PG01037, a novel dopamine D3 receptor antagonist, inhibits the effects of methamphetamine in rats

Abstract

Our previous studies have shown that the selective dopamine D(3) receptor antagonists SB-277011A or NGB 2904 significantly attenuate cocaine self-administration under a progressive-ratio reinforcement schedule and cocaine-, methamphetamine- or nicotine-enhanced brain stimulation reward. However, the poor bioavailability of SB-277011A has limited its potential use in humans. In the present study, we investigated the effects of the novel D(3) receptor antagonist PG01037 on methamphetamine self-administration, methamphetamine-associated cue-induced reinstatement of drug seeking and methamphetamine-enhanced brain stimulation reward. Rats were allowed to intravenously self-administer methamphetamine under fixed-ratio 2 and progressive-ratio reinforcement conditions, and then the effects of PG01037 on methamphetamine self-administration and cue-induced reinstatement were assessed. Additional groups of rats were trained for intracranial electrical brain stimulation reward and the effects of PG01037 and methamphetamine on brain stimulation reward were assessed. Acute intraperitoneal administration of PG01037 (3, 10, 30 mg/kg) failed to alter methamphetamine or sucrose self-administration under fixed-ratio 2 reinforcement, but significantly lowered the break-point levels for methamphetamine or sucrose self-administration under progressive-ratio reinforcement. In addition, PG01037 significantly inhibited methamphetamine-associated cue-triggered reinstatement of drug-seeking behavior and methamphetamine-enhanced brain stimulation reward. These data suggest that the novel D(3) antagonist PG01037 significantly attenuates the rewarding effects as assessed by progressive-ratio self-administration and brain stimulation reward, and inhibits methamphetamine-associated cue-induced reinstatement of drug-seeking behavior These findings support the potential use of PG01037 or other selective D(3) antagonists in the treatment of methamphetamine addiction.

Figure 1

Chemical structures of D₃ receptor antagonists SB-277011A and PG01037.

Figure 2

Effects of PG01037 (3–30 mg/kg, i.p.) on methamphetamine self-administration under fixed-ratio 2 (FR2) reinforcement schedules in rats. (A) There was no significant effect of PG01037 on the rate of infusion for methamphetamine self-administration. (B) There was no effect of PG0137 on inactive lever presses.

Figure 3

Effects of PG01037 (3–30 mg/kg, i.p.) on methamphetamine self-administration under a progressive ratio (PR) schedule of reinforcement. Panel A shows representative individual responding curve for methamphetamine (0.05 mg/kg/infusion) after vehicle (upper trace) or 10 mg/kg PG01037 (lower trace) pretreatment. Panel B shows a significant reduction in PR breakpoint following pretreatment with PG01037. Data are presented as percent change from baseline. ***p < 0.001, when compared with the vehicle treatment group.

Figure 4

Effect of PG01037 (3–30 mg/kg, i.p.) on oral sucrose self-administration. Panel A shows no significant effect of PG01037 on sucrose self-administration under an FR2 schedule of reinforcement. Panel B shows a significant and dose dependent reduction of PR break-points levels for oral sucrose following pretreatment with PG01037. Data are presented as percent change from baseline. ***p < 0.001, when compared with the vehicle treatment group.

Figure 5

Effects of PG01037 (3–30 mg/kg, i.p.) on reinstatement of cue-induced drug-seeking behavior triggered by presentation of methamphetamine-associated cues. Panel A shows a statistically significant reduction in cue-induced methamphetamine seeking after 10 and 30 mg/kg PG01037, but not 3 mg/kg PG01037 when compared with vehicle treatment group **p<0.01. In contrast, Panel B shows that PG01037 had no significant effect on inactive lever presses in the last self-administration sessions, last extinction sessions, or during the cue-induced reinstatement test.

Figure 6

Effect of PG01037 (0–30 mg/kg, i.p.) and methamphetamine on brain-stimulation reward (BSR). Panel A shows that PG01037 (10 or 30 mg/kg, but not 3 mg/kg), significantly attenuated methamphetamine-enhanced BSR, as assessed by BSR threshold (θ₀). PG01037 alone, at 30 mg/kg, but not 3 or 10 mg/kg, also produced a significant inhibition of BSR. Panel B shows that neither PG01037 nor methamphetamine altered Y_max levels at any doses tested. **p < 0.01, ***p < 0.001, compared with the vehicle treatment group.