The Role of Dopamine D1 and D3 Receptors in N-Methyl-D-Aspartate (NMDA)/GlycineB Site-Regulated Complex Cognitive Behaviors following Repeated Morphine Administration

Abstract

Background: Opiate addiction is associated with complex cognitive impairment, which contributes to the development of compulsive drug use and relapses. Dopamine and N-methyl-D-aspartate receptors play critical roles in opiate-induced cognitive deficits. However, the roles of D1 and D3 receptors in the N-methyl-D-aspartate/glycineB receptor-regulated cognitive behaviors induced by morphine remain unknown.

Methods: The 5-choice serial reaction time task was used to investigate the cognitive profiles associated with repeated morphine administration in D1 (D1-/-)- and D3 (D3-/-)-receptor knockout mice. The expression of phosphorylated NR1, Ca2+/calmodulin-dependent protein kinase II (CaMKII), and cAMP response element-binding protein (CREB) in the brain was examined by western blotting. D1-/- and D3-/- mice were treated with the N-methyl-D-aspartate/glycineB site agonist l-aminocyclopropanecarboxylic acid and the antagonist L-701,324 to chronically disrupt N-methyl-D-aspartate receptor function and investigate their effects on morphine-induced cognitive changes.

Results: Repeated morphine administration impaired attentional function and caused impulsive and compulsive behaviors. D1-/- mice exhibited hardly any premature nosepokes. D3-/- mice showed robustly increased morphine-induced impulsive behavior. The numbers of premature responses were decreased by L-701,324 administration and increased by ACPC administration; these effects were completely abolished in D1-/- mice due to their inability to perform reward-based tasks. In contrast, the inhibitory effects of L-701,324 on impulsive behavior were significantly augmented in D3-/- mice.

Conclusions: N-methyl-D-aspartate/glycineB site functions may contribute to morphine-induced cognitive deficits, especially those related to impulsive behavior. D1 and D3 receptors may have contrasting effects with respect to modulating impulsive behavior. D3 receptors have inhibitory effects on impulsive behaviors, and these effects are clearly mediated by N-methyl-D-aspartate/glycineB receptor and μ-opioid receptor interactions.

Keywords: NMDA receptor; dopamine receptor; impulsive behavior; morphine.

Figure 1.

5-Choice serial reaction time task (5-CSRTT) baseline performance in the D1^-/- and D3^-/- mice. The training sessions were performed from days 1 to 7. The values represent the mean ± SEM. The final performance on day 7 was analyzed by 1-way ANOVA. Sidak’s posthoc test was used to analyze difference between genotypes. *P<.05, **P<.01, ***P<.0001, compared with WT mice. ^#P < .05, ^##P < .01, ^###P < .0001, compared between D1^-/- and D3^-/- mice.

Figure 2.

Effects of repeated morphine administration in D1^-/- or D3^-/- mice. Mice were administered 10 mg/kg morphine i.p. for 7 days. The values represent the mean ± SEM. Two-way ANOVA followed by Sidak’s multiple comparisons test was used to reveal difference between groups. *P < .05, **P < .01, morphine-treated mice were compared with their saline-treated counterparts. ^#P < .05, ^##P < .01, ^###P<.0001, D1^-/- and D3^-/- mice were compared with WT mice with the morphine and saline treatments.

Figure 3.

Effects of repeated morphine administration on NR1-Ca²⁺/calmodulin-dependent protein kinase II (CaMKII)-cAMP response element-binding protein (CREB) phosphorylation. Mice were administered 10 mg/kg morphine i.p. for 7 days. The relative fold changes in the levels of phosphorylated (a) NR1, (b) CaMKII, and (c) CREB protein were analyzed. The protein levels in the frontal cortex (FC) of the saline group were set as 1. The values represent the mean±SEM. Morphine-treated mice were compared with their saline-treated counterparts, *P<.05, **P<.01, ***P<.0001. (d) Schematic representation showing the locations of the excised brain regions (blue area). Figures were adapted from atlas of Paxinos and Watson (George Paxinos, 2001). NAc, nucleus accumbens; dHIP, dorsal hippocampus.

Figure 4.

Effects of l-aminocyclopropanecarboxylic acid (ACPC) and 7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolone (L-701,324) administration on morphine-induced cognitive and behavioral changes. (a) Mice received ACPC (200 mg/kg), L-701,324 (3 mg/kg), L-701,324+ACPC, or Veh (1% Tween-80 vehicle) i.p. once per day for 7 consecutive days. Premature responses and perseverative responses are showed. (b) Mice received ACPC, L-701,324, or vehicle 15 minutes before 10 mg/kg morphine or saline administration. 5-Choice serial reaction time task (5-CSRTT) performance was analyzed after 7 days of treatment. *P < .05, **P < .01, ***P < .0001, compared with Veh+Saline controls. #P<.05, ##P<.01, ###P<.0001, comparison between the 2 indicated groups.

Figure 5.

Effects of l-aminocyclopropanecarboxylic acid (ACPC)/7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(1H)-quinolone (L-701,324) on morphine-induced cognitive and behavioral changes in D3^-/- mice. (a) D3^-/- mice were administered ACPC (200 mg/kg), L-701,324 (3 mg/kg), or Veh (1% Tween-80) i.p. in combination with 10 mg/kg morphine or saline for 7 days. *P < .05, ***P < .0001, vs Veh controls within the saline- or morphine-treated groups. (b) The fold changes in the numbers of premature and perseverative responses in wild-type (WT) and D3^-/- mice. In each genotype, the data from the Veh+Saline group were set as 1, and the data from the other treatment groups are expressed as the relative fold change vs the Veh+Saline group. *P < .05, ***P < .0001, comparison between the 2 indicated groups.