Post-retrieval disruption of a cocaine conditioned place preference by systemic and intrabasolateral amygdala beta2- and alpha1-adrenergic antagonists

Abstract

Previous work has demonstrated post-retrieval impairment in associative learning paradigms, including those mediated by drugs of abuse, using nonspecific beta-adrenergic receptor (beta-AR) antagonists. Remarkably little is known about the role of the specific beta-AR subtypes, or other adrenergic receptors, in these effects. The current study examined the effects of beta(1) and beta(2), as well as alpha(1)-adrenergic receptor antagonism following retrieval of a cocaine conditioned place preference (CPP). We found that rats administered the beta(2) antagonist ICI 118,551 (8 mg/kg intraperitoneal [IP]) or the alpha(1) antagonist prazosin (1 mg/kg IP) following a drug-free test for CPP showed attenuated preference during a subsequent test, while the beta(1) antagonist betaxolol (5 or 10 mg/kg IP) and a lower dose of prazosin (0.3 mg/kg IP) had no effect. Furthermore, post-test microinfusion of ICI 118,551 (6 nmol/side) or prazosin (0.5 nmol/side) into the basolateral amygdala (BLA) also impaired a subsequent preference. Systemic or intra-BLA ICI 118,551 or prazosin administered to rats in their home cages, in the absence of a preference test, had no effect on CPP 24 h later. ICI 118,551 also attenuated the FOS response in the BLA induced by the CPP test. These results are the first to demonstrate a role for alpha(1)- and beta(2)-specific adrenergic mechanisms in post-retrieval memory processes. These systemic and site-specific injections, as well as the FOS immunohistochemical analyses, implicate the importance of specific noradrenergic signaling mechanisms within the BLA in post-retrieval plasticity.

Figure 1.

Post-retrieval administration of betaxolol had no effect on a subsequent cocaine-induced conditioned place preference (CPP). (A) Cocaine induced a CPP for the cocaine-paired floor during test 1. Data represent mean (+ SEM) time spent on the GRID floor for the GRID+ and GRID− subgroups during the 15-min drug-free test. All groups showed a significant preference for the cocaine-paired floor. (B) Post-retrieval betaxolol following test 1 did not affect a cocaine-induced CPP during test 2. Data represent mean (+ SEM) time spent on the GRID floor for the GRID+ and GRID− subgroups during the first 15 min of a 25-min drug-free test. Rats treated with betaxolol following test 1 continued to show a significant preference for the cocaine-paired floor during test 2. *P < 0.017 (Bonferroni-corrected α/3).

Figure 2.

Post-retrieval administration of ICI 118,551 attenuated a subsequent cocaine-induced conditioned place preference (CPP). (A) Cocaine induced a CPP for the cocaine-paired floor during test 1. Data represent mean (+ SEM) time spent on the GRID floor for the GRID+ and GRID− subgroups during the 15-min drug-free test. Both groups showed a significant preference for the cocaine-paired floor. (B) Post-retrieval ICI 118,551 following test 1 attenuated a cocaine-induced CPP during test 2. Data represent mean (+ SEM) time spent on the GRID floor for the GRID+ and GRID− subgroups during the first 15 min of a 25-min drug-free test. Rats treated with ICI 118,551 following test 1 showed no significant preference for the cocaine-paired floor during test 2, while vehicle-treated rats continued to show a significant CPP. *P < 0.025 (Bonferroni-corrected α/2).

Figure 3.

No effect of ICI 118,551 on a cocaine conditioned place preference (CPP) when administered in the absence of re-exposure. Data represent mean (+ SEM) time spent on GRID floor for the GRID+ and GRID− subgroups during the first 15 min of the 25-min drug-free test. Groups that received ICI 118,551 or vehicle in the absence of test 1 (NR) both showed a significant cocaine CPP during test 2. *P < 0.025 (Bonferroni-corrected α/2). NR indicates no re-exposure.

Figure 4.

Post-retrieval administration of the highest dose of prazosin attenuated a subsequent cocaine-induced conditioned place preference (CPP). (A) Cocaine induced a CPP for the cocaine-paired floor during test 1. Data represent mean (+ SEM) time spent on GRID floor for the GRID+ and GRID− subgroups during the 15-min drug-free test. Prior to prazosin administration, all groups showed a significant preference for the cocaine-paired floor. (B) Post-retrieval prazosin attenuated a cocaine-induced CPP. Data represent mean (+ SEM) time spent on GRID floor for the GRID+ and GRID− subgroups during the first 15 min of the 25-min drug-free test. Rats treated with 1 mg/kg prazosin following test 1 showed no preference for the cocaine-paired floor during test 2, while rats administered vehicle or 0.3 mg/kg prazosin continued to express a significant preference for the cocaine-paired floor. *P < 0.017 (Bonferroni-corrected α/3).

Figure 5.

No effect of prazosin on a cocaine conditioned place preference (CPP) when administered in the absence of re-exposure. Data represent mean (+ SEM) time spent on GRID floor for the GRID+ and GRID− subgroups during the first 15 min of the 25-min drug-free test. Groups that received vehicle or 1 mg/kg prazosin in the absence of test 1 (NR) both showed a significant cocaine CPP during test 2. *P < 0.025 (Bonferroni-corrected α/2). NR indicates no re-exposure.

