Differential effects of blockade of dopamine D1-family receptors in nucleus accumbens core or shell on reinstatement of heroin seeking induced by contextual and discrete cues

Abstract

In humans, exposure to environmental contexts previously associated with heroin intake can provoke drug relapse, but the neuronal mechanisms mediating this relapse are unknown. Using a drug relapse model, we found previously that reexposing rats to heroin-associated contexts, after extinction of drug-reinforced responding in different contexts, reinstates heroin seeking. This effect is attenuated by inhibition of glutamate transmission in the ventral tegmental area and medial accumbens shell, components of the mesolimbic dopamine system. Here, we explored the role of dopamine of the accumbens in context-induced reinstatement by using the D1-family receptor antagonist SCH 23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride]. Rats were trained to self-administer heroin for 12 d; drug infusions were paired with a discrete tone-light cue. Subsequently, the heroin-reinforced 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. When tested in the original drug self-administration context, systemic and medial or lateral accumbens shell SCH 23390 injections attenuated context-induced reinstatement of heroin seeking, whereas accumbens core SCH 23390 injections were ineffective. In contrast, core but not lateral or medial shell SCH 23390 injections attenuated discrete-cue-induced reinstatement in a nondrug context after extinction of lever presses without this cue. Results indicate that activation of medial and lateral accumbens shell D1-family dopamine receptors mediate context-induced reinstatement of heroin seeking and provide the first demonstration for a role of lateral shell dopamine in conditioned drug effects. Results also demonstrate novel dissociable roles of accumbens core and shell in context- versus discrete-cue-induced reinstatement of heroin seeking.

Figure 1.

Heroin self-administration training and extinction of the drug-reinforced responding (experiments 1 and 2). A, Training, Mean ± SEM number of infusions and active and inactive lever responses during the 12 d of heroin self-administration training. Rats were trained on a fixed ratio 1 reinforcement schedule with a 2.3 s timeout period; active lever presses reflect infusion plus 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 = 125). B, Extinction, Mean number of presses on the previously active lever and on the inactive lever during the first 14 extinction sessions, conducted in the absence of heroin and in a context different from the training context. Data are from all rats in experiments 1 and 2.

Figure 2.

Effects of systemic SCH 23390 injections on context-induced reinstatement of heroin seeking. A, Active lever, Mean ± SEM number of presses on the active lever after injections of vehicle or SCH 23390 before exposure to the training context or the extinction context (n = 10–11 per dose). B, Inactive lever, Mean number of presses on the inactive lever during testing. *p < 0.05, different from the vehicle condition.

Figure 3.

Effects of medial and lateral accumbens shell and accumbens core SCH 23390 injections on context-induced reinstatement of heroin seeking. A, Active lever, Mean ± SEM number of presses on the active lever after bilateral injections of vehicle or SCH 23390 before exposure to the training or the extinction context (n = 8–16 per dose). B, Inactive lever, Mean number of presses on the inactive lever during testing. *p < 0.05, different from the vehicle condition. C, Cannulae placement, Representative pictures of bilateral cannulas and injector placements and approximate placements of the injector tips (Paxinos and Watson, 2005); the numbers on the plates are in millimeters anterior from bregma.

Figure 4.

Effects of medial and lateral accumbens shell and accumbens core SCH 23390 injections on discrete-cue-induced reinstatement of heroin seeking. A, Active lever, Mean ± SEM number of presses on the active lever after bilateral injections of vehicle or SCH 23390 before exposure to the cue or no cue condition (n = 7–9 per dose). B, Inactive lever, Mean number of responses on the inactive lever during testing. C, Cannulae placement, Representative pictures of bilateral cannulas and injector placements and approximate placements of the injector tips (Paxinos and Watson, 2005); the numbers on the plates are millimeters anterior from bregma.

Figure 5.

Effect of accumbens SCH 23390 injections on sucrose self-administration. Mean ± SEM number of responses on the active lever after bilateral injections of vehicle or SCH 23390 (n = 6–7 per accumbens site). No significant effects were observed.