Animal research on addiction is stymied by a translational problem. Despite strides toward understanding circuit and molecular mechanisms of addiction, treatment options remain largely unchanged. This impasse is partly due to limitations in construct and predictive validity of animal models of addiction, which rarely incorporate social factors. To address this gap, Caprioli (the Principal Investigator) and others, developed an operant model to study incubation of methamphetamine (Meth) craving after choice-based voluntary abstinence where rats can choose between Meth or social interaction with a peer. They found that social-abstinence prevented the emergence of incubation of craving, a time-dependent increase in cue-induced drug seeking after abstinence from drug self-administration. Here we propose to investigate the neurobiological underpinnings of this phenomenon.
Based on the evidence that incubation of cocaine and Meth craving after forced abstinence is promoted by the accumulation of Ca2+-permeable AMPARs (CP-AMPARs) in nucleus accumbens (NAc) synapses we formulate our overarching hypothesis as follow: incubation of Meth craving is prevented by social self-administration via an attenuation of CP-AMPARs accumulation. We propose to use biochemical and electrophysiological approaches in two distinct experiments: 1) We will use western blot to determine the subunit composition of AMPARs in the NAc core (Aim 1)
and 2) patch clamp to determine the nature of excitatory transmission onto medium spiny neurons of the NAc (Aim 2) during incubation of Meth craving after forced and voluntary abstinence.
This proposal is innovative on several counts: (i) The demonstration of incubation of Meth craving in human studies provides support for the translational potential of therapeutic targets for relapse uncovered through rodent mechanistic studies. (ii) 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. (iii) To the best of our knowledge there are only 10 papers available on the incubation of Meth craving after forced abstinence, focusing primarily on behavioral pharmacology, neural circuitry and epigenetics; our focus on synaptic transmission is relatively unique and is one of the aspects of our research that will open novel future directions in the therapeutic setting. (iv) Showing that incubation and CP-AMPAR adaptations do not occur in the social voluntary abstinence relative to the forced abstinence condition will represent the first neurobiological correlate underlying the therapeutic efficacy of communal-living setting for individuals recovering from substance abuse. Notably, behavioral therapies such as contingency-management or community-living are the only effective treatment for many Meth addicts because of the absence of approved pharmacological therapies. In turn, this will pave the path to new molecular studies addressing the basis of this dissociation which might be relevant for treatment and therapy. (v) The suggested work combines complex behavior and state-of-the-art electrophysiological and biochemical approaches; the convergence of such approaches to study adult rats is still relatively rare.