Figure 6.

No effect of prazosin or ICI 118,551 when administered after one of two distinct CS exposures. Data represent mean (+ SEM) time spent on GRID floor for the GRID+ and GRID− subgroups during the first 15 min of the 25-min test. Groups that received vehicle, 1 mg/kg prazosin, or 8 mg/kg ICI 118,551 after exposure to one of the floor cues (and vehicle after the other) showed no change in neutral preference for the two cues.

Figure 7.

Post-retrieval intra-BLA administration of prazosin and ICI 118,551 attenuated a subsequent cocaine-induced conditioned place preference (CPP). (A) Cocaine induced a CPP for the cocaine-paired floor during test 1. Data represent mean (+ SEM) time spent on the GRID floor for the GRID+ and GRID− subgroups during the 15-min drug-free test. All groups showed a significant preference for the cocaine-paired floor. (B) Post-retrieval intra-BLA prazosin and ICI 118,551 following test 1 attenuated a cocaine-induced CPP during test 2. Data represent mean (+ SEM) time spent on the GRID floor for the GRID+ and GRID− subgroups during the first 15 min of a 25-min drug-free test. Rats treated with prazosin or ICI 118,551 following test 1 showed no significant preference for the cocaine-paired floor during test 2, while vehicle-treated rats continued to show a significant CPP. *P < 0.017 (Bonferroni-corrected α/3).

Figure 8.

No effect of intra-BLA administration of prazosin or ICI 118,551 on a cocaine conditioned place preference (CPP) when administered in the absence of re-exposure. Data represent mean (+ SEM) time spent on GRID floor for the GRID+ and GRID− subgroups during the first 15 min of the 25-min drug-free test. Groups that received vehicle, prazosin, or ICI 118,551 in the absence of test 1 (NR) all showed a significant cocaine CPP during test 2. *P < 0.017 (Bonferroni-corrected α/3). NR indicates no re-exposure.

Figure 9.

Areas in gray represent the cannula placements for intra-BLA studies. All cannulae were located within the gray areas. The far left represents A/P coordinate with respect to bregma. Smaller numbers to the right and left of figure represent number of cannula placements within that bregma level. The lower-most figure is a representative slice from an intra-BLA bilaterally cannulated animal. White arrows indicate placement of dye injection.

Figure 10.

FOS-IR in the BLA after exposure to the CS+/CS− condition (choice floor) was higher than after exposure to either the CS+ or CS− conditions. (A) Animals in the CS+/CS− condition showed a conditioned place preference (CPP). Data represent mean (+ SEM) time spent on the GRID floor for the GRID+ and GRID− subgroups during the 15-min drug-free test. (B) Across the BLA (−1.80 to −3.30), FOS-IR was significantly higher in the CS+/CS− condition than in the CS+ or CS− conditions. Data represent mean number of FOS-positive cells. (C) Across distinct bregma levels of the BLA, a similar pattern emerged in the most posterior region. Data represent mean number of FOS-positive cells. There were no differences in FOS-IR between the three floor conditions in bregma level A (−1.80 to −2.30). In bregma level B (−2.30 to −2.80), there was significantly higher FOS-IR in the CS+/CS− condition compared with the CS− condition, whereas the CS+ was not significantly different than either of the other two floor conditions. In bregma level C (−2.80 to −3.30), FOS-IR was significantly higher in the CS+/CS− condition than in both the CS+ or CS− conditions, which showed similar levels of FOS response. (D) Representative FOS-IR from each of the three floor configurations. Shaded in light gray in the upper left panel is the entire BLA as analyzed for immunohistochemistry. The dark gray box on the right side of the upper left panel indicates the area represented by the representative FOS-IR panels. *P < 0.05.

Figure 11.

Pretreatment with ICI 118,551 attenuated the FOS response in bregma level C of the BLA, while pretreatment with prazosin trended toward an attenuation of the FOS response. (A) Animals in the CS+/CS− conditions showed a conditioned place preference (CPP) that was unaffected by pretreatment. Data represent mean (+ SEM) time spent on the GRID floor for the GRID+ and GRID− subgroups during the 15-min drug-free test. Animals pretreated with vehicle, prazosin, or ICI-118,551 all showed place preference (but see Results). (B) In bregma range C of the BLA (−2.80 to −3.30), FOS-IR was significantly attenuated in both the CS+/CS− and CS+ conditions in animals pretreated with 8 mg/kg ICI 118,551. FOS-IR was largely unaffected by prazosin pretreatment, though there was a nonsignificant decrease in the CS+/CS− condition. Furthermore, FOS-IR in the vehicle-treated CS+/CS− was significantly higher than in animals that did not receive cocaine during conditioning but were tested in the presence of the choice floor (CS−/CS−). Data represent mean number of FOS-positive cells in each condition. *P < 0.05; ⁺P < 0.05 (compared with VEH CS+/CS−); ^aP = 0.10 (compared with VEH CS+/CS−); ^bP < 0.05 (compared with VEH CS+); ^cP < 0.05 (compared with CS−/CS−). VEH indicates vehicle; PRAZ-1, 1 mg/kg prazosin; ICI-8, 8 mg/kg ICI 118,551; and NP, no procedures.