Role of the lateral habenula in impulsive behavior

在过去的几年中，我们在大鼠中使用冲动寻药的行为模型取得了很大进展，在该模型中，经过训练的大鼠自我施用精神兴奋剂可卡因，随后被训练为在没有刺激（灯亮）时表明它不可用（NoGo时期）时抑制对药物的反应。 因此，老鼠知道只有当刺激存在时（Go）才可以增强可卡因，并且他们学会在此期间抑制反应。 然后我们证明，在 NoGo 期间抑制称为外侧缰核 (LHb) 的大脑区域可防止这种反应抑制，随后，抑制毒蕈碱乙酰胆碱受体 (mAChR) 也可防止这种反应抑制。 由于这些结果，我们扩大了这些研究，以定义 LHb 中乙酰胆碱 (ACh) 作用的细胞机制，并研究了内源性大麻素 (eCB) 系统在此反应中的作用。 迄今为止，我们的工作表明，内源性 ACh 通过刺激 M2 mAChR 亚型来促进 LHb 的冲动控制，并且通过 delta-9-THC（大麻植物中发现的精神活性分子）激活 LHb 大麻素 1 型受体 (CB1R)，增加冲动性可卡因寻求行为。 这些研究很重要，因为冲动行为是戒毒的主要障碍，而且冲动与许多精神疾病有关，例如注意力缺陷多动障碍（ADHD）和强迫症（OCD）。此外，在士兵和平民中，在创伤性脑损伤（TBI）后也经常观察到冲动行为，因此与急性脑损伤有关。 我们最近发表了我们的研究成果，表明 LHb 中的 mAChR 与寻求可卡因相关的冲动行为有关，并且我们目前正在研究 LHb 和该系统在大鼠非药物成瘾模型的冲动行为中的作用。

In the past few years we have made much progress using a behavior model of impulsive drug seeking in rats in which rats trained to self-administer the psychostimulant cocaine are subsequently trained to withhold responding for the drug when the absence of a stimulus (light on) indicates that it is not available (NoGo period). Thus, the rats learn that cocaine reinforcement is only available when the stimulus is present (Go) and they learn to withhold the response during this period. We then demonstrated that inhibition of a brain region known as the lateral habenula (LHb) prevented this response inhibition during NoGo periods and later, that inhibition of muscarinic acetylcholine receptors (mAChRs) also prevented this response inhibition. Because of these results we have expanded these studies to define cellular mechanisms of acetylcholine (ACh) action in the LHb, as well as investigated a role for the endogenous cannabinoid (eCB) system in this response. To date, our work shows that endogenous ACh acts to facilitate impulse control in the LHb by stimulating an M2 mAChR subtype, and that activation of LHb cannabinoid type 1 receptors (CB1Rs) by delta-9-THC, the psychoactive molecule found in the cannabis plant, increases impulsive cocaine seeking behavior. These studies are important because impulsive behavior is a major impediment to abstinence from drug use and because impulsivity is linked to many psychiatric conditions, such as attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Moreover, impulsive behavior is also often observed following traumatic brain injury (TBI) in both soldiers and civilians, and therefore is relevant to acute brain damage. We have recently published our work implicating mAChRs in the LHb in impulsive behavior relating to cocaine seeking, and we are currently investigating the role of the LHb and this system in impulsive behavior in non-drug addiction models in rats.