Cued Reinstatement of Cocaine but Not Sucrose Seeking Is Dependent on Dopamine Signaling in Prelimbic Cortex and Is Associated with Recruitment of Prelimbic Neurons That Project to Contralateral Nucleus Accumbens Core.

Background: Drug cues recruit prelimbic cortex neurons that project to ipsilateral nucleus accumbens core. However, it is not known if the same is true for prelimbic cortex projections that decussate to innervate contralateral nucleus accumbens core. Further, a role for prelimbic cortex dopamine signaling in cued reinstatement of cocaine seeking has not been shown.

Dorsal Hippocampus Drives Context-Induced Cocaine Seeking via Inputs to Lateral Septum.

Lateral septum (LS) has re-emerged as an important structure in reward and addiction; however, LS afferents that drive addiction behaviors are unknown. Here, we used a modified self-administration/reinstatement procedure combined with anatomical, pharmacological, and chemogenetic techniques to characterize LS, and hippocampal inputs to LS, in two established triggers of drug relapse-context- and cue-induced reinstatement of cocaine seeking. We found that inactivation of LS neurons attenuated both context- and cue-induced reinstatement of cocaine seeking.

Prelimbic to Accumbens Core Pathway Is Recruited in a Dopamine-Dependent Manner to Drive Cued Reinstatement of Cocaine Seeking.

Unlabelled: Glutamate inputs to nucleus accumbens (NAc) facilitate conditioned drug-seeking behavior and primarily originate from medial prefrontal cortex (mPFC), basolateral amygdala (BLA), and ventral subiculum of the hippocampus (vSub). These regions express Fos (a marker of neural activity) during cue-induced reinstatement of cocaine seeking, but only subpopulations of neurons within these regions drive drug seeking. One way to identify and functionally distinguish neural subpopulations activated during drug-seeking is to examine their projection targets.

Differential roles of medial prefrontal subregions in the regulation of drug seeking.

The prefrontal cortex plays an important role in shaping cognition and behavior. Many studies have shown that medial prefrontal cortex (mPFC) plays a key role in seeking, extinction, and reinstatement of cocaine seeking in rodent models of relapse. Subregions of mPFC appear to play distinct roles in these behaviors, such that the prelimbic cortex (PL) is proposed to drive cocaine seeking and the infralimbic cortex (IL) is proposed to suppress cocaine seeking after extinction.

Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking.

The ventral pallidum is centrally positioned within mesocorticolimbic reward circuits, and its dense projection to the ventral tegmental area (VTA) regulates neuronal activity there. However, the ventral pallidum is a heterogeneous structure, and how this complexity affects its role within wider reward circuits is unclear. We found that projections to VTA from the rostral ventral pallidum (RVP), but not the caudal ventral pallidum (CVP), were robustly Fos activated during cue-induced reinstatement of cocaine seeking--a rat model of relapse in addiction.