Preclinical research in addiction is stymied by a translational problem. This impasse is due to limitations in the construct and predictive validity of animal models of addiction, which rarely incorporate social factors. In humans, adverse social interactions and social isolation promote drug self-administration and relapse, while prosocial interactions has a protective role. The cellular and circuit mechanisms underlying the protective effect of volitional social interaction on drug addiction are unknown. To address this gap in knowledge, we have recently developed an operant social-based voluntary abstinence (SVA) procedure and found that rats with a history of social interaction and methamphetamine (Meth) self-administration (SA) strongly prefer social interaction over Meth infusions. SVA also prevented the emergence of Meth craving and our preliminary results suggests that is doing so by preventing the accumulation of Calcium-permeable AMPA receptors (CP-AMPARs) in the nucleus accumbens (NAc). The present proposal is relevant to Sapienza missions (reduce the burden of illnesses), because it explores the neurobiological mechanisms associated to the protective effect of social interaction on Meth craving. Notably, the animal model is homologous to the clinical scenario of the social community reinforcement approach, a behavioral strategy largely employed in the context of drug relapse prevention.
Based on our preliminary data and the literature, in Aim 1 we contrast the forced and SVA animal models of drug craving and investigate similarities and differences in the synaptic adaptations underlying Meth craving occurring in the NAc. Next, in Aim 2 we propose to explore the paraventricular nucleus (PVN) --> NAc projections (and the role of oxytocin) on the protective effect of social-based voluntary abstinence on Meth craving.
This proposal is innovative on several counts: (i) The incubation model provides a unique approach that specifically focuses on relapse which occur in humans. Traditionally relapse studies have been conducted with reinstatement models that rely on extinction training. These models are not well suited to understand the plasticity that maintains drug craving because extinction training itself induces plasticity in the reward circuitry. Moreover, drug addicts do not undergo extinction training as part of their treatment. (ii) At present, there are only few papers available on the incubation of Meth craving after forced abstinence, focusing primarily on behavioral pharmacology and epigenetics; our focus on brain circuits and synaptic transmission is relatively unique and is one of the aspects of our research that will open novel future directions in the therapeutic setting. (iii) Showing that incubation and CP-AMPARs adaptations are less persistent (or not expressed at all) in the SVA relative to the forced abstinence condition will represent the first neurobiological correlate underlying the therapeutic efficacy of CRA, the only effective treatment for many Meth addicts. In turn, this will pave the path to new molecular studies addressing the basis of this dissociation which might be extremely relevant for treatment and therapy. (iv) The suggested work combines complex behavior, electrophysiological and biochemical approaches; the convergence of such approaches to study adult rats is still relatively rare.
Notably: Dendritic translation is critical for synaptic plasticity and is altered in disease states, however relatively little is known on the persistent alterations in translation in the NAc (or other brain regions). Even if our hypotheses will not be confirmed, our experiments will shed light on the function of NAc-MSNs both under normal conditions, after Meth exposure or after social interactions.
Social and economic impact. While this project focuses mainly on physiological aspects and do not directly address the human condition, it will provide a strong framework to interpret the profound social dysregulation present in drug addicts and plan new tailored therapeutic strategies.
In order to improve the advancement of research, data collected from experiments specified in this proposal will be published and available through PMC. We will choose an open access format, now embraced by publishers, to facilitate the spread of the findings. Given the quality of the proposal, the quality of the support offered by Sapienza and the quality of the collaborators we are confident that the publications will have a large impact on the scientific community by: (1) enabling novel research on new combined behavioral/pharmacological treatment strategies (2) consequences of Meth-induced synaptic plasticity for NAc function (3) facilitating the implementation of CRA into a multisystemic therapy. In addition, collected data will be presented at several oral presentations and poster sessions, facilitating dissemination of knowledge to the experts in our field.
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