Investigating the role of interoceptive mechanisms in the development of biobehavioural markers of drug addiction.

内感受（感知身体内部状态的能力）在适应和不适应行为中的作用仍然难以捉摸。本研究项目的目的是更好地了解外周阿片系统在内感受中的作用及其在适应不良行为中的作用，例如在强迫性中观察到的行为，其疾病模型是药物成瘾。因此，成瘾的一个未被研究的特征是内感受功能障碍和相关的洞察力损害，表现在大脑的几个整合层面，从感觉处理到情绪调节和元认知。吸毒成瘾者在成本效益决策任务中表现出缺陷，这些任务依赖于内感受机制及其神经关联——岛叶皮层。此外，吸烟者的岛叶皮层病变导致戒烟的可能性增加。在临床前啮齿类动物模型中，可卡因甲氧基醚（一种不能到达大脑的可卡因类似物）已被证明维持最初由可卡因增强的工具性反应，这表明可卡因的内感受特性在有可卡因自我给药史的个体中获得增强特性。尽管有令人信服的证据表明，内感受及其神经基质岛叶皮层有助于药物成瘾行为特征的发展，但关于潜在的分子和细胞机制的证据很少。阿片类药物的中枢与外周（因此是内感受性）阿片类药物能机制在多大程度上有助于形成内感受性线索和阿片类药物成瘾相关行为的发展，仍有待确定。该项目的目的是调查外周阿片系统在内感受中的作用及其对个体易患药物成瘾的贡献。我们将结合Belin实验室开发和完善的啮齿动物药物成瘾模型，对行为老鼠的神经网络进行相关性和因果性调查，并在神经和电路水平上对分子相关性进行死后调查。在药物鉴别任务中，我们将初步研究大鼠是否能够在有或没有外周阿片拮抗剂的情况下区分海洛因和运载工具。这将提示外周阿片受体在海洛因内感受信息传递中的作用。随后，使用自我给药范例，我们将测试外周阿片受体的阻断是否会影响海洛因的强化特性。这意味着预先给大鼠注射选择性外周阿片受体拮抗剂，观察它们对获得自我给药和失去对海洛因摄入控制的影响。此外，我们将采用更复杂的自我管理范式来研究药物准备行为的各个方面，如强迫性寻求。接下来，我们计划使用纤维光度法来研究海洛因寻求行为期间岛叶皮层的细胞动力学；从而建立神经关联，补充行为实验。此外，我们的目标是利用光遗传学选择性地操纵神经回路来研究回路的功能，并潜在地研究突触机制。这将使我们能够识别易受药物滥用潜力影响的生物行为标记，并更好地理解内感受在这一过程中所起的作用。

The role of interoception, the ability to sense the internal state of the body, in adaptive and maladaptive behaviour remains elusive. The purpose of the present research project, is better to understand the role of the peripheral opiate systems in interoception and its role in maladaptive behaviours, such as those observed in compulsivity, a disease model of which is drug addiction. Thus, an under-investigated characteristic of addiction is the dysfunction in interoception and the associated impairment in insight, manifested at several levels of integration of the brain, from sensory processing to emotion regulation and meta-cognition. Drug addicts display deficits in cost-benefit decision making tasks which rely on interoceptive mechanisms and its neural correlate, the insular cortex. Furthermore lesions of the insular cortex in smokers have led to an increased likelihood of cessation of smoking. In preclinical rodent models, cocaine methiodide (an analogue of cocaine that does not reach the brain) has been shown to maintain instrumental responses initially reinforced by cocaine demonstrating that the interoceptive properties of cocaine acquire reinforcing properties in individuals with a history of cocaine self-administration. Despite the compelling evidence showing that interoception and its neural substrate, the insular cortex, contribute to the development of behavioural characteristics of drug addiction, evidence is poor on the underlying molecular and cellular mechanisms. The extent to which central versus peripheral (hence interoceptive) opioidergic mechanisms of opiates contribute to the formation of interoceptive cues and development of addiction-related behaviours for opiates remains to be established. The aim of this project is to investigate the role of the peripheral opiate system in interoception and its contribution to the individual vulnerability to develop drug addiction. We will combine rodent models of drug addiction developed and refined in the Belin lab with correlational and causal interrogation of neural networks in behaving rats and post-mortem investigations of molecular correlates at the neural and circuit level. We will initially investigate if rats can discriminate heroin from a vehicle with or without the presence of a peripheral opioid antagonist in a drug discrimination task. This will indicate the role peripheral opioid receptors play in the relaying of interoceptive information of heroin. Subsequently, using a self-administration paradigm, we will test if the blockade of peripheral opioid receptors affects the reinforcing properties of heroin. This will mean pre-treating rats with injections of selective antagonists of peripheral opioid receptors and looking at their effects on acquisition of self-administration and loss of control over heroin intake. Furthermore we will employ more complex self-administration paradigms to look at facets of drug-preparatory behaviour such as compulsive seeking. Next we plan to use fibre photometry to investigate the cellular dynamics in the insular cortex during heroin-seeking behaviour; thus establishing neural correlates complementing the behavioural experiments. Furthermore, we aim to selectively manipulate neural circuits using optogenetics to functionally study the circuits and potentially investigate synaptic mechanisms. This will enable us to identify biobehavioural markers of the vulnerability to the abuse potential of drugs and better understand the role interoception plays in this process.