A role of ventral tegmental area glutamate in contextual cue-induced relapse to heroin seeking

Abstract

The environmental context previously associated with opiate use plays an important role in human relapse, but the neuronal mechanisms involved in context-induced drug relapse are not known. Using a rat relapse model, we determined the effect of a group II metabotropic glutamate receptor agonist [LY379268 ((-)-2-oxa-4-aminobicylco hexane-4,6-dicarboxylic acid)] on contextual cue-induced reinstatement of heroin seeking. LY379268, which acts centrally to reduce evoked glutamate release, was injected systemically or directly into the ventral tegmental area (VTA), a brain area involved in opiate reward and conditioned drug effects. Rats were trained to self-administer intravenous heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Subsequently, lever pressing was extinguished in the presence of the discrete cue in a context that differed from the drug self-administration context in terms of visual, auditory, tactile, and circadian cues. After extinction of lever responding, LY379268 was injected systemically or into the VTA, and nonreinforced responding was determined in the extinction context or the drug context. Exposure to the heroin-associated context induced robust reinstatement of drug seeking, and this effect was attenuated by systemic or intra-VTA injections of LY379268. Results indicate that glutamate transmission in the VTA plays an important role in contextual cue-induced relapse to heroin seeking.

Figure 1.

Context-induced reinstatement of heroin seeking. A, Training, Mean ± SEM infusions and responses on the active and inactive levers during the 12 d of training. Data are from all of the rats (n = 42). B, Extinction, Mean responses on the previously active lever and on the inactive lever during the 3 hr extinction sessions, conducted in the presence of the heroin-associated discrete tone-light cue. There were no differences in lever responding between rats that underwent extinction in the same (A-A-A and A-A-B) or different (A-B-B and A-B-A) context as the training context. C, Testing, Mean active and inactive lever responses during the 1 hr reinstatement test session in the four groups of Exp. 1. ^*p < 0.05 indicates different from control and novel groups; n = 9-11 per group.

Figure 2.

Effects of LY379268 on context-induced reinstatement of heroin seeking. Mean ± SEM responses on the active lever (3 hr sessions) after systemic (A) or intra-VTA (B) injections of the vehicle or LY379268. C, Apictograph of VTA cannula placements. Rats were tested in both the extinction (context B) and the training (context A) context. ^*p < 0.05 indicates different from vehicle; n = 8-10 per dose.