Kelly Megan, Garner Merrick, Cooper Emily M, Orsini Caitlin A
Department of Psychology, The University of Texas at Austin, Austin TX 78712, United States.
Department of Psychology, The University of Texas at Austin, Austin TX 78712, United States; Department of Neurology, The University of Texas at Austin, Austin TX 78712, United States; Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin TX 78712, United States.
Neurobiol Learn Mem. 2025 Jan;217:108018. doi: 10.1016/j.nlm.2024.108018. Epub 2024 Dec 20.
The ability to choose between options that differ in their risks and rewards depends on brain regions within the mesocorticolimbic circuit and regulation of their activity by neurotransmitter systems. Dopamine neurotransmission in particular plays a critical role in modulating such risk-taking behavior; however, the contribution of other major modulatory neurotransmitters, such as acetylcholine, is not as well-defined, especially for decision making in which the risk associated with more rewarding outcomes involves adverse consequences. Consequently, the goal of the current experiments was to examine how cholinergic signaling influences decision making involving risk of explicit punishment. Male and female rats were trained in a decision-making task in which they chose between a small safe food reward and a larger food reward accompanied by a risk of footshock punishment. After training in this task, the effects of nicotinic and muscarinic agonists and antagonists on risk-taking performance were evaluated. Neither nicotine, a nicotinic receptor agonist, nor mecamylamine, a nicotinic receptor antagonist, affected preference for the risky lever, although mecamylamine did alter latencies to press the risky lever and the percentage of omissions. The muscarinic receptor agonist oxotremorine decreased preference for the large, risky lever; similar effects on behavior were observed with the administration of the muscarinic receptor antagonist scopolamine. Control experiments were therefore conducted in which these same muscarinic receptor ligands were administered prior to testing in a reward discrimination task. These experiments revealed that the effects of oxotremorine and scopolamine on risk taking may be due to altered motivational processes rather than to changes in sensitivity to risk of punishment. Importantly, there were no sex differences in the effects of cholinergic manipulations on preference for the large, risky lever. Collectively, these findings suggest that in both males and females, cholinergic signaling via muscarinic receptors is involved in decision making involving risk of explicit punishment, with a specific role in modulating sensitivity to differences in reward magnitude. Future studies will expand upon this work by exploring whether targeting cholinergic receptors has therapeutic potential for psychiatric conditions in which risk taking is pathologically altered.
在不同风险和回报的选项之间进行选择的能力取决于中脑皮质边缘回路中的脑区以及神经递质系统对其活动的调节。特别是多巴胺神经传递在调节这种冒险行为中起着关键作用；然而，其他主要调节性神经递质（如乙酰胆碱）的作用尚未明确界定，尤其是对于与更有回报结果相关的风险涉及不良后果的决策。因此，当前实验的目的是研究胆碱能信号如何影响涉及明确惩罚风险的决策。雄性和雌性大鼠接受了一项决策任务训练，在该任务中，它们要在少量安全食物奖励和大量食物奖励之间做出选择，而大量食物奖励伴随着足部电击惩罚的风险。在完成该任务的训练后，评估了烟碱型和毒蕈碱型激动剂和拮抗剂对冒险行为表现的影响。烟碱型受体激动剂尼古丁和烟碱型受体拮抗剂美加明均未影响对风险杠杆的偏好，尽管美加明确实改变了按下风险杠杆的潜伏期和遗漏百分比。毒蕈碱型受体激动剂氧化震颤素降低了对大的、有风险杠杆的偏好；给予毒蕈碱型受体拮抗剂东莨菪碱也观察到了类似的行为效应。因此进行了对照实验，在奖励辨别任务测试前给予相同的毒蕈碱型受体配体。这些实验表明，氧化震颤素和东莨菪碱对冒险行为的影响可能是由于动机过程的改变，而不是对惩罚风险敏感性的变化。重要的是，胆碱能操作对大的、有风险杠杆偏好的影响不存在性别差异。总的来说，这些发现表明，在雄性和雌性中，通过毒蕈碱型受体的胆碱能信号参与了涉及明确惩罚风险的决策，在调节对奖励大小差异的敏感性方面具有特定作用。未来的研究将通过探索靶向胆碱能受体是否对冒险行为发生病理性改变的精神疾病具有治疗潜力来扩展这项工作。
