Selective blockade of dopamine D3 receptors enhances while D2 receptor antagonism impairs social novelty discrimination and novel object recognition in rats: a key role for the prefrontal cortex

Abstract

Dopamine D(3) receptor antagonists exert pro-cognitive effects in both rodents and primates. Accordingly, this study compared the roles of dopamine D(3) vs D(2) receptors in social novelty discrimination (SND), which relies on olfactory cues, and novel object recognition (NOR), a visual-recognition task. The dopamine D(3) receptor antagonist, S33084 (0.04-0.63 mg/kg), caused a dose-related reversal of delay-dependent impairment in both SND and NOR procedures in adult rats. Furthermore, mice genetically deficient in dopamine D(3) receptors displayed enhanced discrimination in the SND task compared with wild-type controls. In contrast, acute treatment with the preferential dopamine D(2) receptor antagonist, L741,626 (0.16-5.0 mg/kg), or with the dopamine D(3) agonist, PD128,907 (0.63-40 μg/kg), caused a dose-related impairment in performance in rats in both tasks after a short inter-trial delay. Bilateral microinjection of S33084 (2.5 μg/side) into the prefrontal cortex (PFC) of rats increased SND and caused a dose-related (0.63-2.5 μg/side) improvement in NOR, while intra-striatal injection (2.5 μg/side) had no effect on either. In contrast, bilateral microinjection of L741,626 into the PFC (but not striatum) caused a dose-related (0.63-2.5 μg/side) impairment of NOR. These observations suggest that blockade of dopamine D(3) receptors enhances both SND and NOR, whereas D(3) receptor activation or antagonism of dopamine D(2) receptor impairs cognition in these paradigms. Furthermore, these actions are mediated, at least partly, by the PFC. These data have important implications for exploitation of dopaminergic mechanisms in the treatment of schizophrenia and other CNS disorders, and support the potential therapeutic utility of dopamine D(3) receptor antagonism.

Figure 1

Position of injection sites in the rat PFC (upper, +3.2 mm from Bregma) and striatum (lower diagram, +0.48 mm from Bregma) of rats used for behavioral studies on coronal sections taken from Paxinos and Watson (1997) together with a schematic representation of the injector.

Figure 2

Dose–response effect of, and interaction between the preferential dopamine D₃ receptor antagonist, S33084, and the preferential dopamine D₂ receptor antagonist, L741,626 on social novelty discrimination (SND) in the rat. Data in (a, c, and e) show time spent investigating the novel compared with the familiar juvenile in P2 following a 30-min inter-trial interval (mean±SEM of juvenile exploration). ^***P<0.001 from the novel juvenile at the same dose in the same treatment group (Bonferroni post hoc). Panels (b), (d) and (f) show the SND ratio (novel/familiar) for the same behaviour, ^*P<0.01 compared with vehicle, ^**P<0.01 compared with vehicle/vehicle group, ⁺⁺P<0.01 compared with vehicle/S33084 group. Numbers in parentheses indicate number of rats in each group. Note the D₃ receptor antagonist restores a time delay-induced reduction in SND (a, b) which is prevented by the D₂ receptor antagonist (e, f), while the latter has no effect on its own at this inter-trial internal (c, d).

Figure 3

Dose–response effects of the preferential dopamine D₃ receptor antagonist, S33084, the preferential dopamine D₂ receptor antagonist, L741,626 and the dopamine D₃ agonist, PD128,907, on social novelty discrimination (SND) with no inter-trial delay in the rat. Data in (a, c, and e) show time spent investigating the novel compared with the familiar juvenile in P2 (mean±SEM of juvenile exploration). ^*P<0.05, ^**P<0.01, and ^***P<0.001 from the novel juvenile at the same dose in the same treatment group (Bonferroni post hoc following ANOVA). The SND ratio (novel/familiar) is shown in (b), (d), and (f). ^**P<0.05 and ^***P<0.001 compared with vehicle. Numbers in parentheses indicate the number of rats in each group. Note that while the D₃ receptor antagonist has no effect on SND, both the D₂ receptor antagonist and D₃ receptor agonist impair recognition of the novel juvenile in P2.

Figure 4

Effect of bilateral microinjection of the preferential dopamine D₃ receptor antagonist S33084 into the prefrontal cortex (a) or striatum (c) on social novelty discrimination (SND) in the rat. Bars show juvenile exploration (sec, mean±SEM) following a 30-min inter-trial interval. ^***P<0.001 from the novel juvenile in the same treatment group (Bonferroni post hoc following ANOVA). Panels (b) and (d) show the SND ratio (novel/familiar) following microinjection of S33084 (2.5 μg/side) into the prefrontal cortex and striatum, respectively. ^**P<0.01 compared with vehicle. Numbers in parentheses indicate the number of rats in each group. Note that S33084 only attenuated SND when injected into the prefrontal cortex and not into the striatum.

