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

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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.