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

内感受（interoception），即感知身体内部状态的能力，在适应和适应不良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，例如在强迫症中观察到的作用，其中一种疾病模型是药物成瘾。因此，成瘾的一个研究不足的特征是内感受功能障碍和相关的洞察力障碍，表现在大脑的几个整合水平上，从感觉处理到情绪调节和元认知。药物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相关物岛叶皮层。此外，吸烟者的岛叶皮层损伤导致戒烟的可能性增加。在临床前啮齿动物模型中，已显示可卡因甲碘化物（一种不能到达大脑的可卡因类似物）可维持最初由可卡因加强的仪器反应，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加强特性。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，有助于药物成瘾的行为特征的发展，证据是穷人的潜在的分子和细胞机制。阿片类药物的中枢与外周（因此是内感受性）阿片能机制在多大程度上有助于内感受性线索的形成和阿片类药物成瘾相关行为的发展仍有待确定。本研究旨在探讨外周阿片系统在内感受中的作用及其对个体发展为药物成瘾的易感性的贡献。我们将结合联合收割机药物成瘾的啮齿动物模型开发和完善的贝林实验室与相关性和因果关系的询问神经网络的行为大鼠和死后调查的分子相关性在神经和电路水平。我们将初步调查，如果大鼠可以区分海洛因从车辆或不存在的外周阿片类药物拮抗剂在药物歧视任务。提示外周阿片受体在海洛因内感受性信息传递中的作用。随后，使用自我管理的范例，我们将测试如果外周阿片受体的封锁影响海洛因的强化性能。这将意味着预先注射外周阿片受体的选择性拮抗剂治疗大鼠，并观察其对获得自我管理和失去对海洛因摄入的控制的影响。此外，我们将采用更复杂的自我管理模式，看看在药物准备行为，如强迫性寻求方面。接下来，我们计划使用纤维光度法来研究在寻求海洛因的行为在岛叶皮层的细胞动力学，从而建立神经相关的行为实验的补充。此外，我们的目标是使用光遗传学选择性地操纵神经回路，以功能性地研究回路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影响的生物行为标志物，并更好地了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.