Role of the lateral habenula in impulsive behavior

在过去的几年里，我们在大鼠的冲动寻求药物行为模型上取得了很大进展，在该模型中，训练成自我给予心理刺激剂可卡因的大鼠随后被训练成当缺乏刺激(亮起)表明药物不可用时抑制对药物的反应(NoGo期)。因此，大鼠了解到，只有当刺激存在(GO)时，可卡因强化才可用，并且它们学会在这段时间内抑制反应。然后，我们证明了在NoGo时期，抑制被称为外侧缰核(LHb)的大脑区域可以阻止这种反应抑制，后来，抑制毒碱样乙酰胆碱受体(MAChRs)也可以阻止这种反应抑制。由于这些结果，我们扩大了这些研究，以确定乙酰胆碱(ACh)在LHb中作用的细胞机制，并研究内源性大麻素(ECB)系统在这一反应中的作用。到目前为止，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，而大麻植物中发现的精神活性分子Delta-9-THC激活LHb大麻素1型受体(CB1Rs)，增加了冲动的可卡因寻找行为。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，如注意力缺陷多动障碍(ADHD)和强迫症(OCD)。此外，士兵和平民在创伤性脑损伤(TBI)后也经常出现冲动行为，因此与急性脑损伤有关。我们最近发表了我们的工作，发现LHb中的mAChRs与寻求可卡因相关的冲动行为有关，目前我们正在研究LHb和这个系统在非药物成瘾大鼠冲动行为中的作用。

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.