The D3 receptor antagonist SR 21502 reduces cue-induced reinstatement of methamphetamine-seeking in rats

Abstract

There is as of yet no FDA-approved medication for methamphetamine use disorder. Although dopamine D3 receptor antagonists have been shown to be useful in reducing methamphetamine seeking in animal models their translation to the clinic has been hindered because currently tested compounds can produce dangerously high blood pressure. Thus, it is important to continue to explore other classes of D3 antagonists. We report here the effects of SR 21502, a selective D3 receptor antagonist, on cue-induced reinstatement (i.e., relapse) of methamphetamine-seeking in rats. In Experiment 1, rats were trained to self-administer methamphetamine under a fixed ratio schedule of reinforcement followed by extinction of the response. Then, animals were tested with one of several doses of SR 21502 on cue-induced reinstatement of responding. SR 21502 significantly reduced cue-induced reinstatement of methamphetamine-seeking. In Experiment 2, animals were trained to lever press for food under a PR schedule and tested with the lowest dose of SR 21502 that caused a significant reduction in Experiment 1. These animals responded on average 8 times more than the vehicle-treated rats in Experiment 1, eliminating the possibility that SR 21502-treated rats in Experiment 1 responded less because they were incapacitated. In summary, these data suggest that SR 21502 may selectively inhibit methamphetamine-seeking and may constitute a promising pharmacotherapeutic agent for methamphetamine or other drug use disorders.

Keywords: Dopamine receptors; Psychostimulants; Relapse; Substance use disorder; Treatment.

Figure 1:

D3 receptor binding mode comparison of SR 21502 (A) and eticlopride (B). Residues variated between D3 and D2 receptors are represented in golden carbons. Salt-bridge, hydrogen bond, and hydrophobic contacts are indicated by cyan, black, and orange dashed lines respectively.

Figure 2:

A. Mean (± SEM) number of methamphetamine infusions across 15 daily self-administration sessions. B. Mean (+SEM) number active and inactive lever presses across 15 daily methamphetamine self-administration sessions.

Figure 3:

Mean (± SEM) number of active and inactive lever presses across 15 daily extinction sessions.

Figure 4:

Left panel: mean (±SEM) number of presses on the active and inactive levers averaged across the last three extinction sessions for all animals separated into eventual SR 21502 dose groups. Right panel: mean (±SEM) number of presses on the active and inactive levers during the reinstatement test for all groups treated with vehicle or a dose of SR 21502. * Significant phase by lever interaction (i.e., reinstatement effect) p < .05.

Figure 5:

Mean (±SEM) number of lever presses for the same vehicle-treated reinstatement group shown in Figure 3 and a group lever pressing under a progressive ratio schedule of food reinforcement and treated with the 15mg/kg dose of SR21502.