P.2.030 - Investigating the neural mechanisms of compulsive reward seeking in rats

Abstract

Substance addiction is a chronic relapsing brain disorder, characterised by loss of control over substance intake. Despite a high prevalence and enormous costs to society, treatment options for addiction are limited in number and efficacy. The neural underpinnings of loss of control are poorly understood, while restoring control over substance intake is a promising treatment strategy for addictive disorders. Loss of control over substance intake has been operationalised as resistance to adversity in rodent models, since people suffering from addiction continue substance use despite their awareness of its negative consequences [1,2]. Importantly, the negative consequences of continued substance use are often unpredictable in humans. Therefore, the primary aim of this study was to develop a novel paradigm to study loss of control over substance use in rats that captures these aspects. This novel model allows us to measure reward seeking under threat of adversity in a within-subjects design. Outbred Lister-Hooded rats were trained to lever press for a reward (i.e. alcohol or sucrose). Subsequently, they were confronted with a tone cue during reward-seeking that functions as a warning sign since lever pressing during tone presentation results in a probabilistic footshock. We observed reduced responding in sessions during which the tone was presented compared to baseline sessions without a tone. This was observed when rats were lever pressing for either alcohol or sucrose. Also, the amount of responding in sessions in which the tone was presented was stable over time, allowing for repeated testing and within-subject comparisons. By increasing the shock intensity over sessions, we found that the optimal shock intensity at which most rats showed suppression of seeking was 0.25 mA. In ongoing experiments, we are applying this novel paradigm to study the neural underpinnings of loss of control. Previous studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control promotes compulsive substance use [3-5]. More specifically, dysfunction of the prelimbic prefrontal cortex (PrL) is thought to contribute to control over substance intake. Therefore, the secondary aim of this study was to test the hypothesis that PrL activity is necessary to maintain control over reward seeking behaviour under threat of adversity. We used chemogenetic inactivation of the PrL using designer receptors exclusively activated by designer drugs (DREADD) by bilaterally infusing an adeno-associated DREADD expressing virus (AAV5-CamKII-hM4D-mCherry) in the PrL. In initial experiments, we observed no significant effect of DREADD ligand clozapine-N-oxide (CNO) on sucrose seeking under threat of adversity. Taken together, we successfully implemented a novel paradigm that captures behavioural control over substance seeking in the face of adversity. It allows for within-subject comparisons and repetitive examination, which is essential for chemogenetic and pharmacological studies. Therefore, this model enables us to unravel the neurobiological mechanisms involved in loss of control over substance use. In ongoing experiments, we apply this model to determine the involvement of the PrL on alcohol seeking behaviour in this task.