Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking

Abstract

Using a rat relapse model, we previously reported that re-exposing rats to a drug-associated context, following extinction of operant responding in a different context, reinstates heroin seeking. In an initial pharmacological characterization, we found that the mGluR2/3 agonist LY379268, which acts centrally to reduce evoked glutamate release, attenuates context-induced reinstatement of heroin seeking when injected systemically or into the ventral tegmental area, the cell body region of the mesolimbic dopamine system. Here, we tested whether injections of LY379268 into the nucleus accumbens (NAc), a terminal region of the mesolimbic dopamine system, would also attenuate context-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin; 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 responding, LY379268 was injected to different groups of rats into the NAc core or shell or into the caudate-putamen, a terminal region of the nigrastriatal dopamine system. Injections of LY379268 into the NAc shell (0.3 or 1.0 microg) dose-dependently attenuated context-induced reinstatement of heroin seeking. Injections of 1.0 microg of LY379268 into the NAc core had no effect, while a higher dose (3.0 microg) decreased this reinstatement. Injections of LY379268 (3.0 microg) 1.5 mm dorsal from the NAc core into the caudate-putamen were ineffective. Results suggest an important role of glutamate transmission in the NAc shell in context-induced reinstatement of heroin seeking.

Figure 1

Effects of intra-NAc shell LY379268 injections on context-induced reinstatement of heroin seeking. (a) Training: mean ± SEM infusions, and active and inactive lever responses during the 12 days of heroin self-administration training. Rats were trained on an FR-1 schedule with a 2.3 s timeout period; active lever responses reflect infusion + timeout responses. The unit dose of heroin was 0.1 mg/kg for the first six sessions and 0.05 mg/kg for the last six sessions (n = 25, three groups). (b) Extinction: mean responses on the previously active lever and on the inactive lever during extinction sessions conducted in the absence of heroin and in a context different from the training context (n = 25). (c) Test for reinstatement: active lever: mean responses on the active lever after bilateral intra-NAc shell injections of vehicle, 0.3 or 1.0 μg of LY379268 in the training or the extinction context. *Different from the vehicle condition, p 0.05 (n = 8-9/group). (d) Test for reinstatement: inactive lever: mean responses on the inactive lever after intra-NAc shell injections of vehicle or LY379268. (e) A representative picture of NAc shell injector tip and the approximate placements of the injectors' tip of the rats (Paxinos and Watson, 2005).

Figure 2

Effects of intra-NAc core LY379268 injections on context-induced reinstatement of heroin seeking. (a) Training: mean ± SEM infusions, and active and inactive lever responses during the 12 days of heroin self-administration training. Rats were trained on an FR-1 schedule with a 2.3 s timeout period; active lever responses reflect infusion + timeout responses. The unit dose of heroin was 0.1 mg/kg for the first six sessions and 0.05 mg/kg for the last six sessions (n = 29, three groups). (b) Extinction: mean responses on the previously active lever and on the inactive lever during extinction sessions conducted in the absence of heroin and in a context different from the training context (n = 29). (c) Test for reinstatement: active lever: mean responses on the active lever after bilateral injections of vehicle, 1.0, or 3.0 μg of LY379268 in the training or the extinction context. *Different from the vehicle condition, p < 0.05 (n = 9-10/group). (d) Test for reinstatement: inactive lever: mean responses on the inactive lever after injections of vehicle or LY379268. (e) A representative picture of NAc core injector tip and the approximate placements of the injectors' tip of the rats (Paxinos and Watson, 2005).

Figure 3

Effects of intracaudate-putamen LY379268 injections on context-induced reinstatement of heroin seeking. (a) Training: mean ± SEM infusions, and active and inactive lever responses during the 12 days of heroin self-administration training. Rats were trained on an FR-1 schedule with a 2.3 s timeout period; active lever responses reflect infusion + timeout responses. The unit dose of heroin was 0.1 mg/kg for the first six sessions and 0.05 mg/kg for the last six sessions (n = 15, two groups). (b) Extinction: Mean responses on the previously active lever and on the inactive lever during extinction sessions conducted in the absence of heroin in a context different from the training context (n = 15). (c) Test for reinstatement: active lever: mean responses on the active lever after bilateral injections of vehicle or 3.0 μg of LY379268 in the training or the extinction context (n = 7-8/group). (d) Test for reinstatement: inactive lever: mean responses on the inactive lever after injections of vehicle or LY379268. (e) A representative picture of caudate-putamen injector tip and the approximate placements of the injectors' tip of the rats (Paxinos and Watson, 2005).

Figure 4

Effect of intra-NAc shell or core injections of LY379268 on sucrose self-administration. mean ± SEM responses on the active and the inactive levers after bilateral injections of vehicle or LY379268 into the NAc shell (a) (0.3 and 1.0 μg; n = 5) or into the NAc core (b) (1.0 and 3.0 μg; n = 7). No significant effects were observed.