Context-Dependent and Context-Independent Effects of D1 Receptor Antagonism in the Basolateral and Central Amygdala during Cocaine Self-Administration

Abstract

One way that drugs of abuse perturb the dopamine system is by triggering large amounts of extracellular dopamine to efflux into limbic regions. The basolateral (BLA) and central (CeA) nuclei of the amygdala have been shown to play distinct roles in value representation of primary and conditioned reward. However, the precise role of dopaminergic receptors in the BLA and the CeA during reward-related behaviors remains to be determined. Here we investigate the effects of dopamine D1 receptor blockade in the BLA and the CeA during asymptotic performance of cocaine self-administration and in a novel application of contextual renewal under continued access conditions. After more than three weeks of chained seek-take self-administration of cocaine, male Long Evans rats were given a bilateral intra-BLA or intra-CeA infusion of the D1 antagonist SCH-23390 (2 µg/0.3 µl) for multiple days. Intra-BLA D1 receptor blockade before, but not after the self-administration session, gradually suppressed drug seeking and taking responses and persisted with a change in context with continued D1 blockade. In contrast, intra-CeA D1 receptor blockade caused a rapid reduction in self-administration that showed renewal with a change in context with continued D1 blockade. Further, conditioned place aversion developed with intra-BLA but not intra-CeA infusions. Collectively, these results demonstrate that dopamine D1 receptors in the BLA and CeA both contribute to drug seeking and taking, but may do so through distinct mechanisms.

Keywords: SCH 23390; amygdala; cocaine; contextual renewal; extinction; self-administration.

Figure 1.

Intra-BLA D1 blockade by SCH 23390 progressively decreases cocaine seeking and taking behavior and increases the time to complete each session in Experiment 1. A, Experimental timeline showing the seek-take procedure from acquisition, baseline, Phase 1, and Phase 2 in Experiment 1A. After the acquisition period of 15–20 d, 3 d of stable baseline were recorded before SCH 23390 (n = 13, 2.0 μg/0.3 µl) or saline (n = 10, 0.3 µl) was injected before each session (Phase 1). Subsequently, SCH 23390-treated rats were given saline and saline-treated rats were given SCH 23390 for three additional days (Phase 2). B, SCH 23390 (black filled) administered before each session progressively decreased cocaine seeking. Post hoc analysis revealed differences between saline on Days 2 and 3 of drug treatment (p < 0.05). C, SCH 23390 treatment resulted in an increase in the time to complete each session compared to saline controls (white unfilled). Post hoc analysis revealed differences between saline and drug treatment (p < 0.05). D, SCH 23390 decreased cocaine taking behavior on Days 2 and 3 of drug treatment (p < 0.05). E, In Experiment 1B, SCH 23390 administered after each session (black filled; n = 6) did not alter subsequent cocaine seeking and taking behavior or time to complete each session, relative to two sessions of baseline (gray filled) before and after SCH 23390 treatment (inset; p > 0.1). Error bars indicate SEM; **p < 0.01, *p < 0.05. n.s., non significant.

Figure 2.

Time bin analysis of responding during 3 d of intra-BLA administration of D1 blockade by SCH 23390 and effects on contextual renewal in Experiment 1. A, Time bin analysis of responding during 3 d of intra-BLA administration of D1 blockade by SCH 23390. Results show while rats exhibited a steady rate of responding during the last day of baseline (charcoal), rats showed a greater U-shaped pattern of responding on Day 1 (desert orange) versus Day 2 (purple) and Day 3 (turquoise). B, left panel, Number of infusions per hour on the last day of baseline (gray), SCH 23390 (black), and saline (white) treatment for both groups. Rate analysis revealed an order effect between the SCH/Sal group and the Sal/SCH group (p < 0.05). Rats in the Sal/SCH group (n = 6) were maintained under baseline conditions and continued to show a persistent suppression of the rate of responses in the training context for 2 d (CTX A: Days 10 and 11), exhibited a contextual renewal in a novel context (CTX B: Days 12 and 13), and a resuppression of responding in the training context (paired t test: p < 0.01; CTX A: Day 14). Group raster plot of seek presses of (C) SCH/Sal group, (D) Sal/SCH group, and (E) the Sal/SCH renewal group during baseline (charcoal), Day 1 (desert orange), Day 2 (purple), and Day 3 (teal) of SCH 23390 and saline (white) treatment. In addition, E shows the return to baseline in context A for 2 d (charcoal), test in Context B for 2 d (blue), and a final session in Context A (charcoal); **p < 0.01, *p < 0.05.

Figure 3.

Different sensitivities of suppression between the CeA and BLA on cocaine-seeking behavior and effects on contextual renewal during concurrent D1 blockade in Experiments 2 and 3. A, While D1 blockade (dark filled) in the CeA (n = 6) rapidly decreased cocaine-seeking behavior, D1 blockade in the BLA (n = 7) progressively decreased cocaine-seeking behavior. Saline treatment recovered cocaine-seeking behavior in both the CeA and BLA group. B, Consistent with the results found in Figure 2A, D1 blockade in the BLA (n = 8) and the CeA (n = 9) differentially decreased cocaine-seeking behavior over 2 d in the training context (Context A; red outline) while saline controls (white unfilled: BLA/CeA, n = 7) did not change. On the 3rd day of D1 blockade or saline, groups were moved to Context B (cyan), where the CeA group, but not the BLA group, increased cocaine-seeking behavior (p < 0.05). On the 4th day of D1 blockade, groups were returned to Context A, where both groups showed a suppression of cocaine-seeking behavior. Group raster plot of seek lever presses of the CeA group (C) and BLA group (D) during baseline (charcoal), SCH 23390 treatment in context A (red), SCH 23390 treatment in context B (cyan), and SCH 23390 treatment back in Context A (red); **p < 0.01, *p < 0.05.

Figure 4.

Intra-BLA, but not intra-CeA, D1 blockade by SCH 23390 for 3 d results in a conditioned place aversion in Experiment 4. A, Saline (n = 10), BLA (n = 11), and CeA (n = 5) groups decreased their distance traveled within each session of conditioning, but the BLA and CeA group given SCH 23390 (black filled) had a larger decrease then saline controls (unfilled; p ≤ 0.05). B, Saline, BLA, and CeA groups did not have a preference for the grid or hole floors during the pre-test. However, after 3 d of conditioning, the BLA, but not the saline or CeA groups, showed a significant conditioned place aversion (CS–/CS+: ratio of time spent in non-conditioned side vs conditioned side) during the post hoc test (p < 0.05). C, Representative tracking plots of rats during post hoc test for saline (top, black) and intra-BLA SCH 23390 (red, bottom) groups injected during training on the hole floor. A mid-zone compartment of 18 cm in length (the approximate length of the body of an animal) was used in the analysis to account for when the animal was both on the grid and hole floors. D, While all three groups decreased their distance traveled during the post hoc test, there were no differences between groups (p > 0.9); **p < 0.01, *p < 0.05. n.s., non significant.

Figure 5.

Reconstruction of cannula placement for CeA and BLA groups with representative CeA and BLA photomicrographs. Each charcoal line represents the tip of the infusion cannula that protruded (∼0.75 mm) from the guide cannula.