Dissociation in Conditioned Dopamine Release in the Nucleus Accumbens Core and Shell in Response to Cocaine Cues and during Cocaine-Seeking Behavior in Rats

TLDR

The nucleus accumbens dopaminergic system is known to mediate the reinforcing and locomotor effects of psychostimulants, yet the role of conditioned dopamine release during drug‑seeking remains unclear. This study examined how a cocaine‑associated cue and its noncontingent presentation affect dopamine release in the core and shell of the nucleus accumbens during drug‑seeking behavior. Rats self‑administered cocaine paired with a light cue under a continuous schedule that was later shifted to a second‑order schedule, and microdialysis measured dopamine responses to noncontingent cue and tone presentations before and after a 90‑minute drug‑seeking period. Cocaine self‑administration raised dopamine in both core and shell, a noncontingent cue increased dopamine only in the core, and dopamine remained unchanged during prolonged cue‑driven drug‑seeking, indicating selective mesolimbic activation by drug‑associated stimuli.

Abstract

The dopaminergic innervation of the nucleus accumbens is generally agreed to mediate the primary reinforcing and locomotor effects of psychostimulants, but there is less consensus on conditioned dopamine (DA) release during drug-seeking behavior. We investigated the neurochemical correlates of drug-seeking behavior under the control of a drug-associated cue [a light conditioned stimulus (CS+)] and to noncontingent presentations of the CS+ in the core and shell subregions of the nucleus accumbens. Rats self-administered cocaine under a continuous reinforcement schedule in which a response on one of two identical levers led to an intravenous cocaine infusion (0.25 mg/infusion) and a 20 sec light CS+. Response requirements for cocaine and the CS+ were then progressively increased until stable responding was established under a second-order schedule of reinforcement. During microdialysis, rats were presented noncontingently with a set of 10 sec CS+ and neutral tone stimuli (CS−) before and after a 90 min period during which they responded for cocaine under a second-order schedule. Results showed the following: (1) nucleus accumbens DA increased in both the core and shell during intravenous cocaine self-administration; (2) noncontingent presentations of a cocaine-associated CS+ led to increased DA release selectively in the nucleus accumbens core; and (3) extracellular DA levels were unaltered in both core and shell during a protracted period of drug-seeking behavior under the control of the same cocaine-associated cue. These results indicate that the mesolimbic dopamine system is activated after exposure to drug-associated stimuli under specific conditions.