Role of the lateral habenula in impulsive behavior

在过去的几年里，我们在大鼠的冲动药物寻找行为模型上取得了很大的进展，在这个模型中，经过训练的大鼠可以自我使用精神兴奋剂可卡因，随后，当没有刺激（灯亮）表明它不可用时，我们会训练它们保留对药物的反应。因此，大鼠知道可卡因强化只有在刺激存在时才有效（Go），并且它们学会在此期间保留反应。然后，我们证明，在NoGo期间，被称为外侧缰（LHb）的大脑区域的抑制阻止了这种反应抑制，后来，毒菌碱乙酰胆碱受体（mAChRs）的抑制也阻止了这种反应抑制。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中的作用的细胞机制，并研究了内源性大麻素（eCB）系统在这种反应中的作用。迄今为止，我们的研究表明，内源性ACh通过刺激M2 mAChR亚型来促进LHb的冲动控制，并且大麻植物中发现的精神活性分子-9-四氢大麻酚（delta-9-THC）激活LHb大麻素1型受体（CB1Rs），增加冲动的可卡因寻求行为。这些研究很重要，因为冲动行为是戒除药物使用的主要障碍，因为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）后也经常观察到冲动行为，因此与急性脑损伤有关。在过去的财政年度，我们发表了我们的工作，暗示LHb中的machr与可卡因寻求的冲动行为有关，我们目前正在研究LHb和该系统在非药物成瘾模型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. In the past fiscal year we have 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.