Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior

Abstract

The relative contributions of glutamate and dopamine within the nucleus accumbens to cocaine-induced reinstatement of drug-seeking behavior were assessed. When extinguished cocaine self-administration behavior was reinstated by a cocaine-priming injection, extracellular levels of both dopamine and glutamate were elevated in the nucleus accumbens. However, when yoked cocaine or saline control subjects were administered a cocaine prime, only dopamine levels were elevated. Thus, glutamate increased only when animals reinstated lever pressing, whereas dopamine increased regardless of behavior. The increase in glutamate was not accounted for simply by the act of lever pressing itself, because the cocaine self-administration group still demonstrated elevated glutamate when the levers were withdrawn from the operant chamber. Moreover, reinstatement of lever pressing for food did not elevate extracellular glutamate, indicating that increased glutamate initiated responding selectively for a drug reinforcement. The source of glutamate was shown to be glutamatergic afferents from the prefrontal cortex because inhibiting prefrontal cortical glutamatergic neurons that project to the accumbens prevented the rise in glutamate. Together, these data demonstrate that activation of a glutamatergic projection from the prefrontal cortex to the nucleus accumbens underlies cocaine-primed reinstatement of drug-seeking behavior.

Fig. 1.

Cocaine-induced reinstatement responding is associated with a rise in accumbal glutamate rather than dopamine.A and B depict extracellular levels of glutamate (A) and dopamine (B) within the nucleus accumbens during cocaine-induced reinstatement testing. This figure depicts data from rats that passively received either cocaine (Yoke COC;n = 7) or saline (Yoke SAL; n = 7) in the same temporal pattern that self-administering subjects (SA;n = 6) lever pressed to receive cocaine infusions. Animals that received chronic cocaine displayed decreased basal levels of glutamate (A; SA and Yoke COC) and increased responsivity of dopamine after cocaine challenge (B; time 0 min). All groups showed a reliable increase in extracellular dopamine after COC challenge; however, only SA subjects showed a reliable increase in glutamate. Thus, glutamate levels are most closely related to lever pressing (C). Extinction responding (EXT) is shown for comparison. *p < 0.05 indicates a significant difference from baseline (before COC challenge) or EXT; +p < 0.05 indicates a significant difference from yoked SAL control subjects.

Fig. 2.

Inactivation of the dorsal prefrontal cortex blocks cocaine-induced reinstatement and the associated rise in extracellular glutamate. Extracellular levels of glutamate (A) and dopamine (B) were measured during reinstatement testing. Subjects received microinfusions of either SAL or B/M into the dorsal prefrontal cortex, followed by systemic (intraperitoneal) infusions of either COC or SAL at time 0 min. Thus, there were four treatment conditions (SAL-COC,n = 6; B/M-COC, n = 6; SAL-SAL,n = 5; B/M-SAL, n = 5), with the intracranial treatment indicated first and the systemic treatment second. C shows responding on the active lever during the 2 hr test for reinstatement and, for comparison, shows responding during extinction conditions (EXT). Challenge with systemic SAL (SAL-SAL or B/M-SAL) did not elicit reinstatement or a rise in extracellular levels of glutamate or dopamine within the NAcore. In contrast, challenge with systemic COC elicited both renewed responding on the active lever as well as increases in extracellular levels of glutamate and dopamine within the NAcore. Inactivation of the PFCd with baclofen and muscimol before COC challenge blocked both the rise in extracellular glutamate and behavioral reinstatement but left the rise in NAcore dopamine unaffected (compare SAL-COC with B/M-COC). *p < 0.05 indicates a significant difference from baseline (before COC challenge) or EXT; +p < 0.05 indicates a significant difference from SAL control subjects.

Fig. 3.

The reinstatement-associated increase in accumbal glutamate is activity dependent. One hour before cocaine challenge, TTX (0 or 1 μm; n = 6 per group) was advanced through the dialysis probe. Subjects pretreated with 0 μm TTX showed a reliable increase in extracellular glutamate after COC challenge. This increase was blocked by 1 μm TTX. *p < 0.05 indicates a reliable increase from pre-cocaine baseline.

Fig. 4.

Cocaine-induced glutamate is not a byproduct of lever pressing. This figure shows extracellular glutamate levels measured from the NA of rats that were trained to lever press for cocaine and had their lever pressing extinguished (just like other self-administering subjects). However, the levers were not extended during reinstatement testing. After COC challenge, these subjects (Motor; n = 7) displayed increased levels of glutamate within the NAcore comparable with increases shown by animals allowed to lever press during reinstatement (SA, from Fig. 1), suggesting that the rise in glutamate is not a consequence of behavioral responding.

Fig. 5.

Food reinstatement is not associated with an increase in accumbal glutamate. Some subjects were trained to lever press for food reinforcement (45 mg food pellet) and then had their lever pressing extinguished. A shows extracellular glutamate levels measured in the NAcore during reinstatement elicited by noncontingent food delivery. B shows active lever presses during extinction (EXT) and reinstatement (FOOD;n = 7). Note that, despite responding on the active lever at rates comparable with COC subjects, food animals show no increase in glutamate levels during reinstatement. Data from cocaine animals (SA, from Fig. 1) is shown for comparison.

Fig. 6.

Histology. This figure depicts the placement of microdialysis membranes (A) within the nucleus accumbens core and microinfusion sites within the dorsal prefrontal cortex (B) based on the atlas of Paxinos and Watson (1998). For clarity, placements are only shown for subjects whose data are shown in Figures 1 and 2, but placements for all other subjects fall within the depicted range. Numbers indicate distance from bregma in the anteroposterior plane.