Figure 5

Comparison of the performance of dopamine D₃ receptor deficient (DRD3^−/−) to wild-type (WT) mice on social novelty discrimination (SND) in drug-free panels (a) and (b) and administration of the preferential dopamine D₃ receptor antagonist, S33084. Bars show juvenile exploration (sec, mean±SEM, n=6) following a 30-min inter-trial interval (a, c). ^*P<0.05, ^**P<0.01 and ^***P<0.001 from the novel juvenile at the same dose in the same treatment group (Bonferroni post hoc). The SND ratio (novel/familiar time) is shown in (b) and (d). ^**P<0.01 compared with vehicle. ^*P<0.05 compared with all other groups. Note that DRD3 knockout mice were able to distinguish between the familiar and novel juveniles after a 30-min inter-trial interval when WT mice were unable to discriminate.

Figure 6

Dose–response effect and interaction between the preferential dopamine D₃ receptor antagonist, S33084, and the preferential dopamine D₂ receptor antagonist, L741,626 on performance in the novel object recognition task, using a 4-h inter-trial interval in the rat. Data in (a, c, and e) show the actual time spent investigating the novel compared with the familiar object in the second choice trial (sec, mean±SEM, n=11–12). ^***P<0.001 from the novel object at the same dose within the same treatment group (Bonferonni post hoc following ANOVA). Exploration times were also used to calculate the d2 score (see Materials and methods for definition) as an index of preferential object exploration in the choice trial and is shown (b, d, and f). (b) ^*P<0.05 from the novel object at the same dose. (f) ^**P<0.01 and ^***P<0.001 compared with vehicle/vehicle group, ⁺⁺P<0.01 compared with vehicle/S33084. Note that the D₃ receptor antagonist was able to restore a time induced natural forgetting (a, b) in the novel object discrimination paradigm which was prevented by co-administration of the D₂ receptor antagonist (e, f) while the latter had no effect on its own (c, d).

Figure 7

Examination of the dose–response effects and interaction between the preferential dopamine D₂ receptor antagonist, L741,626, and the dopamine D₃ receptor agonist, PD128,907 on novel object recognition task, using a 2-min inter-trial interval in the rat. Data in (a, c, and e) show the time spent investigating the novel compared with the familiar object in the choice trial (sec, mean±SEM, n=12). ^**P<0.01 and ^***P<0.001 from the novel object at the same dose within the same treatment group (Bonferonni post hoc). Panels (b, d, and f) show the derived d2 score (see Materials and methods for definition). (b, d) ^**P<0.01 compared with vehicle, ^***P<0.01 compared with vehicle, (f) ^**P<0.01 compared with vehicle/vehicle group, ⁺⁺P<0.01 compared with vehicle/PD128,907, Bonferonni post hoc following ANOVA. Both the D₂ receptor antagonist (a, b) and the D₃ receptor agonist (c, d) impaired object discrimination and the effect of the latter was prevented by pretreatment with a D₃ receptor antagonist (e, f).

Figure 8

Comparison of the effect of bilateral microinjection of the preferential dopamine D₃ receptor antagonist, S33084 and the preferential dopamine D₂ receptor antagonist, L741,626, into the rat prefrontal cortex and striatum on novel object recognition using a 4-h and 2-min inter-trial interval, respectively. Panels (a) and (c) show the time spent (mean±SEM, n=8–9) investigating the novel compared with the familiar object in the choice trial following drug injection into the prefrontal cortex. ^**P<0.01 and ^***P<0.001 from the novel object at the same dose within the same treatment group (Bonferonni post hoc). Exploration times were used to calculate as the d2 score (see Materials and methods for definition) (b, d) and evaluate preferential object exploration as an index of recognition memory. ^*P<0.05, ^**P<0.01 and ^***P<0.001 compared with vehicle following ANOVA. Panels (e) and (f) show the derived d2 score from the choice trial exploration times after injection into the striatum of S33084 using a 4-h inter-trial interval or L741,626 using a 2-min inter-trial interval, respectively. When injected into the prefrontal cortex the two antagonists had opposite effects on object discrimination such that the D₃ receptor antagonist reversed natural forgetting (a, b) while the D₂ antagonist impaired discrimination (c, d). In contrast, neither drug had any effect on novel object recognition when injected into the striatum (e, f).