Cortico-striatal synaptic plasticity underlying compulsive reward seeking

Abstract Loss of control over drug intake and persistent drug-seeking despite negative consequences define addiction. Increase dopamine levels in the mesolimbic system may constitute the initial trigger. Optogenetic self-stimulation of VTA DA neurons (oDASS) has thus been proposed as an addiction model. Indeed, lever pressing to turn on a laser aimed at ChR2 expressing DA neurons is strongly reinforcing. Clinical observations indicate that drug-seeking even with the risk of harmful consequences occurs only in a fraction of users, with chronic drug consumption. Here, mice carried out a seek-take chain in order to selectively study compulsive seeking behavior. Once fully established, a probabilistic punishment of the seeking lever led to the emergence of two classes of mice; those that persevered and those that renounced oDASS. Ex vivo characterization of three distinct cortico-striatal streams demonstrated a selective potentiation of excitatory synapses of the orbito-frontal cortex (OFC) to dorsal striatum projection in persevering mice. Taken together, our data indicate a gain-of-function of OFC striatal control in compulsive oDASS.