The impact of COMT inhibition on behaviour and neural activity, and its modulation by genotype and acute stress.

多巴胺是一种化学信使，对许多大脑功能都很重要，包括记忆、情感和动机。这些功能需要维持在适当的水平才能达到最佳状态，正如在各种脑部疾病中看到的那样，过多或过少都是有害的。COMT是一种酶，一种生物催化剂，可以破坏多巴胺。因此，多巴胺水平受到COMT活动的影响。有些人的基因变异使他们的COMT活性低，而另一些人的基因变异使他们的COMT活性高。阻止COMT发挥作用的药物（“COMT抑制剂”）也会降低COMT的活性。我们和其他人已经证明，由于COMT对多巴胺的影响，这两种对COMT活性的影响（来自基因和药物）都会影响记忆和人们的冒险行为。其他研究表明，COMT也会影响人们的情绪状态。这项拨款旨在帮助我们更好地了解COMT抑制剂药物治疗精神疾病的潜力，其中许多包括记忆、冒险和控制情绪的问题。首先，我们将测量药物和基因变异如何相互作用，影响人们的情绪，以及他们如何处理风险和回报。其次，有证据表明，COMT的基因变异会影响人们应对压力的能力，而压力会对记忆和情绪状态产生负面影响。因此，我们将研究这种关系是如何受到COMT抑制剂的影响的，以及在压力情况下和之后大脑中究竟发生了什么。这些研究的结果将帮助我们更好地了解COMT抑制剂作为精神疾病有用药物的潜力，以及一个人的基因构成是否会影响他们对这些药物的反应。该研究还将提供有关COMT如何调节多巴胺及其在脑部疾病中的异常功能的更广泛价值的信息。

Dopamine is a chemical messenger important for many brain functions, including memory, emotion and motivation. It needs to be maintained at the right level for these functions to be optimal, and either too much or too little is harmful, as seen in various brain diseases. COMT is an enzyme, a biological catalyst, which destroys dopamine. As a result, dopamine levels are influenced by the activity of COMT. Some people have a genetic variant that gives them low COMT activity, whilst others have a variant that leads to high activity. COMT's activity can also be reduced by drugs which prevent it working (a 'COMT inhibitor'). We and others have shown that both of these influences on COMT activity (from the gene, and from the drug) can affect memory and how people take risks, because of COMT's effects on dopamine. Other studies suggest that COMT also affects people's emotional state. This grant aims to help us understand better the potential of COMT inhibitor drugs for treating psychiatric disorders, many of which include problems with memory, risk taking, and controlling emotion. First, we will measure how the drug and the genetic variant interact to affect people's emotions and how they deal with risk and reward. Second, there is evidence that the genetic variation in COMT affects how well people cope with stress, and stress can have negative effects on memory and emotional state. We will therefore study how this relationship is affected by the COMT inhibitor and what exactly is going on in the brain during and after a stressful situation. The results of these studies will help us understand much better the potential of COMT inhibitors as useful drugs for psychiatric disorders, and whether a person's genetic make-up affects how they respond to them. The research will also provide information of wider value about how COMT regulates dopamine and its abnormal function in brain diseases.