Involvement of Dopamine D1/D5 and D2 Receptors in Context-Dependent Extinction Learning and Memory Reinstatement

Abstract

Dopamine contributes to the regulation of higher order information processing and executive control. It is important for memory consolidation processes, and for the adaptation of learned responses based on experience. In line with this, under aversive learning conditions, application of dopamine receptor antagonists prior to extinction result in enhanced memory reinstatement. Here, we investigated the contribution of the dopaminergic system to extinction and memory reinstatement (renewal) of an appetitive spatial learning task in rodents. Rats were trained for 3 days in a T-maze (context "A") to associate a goal arm with a food reward, despite low reward probability (acquisition phase). On day 4, extinction learning (unrewarded) occurred, that was reinforced by a context change ("B"). On day 5, re-exposure to the (unrewarded) "A" context took place (renewal of context "A", followed by extinction of context "A"). In control animals, significant extinction occurred on day 4, that was followed by an initial memory reinstatement (renewal) on day 5, that was, in turn, succeeded by extinction of renewal. Intracerebral treatment with a D1/D5-receptor antagonist prior to the extinction trials, elicited a potent enhancement of extinction in context "B". By contrast, a D1/D5-agonist impaired renewal in context "A". Extinction in the "A" context on day 5 was unaffected by the D1/D5-ligands. Treatment with a D2-receptor antagonist prior to extinction had no overall effect on extinction in context "B" or renewal in context "A", although extinction of the renewal effect was impaired on day 5, compared to controls. Taken together, these data suggest that dopamine acting on the D1/D5-receptor modulates both acquisition and consolidation of context-dependent extinction. By contrast, the D2-receptor may contribute to context-independent aspects of this kind of extinction learning.

Keywords: behavior; dopamine; extinction learning; hippocampus; rodent; spatial learning.

Figure 1

Antagonism of dopamine D1/D5-receptors enhances extinction, but does not affect renewal. Agonist activation of dopamine D1/D5-receptors has no effect on context–dependent extinction, but impairs renewal. Animals participated in 20 trials per day. Bar charts represent the number of correct arm choices in the first and second set of 10 trials on each test day. Three days of acquisition training (day 1–5), in context “A” were followed by extinction learning in a new context (day 4, context “B”) and re-exposure to the original context (context “A”) on day 5. Extinction of the learned conditioned stimulus (CS)-unconditioned stimulus (US) response occurred in the “A” context in control animals on day 5 (second 10 trials). No food was available on days 4 and 5. The arrow signifies the time of antagonist/vehicle-injection. The vehicle data for the antagonist group are labelled as “SCH 23390 vehicle” (yellow bars) and for the agonist group are labelled as “ChloroPB vehicle” (blue bars) Treatment of the animals with the dopamine D1/D5-receptor antagonist, SCH 23390 (dark gray bars), prior to the extinction learning trials on day 4 resulted in a significant enhancement of extinction (in the “B” context) compared to vehicle-treated controls (yellow bars). On day 5, renewal in context “A” was equivalent in both treatment groups (first 10 trials). Extinction of the CS-US response that had been learned in context “A” (2nd set of trials on day 5) was also equivalent in both treatment groups. Animals treated with the dopamine D1/D5-receptor agonist Chloro-PB (white bars) prior to exposure to the “B” context on day 4 showed significant extinction was evident by the 2nd set of 10 trials on day 4, that was not different from controls (blue bars). Upon returning to the same context on day 5, renewal of the conditioned behavior occurred in control animals (first 10 trials), whereas renewal was impaired in animals that had been treated on day 4 with the agonist. Extinction of the CS-US response that had been learned in context “A” (2nd set of trials on day 5) was equivalent in both treatment groups.

Figure 2

Antagonism of dopamine D2-receptors has no effect on context-dependent extinction or renewal. Extinction in the context-independent, context “A” is impaired. Treatment of the animals with the dopamine D2-receptor antagonist, Remoxipride, prior to the extinction learning trials on day 4 had no effect on extinction learning compared to vehicle-treated controls. Both groups exhibited significant extinction in the second set of 10 trials on day 4. On day 5, renewal in context “A” was equivalent in both treatment groups (first 10 trials). Extinction of the CS-US response that had been learned in context “A” (2nd set of trials on day 5) was impaired in the remoxipride-treatment group however.

Figure 3

Antagonism of dopamine D1/D5 impairs decision-time during context-dependent extinction learning. The graph represents the amount of time that was needed to reach the end of an arm (both correct and incorrect choices) after door opening. For each day the time for five contiguous trials was averaged (i.e., four time-points per day are shown). Decision times recorded in animals that were treated with the dopamine D1/D5-receptor antagonist, SCH23390, or vehicle are shown. The vehicle or antagonist solution was injected 30 min prior to extinction learning in day 4. During learning of the task, the time required to reach the end of an arm continuously decreased in conjunction with a steady improvement in correct answers, until a basal level of correct answers was reached on day 3. During the extinction and renewal trials, the decision-time increased in parallel with the decrease of correct choices. The dopamine receptor antagonist significantly decelerated decision time during extinction learning on day 4. No performance differences were noted in drug or vehicle groups on day 5.

Figure 4

Agonist activation of dopamine D1/D5 receptors impairs decision-time during renewal of the learned response. The graphs represent the amount of time that was needed to reach the end of an arm (both correct and incorrect choices) after door opening. For each day the time for five contiguous trials was averaged (i.e., four time-points per day are shown). Decision times recorded in animals that were treated with the dopamine D1/D5-receptor agonist, Chloro-PB, or vehicle are shown. The vehicle, or agonist, solution was injected 30 min prior to extinction learning in day 4. The dopamine receptor agonist significantly impaired decision times during performance trials on day 5. No performance differences were noted in drug or vehicle groups on day 4.

Figure 5

Antagonism of dopamine D2-receptors has no effect on decision-time during context-dependent extinction learning, or renewal of the learned response. The graphs represent the amount of time that was needed to reach the end of an arm (both correct and incorrect choices) after door opening. For each day the time for five contiguous trials was averaged (i.e., four time-points per day are shown). Decision times recorded in animals that were treated with the dopamine D2-receptor antagonist, Remoxipride, or vehicle are shown. The vehicle or antagonist solution was injected 30 min prior to extinction learning in day 4. The dopamine D2-receptor antagonist had no significant effect on decision time during extinction learning on day 4, or renewal on day 5.