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, 12 (4), 399-406

Systemic Blockade of D2-like Dopamine Receptors Facilitates Extinction of Conditioned Fear in Mice

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Systemic Blockade of D2-like Dopamine Receptors Facilitates Extinction of Conditioned Fear in Mice

Ravikumar Ponnusamy et al. Learn Mem.

Abstract

Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder. Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats. One day after fear conditioning mice with three pairings of a white noise conditional stimulus (CS) with moderate footshock, we injected the D2 antagonist, sulpiride, the D2 agonist, quinpirole, or vehicle, just before repeated CS presentations to generate extinction. We assayed fear by measuring behavioral freezing during extinction presentations and then drug-free during CS presentations 1 d later. We found that sulpiride injections before extinction training facilitated extinction memory 24 h later, while quinpirole partially blocked extinction memory compared with vehicle-injected controls. Notably, sulpiride treatment yielded significant extinction after spaced CS presentations, which yield no extinction at all in vehicle-treated mice. These findings suggest that dopamine D2-mediated signaling contributes physiological inhibition of extinction, and that D2 antagonists may be useful adjuncts to behavior therapy of human anxiety disorders.

Figures

Figure 1.
Figure 1.
Dose-finding experiments for sulpiride and quinpirole. (A) Protocol for dose-finding experiment for sulpiride. Dark box indicates phase of experiment shown in graphs. Mice were injected with vehicle or the indicated doses of sulpiride 45 min before fear conditioning with three pairings of CS and US. One day later, they were tested for fear of the CS in a different context. Dark box indicates the part of the protocol illustrated in the graph below. (B) Average freezing during three CS presentations at test. (*) P < 0.05 vs. vehicle-treated animals. n's = 8/group. (C) Protocol for the dose-finding experiment for quinpirole. Mice were fear conditioned with three CS–US pairings on Day 1. On Day 2, they were injected with vehicle or the indicated doses of quinpirole 30 min before 30 CS presentations, or no CS presentations for retention control (RC) groups, in a different context from conditioning. On Day 3, all groups were tested for fear of the CS in the extinction context. (D) Average freezing during three CS presentations at test. (+) P < 0.01 vs. both RC groups. (*) P < 0.05 vs. vehicle-treated. n's = 7 or 8/group.
Figure 2.
Figure 2.
Effect of D2 dopaminergic agents on long-term extinction memory. (A) Protocol for experiments. Mice were fear conditioned on Day 1 with three CS–US pairings in Context A. On Day 2, they were injected with vehicle or sulpiride (20 mg/kg) 45 min before or with quinpirole (1 mg/kg) 30 min before extinction with the indicated number of CS presentations in Context B. Retention control (RC) groups spent equivalent times in Context B, but received no CS presentations. On Day 3, all mice were tested for freezing during three CS presentations in Context B, and the results are averaged in the graphs. Separate experiments examined the effects of vehicle, sulpiride, and quinpirole on extinction with 0 (B), 5 (B,C), 10 (D), 20 (E), or 40 (F) nonreinforced CS presentations (n's = 7 or 8/group). (G) Presentation of these data normalized to the RC group in each experiment. (*) P < 0.05 vs. RC; (+) P < 0.05 vs. sulpiride extinction; (#) P < 0.05 vs. quinpirole extinction.
Figure 3.
Figure 3.
Effect of D2 dopaminergic agents on extinction acquisition. Data are consolidated for the first five CS presentations in the 5, 10, 20, and 40 massed extinction experiments, since all animals were treated the same during those presentations (n = 35–36). (A) Schema of experiment. (B) Average freezing during each presentation. Mixed ANOVA is significant for interaction, group and time (P < 0.05).
Figure 4.
Figure 4.
Effect of D2 dopaminergic agents on response to spaced CS presentations. (A) Protocol for experiment. Mice were fear conditioned on Day 1 with three CS–US pairings in Context A. On Day 2, they were injected with vehicle or sulpiride (20 mg/kg) 45 min before or with quinpirole (1 mg/kg) 30 min before seven spaced CS presentations in Context B (20 min ITI). RC group spent equivalent times in Context B, but received no CS presentations. On Day 3, all mice were tested for freezing during three CS presentations in Context B, and the results are averaged in the graphs. (B) Freezing during the CS presentations. Mixed ANOVA significant only for time. (C) Freezing at Day 3 test, drug-free. (*) P < 0.05 compared with all other groups.
Figure 5.
Figure 5.
Effect of D2 dopaminergic agents on locomotion. (A) Experimental protocol. Mice were injected with vehicle, sulpiride, or quinpirole before being placed in the open field for 1 h on Day 1 (B). On Day 2, they were returned to the open field, drug-free. (*) P < 0.05 vs. vehicle group.

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