Role of dopamine D1 and D2 receptors in the nucleus accumbens in mediating reward

Abstract

The objectives of this study were to examine the involvement of D1 and D2 receptors within the nucleus accumbens (ACB) in mediating reinforcement. The intracranial self-administration (ICSA) of D1 and D2 agonists was used to determine whether activating D1 and/or D2 receptors within the ACB of Wistar rats is reinforcing. At concentrations of 0.25, 0.50, and 1.0 mM (25, 50, and 100 pmol/100 nl of infusion), neither the D1 agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393 (SKF)] hydrochloride nor the D2 agonist (-)-quinpirole (Quin) hydrochloride was self-administered into the shell region of the ACB. On the other hand, equimolar mixtures of SKF and Quin (SKF+Quin), at concentrations of 0.25, 0.50, and 1.0 mM each, were significantly self-infused into the ACB shell. The core region of the ACB did not support the ICSA of SKF+Quin at any of these concentrations. Rats increased lever pressing when the response requirement was increased from a fixed ratio 1 (FR1) to FR3, and they responded significantly more on the infusion lever than they did on the control lever. Coadministration of either 0.50 mM R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine (SCH 23390) hydrochloride, a D1 antagonist, or 0.50 mM S(-)-sulpiride, a D2 antagonist, completely abolished the ICSA of the mixture of SKF+Quin (each at 0.50 mM) into the ACB shell. The present results suggest that concurrent activation of D1- and D2-type receptors in the shell of the ACB had a cooperative effect on DA-mediated reward processes.

Fig. 1.

Injection placements in experiment 1. Cannula placements that were included for shell infusions were depicted on theleft, whereas cannula placements included for core infusions were depicted on the right. Thenumbers on the right indicate distances (in millimeters) from bregma. The drawings are based on the rat brain atlas of Paxinos and Watson (1986), and the divisions between the shell and core are based on the study by Jongen-Relo et al. (1994).Co, Core; CPu, caudate putamen;Sh, shell.

Fig. 2.

Photomicrographs showing a shell and core placement in the ACB. A, A typical shell placement that supported a high level of self-infusion of SKF+Quin. B, A core placement that supported a low level of self-infusion of SKF+Quin.

Fig. 3.

Intra-ACB self-administration of D₁and D₂ agonists: dose–response analyses. Rats were assigned to one of three infusate groups: SKF, Quin, or SKF+Quin. During four sessions (3 hr/session), animals were given the opportunity to respond to vehicle and three concentrations (25, 50, and 100 mm) of one of the infusate types. One-way ANOVAs over four concentrations of infusion solutions revealed that the treatment of SKF alone [n = 9; F_(3,24) = 2.50] or Quin alone [n = 10;F_(3,27) = 2.01] into the shell or SKF+Quin into the core [n = 7;F_(3,18) = 2.57] did not produce a statistically reliable effect on infusions, whereas the treatment of SKF+Quin into the shell (n = 9) produced heightened levels of infusions [F_(3,24) = 7.28;p = 0.001]. *p < 0.01 compared with vehicle. Data are the mean ± SEM.

Fig. 4.

Intrashell self-administration of D₁and D₂ agonists: an interactive effect. Rats were assigned to one of three groups. The SKF group (n = 7) received 0.5 mm SKF during the first three sessions and the mixture of 0.5 mm SKF plus 0.5 mm Quin (SKF+Quin) in sessions 4 and 5. Similarly, the Quin group (n = 10) received infusions of 0.5 mmQuin in sessions 1–3, followed by infusions of 0.5 mm SKF plus 0.5 mm Quin in sessions 4 and 5. The SKF+Quin group (n = 6) received infusions of 0.5 mmSKF plus 0.5 mm Quin in sessions 1–3 and 5; in session 4, only vehicle was available. During sessions 1–3, rats receiving SKF+Quin obtained more infusions than did rats receiving SKF or Quin alone (p < 0.001). The SKF and Quin groups exhibited higher levels of self-infusion in session 5, when SKF+Quin was given in place of SKF or Quin alone, than in session 3 (p = 0.01). The replacement of SKF+Quin with vehicle in the SKF+Quin group in session 4 diminished self-infusions (p = 0.02), whereas the group exhibited higher self-infusions in session 5 when SKF+Quin was reinstated (p = 0.04). Data are the mean ± SEM.

Fig. 5.

Lever responses by the SKF+Quin group during acquisition, extinction, and reinstatement sessions. Data are the mean ± SEM. A within-subject experimental design revealed that rats given 0.50 mm SKF plus 0.50 mm Quin showed reliable preference for the infusion lever over the control lever during the first three sessions [F_(1,3) = 13.55; p = 0.01]. It should be noted that the relatively large SEM values were mainly because of the variability among subjects. Within subjects, preference for the infusion lever over the control lever was consistent. The rats exhibited a reduction in lever responses when SKF+Quin was replaced with vehicle in session 4 [the main effect of schedules, F_(1,5) = 7.31; p = 0.04]. Although not statistically reliable, rats tended to increase lever responses when SKF+Quin was reinstated in session 5 [the main effect of schedules,F_(1,5) = 4.61; p = 0.085].

Fig. 6.

Effects of increased lever–response requirements on the self-infusion of the SKF+Quin mixture into the ACB shell. Rats (n = 10) were given the opportunity to self-administer the mixture of 0.5 mm SKF plus 0.5 mm Quin over two sessions. As shown in A, rats exhibited a higher level of lever responses under the FR3 schedule than under the FR1 schedule with the levers collapsed together [F_(1,9) = 8.19; p = 0.02]; rats also exhibited a reliable lever preference for the infusion lever over the control lever with the schedules collapsed together [F_(1,9) = 6.24;p = 0.03]; and the lever × FR schedule interaction was not reliable [F_(1,9) = 2.56]. There was no reliable difference between the schedules in the number of infusions [B; t(9) = 1.47] or in the time needed to complete the session [C;t(9) = 1.90]. Data are the mean ± SEM.

Fig. 7.

Effects of D₁ and D₂antagonists on the intrashell self-administration of SKF+Quin. During three sessions, rats (n = 6) were given the opportunity to self-administer the mixture of 0.5 mm SKF plus 0.5 mm Quin (SKF+Quin) or the SKF+Quin mixture containing either 0.5 mm SCH 23390 (SKF+Quin+SCH) or 0.5 mm sulpiride (SKF+Quin+Sul). The presence of the D₁ antagonist SCH or the D₂ antagonist Sul significantly reduced intrashell self-infusion of SKF+Quin (*p < 0.01). Data are the mean ± SEM.