Gambling and substance use disorders are highly comorbid. Both clinical populations are impulsive and exhibit risky decision-making. Drug-associated cues have long been known to facilitate habitual drug-seeking, and the salient audiovisual cues embedded within modern gambling products may likewise encourage problem gambling. The dopamine neurons of the ventral tegmental area (VTA) are exquisitely sensitive to drugs of abuse, uncertain rewards, and reward-paired cues, and may therefore be the common neural substrate mediating synergistic features of both disorders. To test this hypothesis, we first gained specific inhibitory control over VTA dopamine neurons by transducing a floxed inhibitory DREADD (AAV5-hSyn-DIO-hM4D(Gi)-mCherry) in rats expressing Cre recombinase in tyrosine hydroxylase neurons. We then trained rats in our cued rat gambling task (crGT), inhibiting dopamine neurons throughout task acquisition and performance, before allowing them to self-administer cocaine in the same diurnal period as crGT sessions. The trajectories of addiction differ in women and men, and the dopamine system may differ functionally across the sexes, therefore we used male and female rats here. We found that inhibition of VTA dopamine neurons decreased cue-induced risky choice and reduced motor impulsivity in males, but surprisingly, enhanced risky decision making in females. Inhibiting VTA dopamine neurons also prevented cocaine-induced changes in decision making in both sexes, but nevertheless drove all animals to consume more cocaine. These findings show that chronic dampening of dopamine signalling can have both protective and deleterious effects on addiction-relevant behaviours, depending on biological sex and dependent variable of interest.

中文翻译：

---

多巴胺神经元控制可卡因的使用，决策和冲动的交集

赌博和滥用毒品的疾病非常普遍。两种临床人群都是冲动的并且具有冒险的决策能力。长期以来，人们都知道与毒品有关的线索可以促进惯常的毒品寻找，而现代赌博产品中嵌入的显着视听线索也可能会鼓励问题赌博。腹侧被盖区（VTA）的多巴胺神经元对滥用药物，不确定的奖励和奖励配对线索非常敏感，因此可能是介导这两种疾病的协同特征的常见神经底物。为了验证这一假设，我们首先通过在酪氨酸羟化酶神经元中表达Cre重组酶的大鼠中转导了浮游性抑制性DREADD（AAV5-hSyn-DIO-hM4D（Gi）-mCherry），从而获得了对VTA多巴胺神经元的特异性抑制控制。然后，我们在提示老鼠赌博任务（crGT）中对老鼠进行了训练，在整个任务的获取和执行过程中都抑制了多巴胺神经元，然后才允许它们在与crGT疗程相同的每日时段内自行服用可卡因。男女成瘾的轨迹有所不同，并且多巴胺系统的功能在性别上可能有所不同，因此我们在这里使用了雄性和雌性大鼠。我们发现，对VTA多巴胺神经元的抑制作用可降低男性引起的提示诱发的风险选择并降低运动冲动，但令人惊讶的是，增强了女性的风险决策。抑制VTA多巴胺神经元还可以阻止可卡因引起的男女决策变化，但是仍然驱使所有动物消耗更多的可卡因。