Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors

Abstract

Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.

Figure 1

D1/5 receptor agonist SKF 81297 enhances fear extinction. (a) Mice that received pre-extinction SKF 81297 showed differences in freezing response during Extinction (1, 3, and 10 mg/kg) and Test Day (10 mg/kg). (b) Mice that received pre-session SKF 81297 (10 mg/kg) showed increased locomotor behavior on Day 2 and Day 3. (c) Mice that received SKF 81297 (10 mg/kg) immediately following extinction showed significantly less freezing than saline-treated animals during Test Day 1. (d) Mice that received post-session SKF 81297 (10 mg/kg) on Day 2 did not show a persistent increase of locomotor activity on Day 3. (e) SKF 81297 treatment in combination with extinction decreases freezing compared with animals receiving saline with or without extinction and SKF 81297 without extinction, although there was not a significant interaction between SKF 81297 treatment and extinction. (f and g). Post-session SKF 81297 (10 mg/kg) enhances extinction of cued fear and impairs fear renewal. (f) Freezing during CS-on periods and (g) Freezing during CS-off periods. Mice that received post-session SKF 81297 (10 mg/kg) following cued extinction session showed decreased freezing during cue presentations (a) on Test 1–3, and trended toward significant differences during cue presentations in renewal. Error bars indicate SEM. *p<0.05 significant difference compared with saline. °p=0.0535.

Figure 2

Pre-session SKF 81297 induces CPP and post-session SKF 81297 promotes cocaine CPP extinction. (a) Mice that received pre-session administration of SKF 81297 (SKF Pre-Tx) showed significantly more preference for drug-paired side than post-session treated animals (SKF Post-Tx). (b) Mice that received post-extinction administration of SKF 81297 trended towards decreased preference for cocaine-paired side. (c) Mice with low preference showed no difference between groups. (d) Mice with high preference (over 65%) showed significantly decreased preference for cocaine-paired side with post-extinction SKF 81297 compared with saline-treated mice. Error bars indicate SEM. *p<0.05 significant difference compared with saline.

Figure 3

The biased D1 agonist SKF 83959 does not affect fear extinction, but the broadly efficacious D1 agonist SKF 83822 enhances fear extinction. (a) Mice that received SKF 83959 immediately following extinction showed no difference in freezing compared to vehicle-treated mice during Test Day. (b) Mice that received SKF 83822 (1 mg/kg) immediately following extinction showed a significant difference in freezing compared to vehicle-treated mice during Test Day. Error bars indicate SEM. *p<0.05 significant difference compared with vehicle.