alcohol seeking used (e.g., homecage drinking vs. operant seeking).
METHODS
We characterized the impact of transient inactivation of OFC (primarily lateral and, to a lesser extent, ventral subregions) using inhibitory hM4Di designer receptors exclusively activated by designer drugs (DREADDs). OFC neurons were transiently inhibited during 10% and 20% alcohol (ethanol, EtOH) and sucrose homecage consumption, fixed ratio (FR1) operant self-administration, and cue-induced reinstatement of either 10% EtOH or sucrose in male and female rats.
RESULTS
OFC inactivation did not affect sucrose or EtOH consumption in the homecage, nor did it influence seeking or consumption under FR1 operant conditions. In contrast, OFC inactivation suppressed cued-induced reinstatement for both EtOH and sucrose in both male and female rats.
CONCLUSIONS
Our results are aligned with previous work indicating a selective suppressive effect of OFC inactivation on reinstatement for alcohol and other drugs of abuse. They extend these findings to demonstrate no effect on homecage consumption or FR1 seeking as well as showing an impact of sucrose reinstatement. These data indicate that OFC plays a uniquely important role when reward seeking is driven by associations between external stimuli and internal representations of reward value, both for natural and drug rewards. They further implicate the OFC as a key structure driving relapse-associated seeking and potentially contributing to alcohol use disorder and other diseases of compulsive reward seeking.
背景
眶额皮层（OFC）对结果和主观价值进行内部编码，以促进灵活的奖励寻求。OFC 的激活与人类和动物模型中的药物寻求有关。OFC 在酒精使用中起作用，但动物模型的研究结果相互矛盾，一些研究显示 OFC 失活后寻求减少，但其他研究显示寻求增加或没有变化。部分原因可能是使用了不同的酒精寻求测量方法（例如，自噬饮酒与操作性寻求）。
方法
我们使用专门通过设计药物（DREADDs）激活的抑制性 hM4Di 设计受体，描述了 OFC（主要是外侧，其次是腹侧亚区）短暂失活的影响。OFC 神经元在 10%和 20%酒精（乙醇，EtOH）和蔗糖自噬消耗、固定比例（FR1）操作性自我给药以及 10% EtOH 或蔗糖线索诱导的复吸期间被短暂抑制，在雄性和雌性大鼠中。
结果
OFC 失活不影响蔗糖或 EtOH 在自噬中的消耗，也不影响 FR1 操作性条件下的寻求或消耗。相比之下，OFC 失活抑制了雄性和雌性大鼠的乙醇和蔗糖线索诱导的复吸。
结论
我们的结果与以前的工作一致，表明 OFC 失活对酒精和其他滥用药物的复吸有选择性抑制作用。它们扩展了这些发现，表明对自噬消耗或 FR1 寻求没有影响，并显示了蔗糖复吸的影响。这些数据表明，当奖励寻求由外部刺激和奖励价值的内部表示之间的关联驱动时，OFC 发挥着独特而重要的作用，无论是对自然奖励还是药物奖励。它们进一步暗示 OFC 是驱动与复发相关的寻求的关键结构，并可能导致酒精使用障碍和其他强迫性奖励寻求疾病。
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