Neurobehavioral Precursors of Compulsive Cocaine Seeking in Dual Frontostriatal Circuits
Background. Only some individuals using drugs recreationally eventually develop a substance use disorder, characterised in part by the rigid engagement in drug foraging behaviour (drug seeking), often maintained in the face of adverse consequences (e.g., is compulsive). The neurobehavioral determinants of this individual vulnerability have not been fully elucidated. Methods. Using a prospective longitudinal study involving 40 male rats we combined a multidimensional characterisation of behavioral traits of vulnerability to stimulant use disorder (impulsivity and stickiness) and resilience (sign tracking and sensation seeking/locomotor reactivity to novelty) with magnetic resonance imaging (MRI) to identify in drug-naïve subjects the structural and functional brain correlates of the later emergence of compulsive drug seeking. We developed a novel behavioral procedure to investigate in subjects with a prolonged history of cocaine seeking under the control of the conditioned reinforcing properties of a drug-paired Pavlovian conditioned stimulus, the individual tendency to persist in drug seeking behavior in the face of punishment in a drug free state. Results. We report that in drug-naïve rats the future tendency to develop compulsive cocaine seeking is characterised by behavioral stickiness-related functional hypoconnectivity between the prefrontal cortex and posterior dorsomedial striatum in combination with impulsivity-related structural alterations in the infralimbic cortex, anterior insula and nucleus accumbens. Conclusions. These findings show that the vulnerability to develop compulsive cocaine seeking behavior stems from pre-existing structural or functional changes in two distinct cortico-striatal systems that underlie deficits in impulse control and goal-directed behavior.
Medical Research Council (MR/N02530X/1)