Blockade of D3 receptors by YQA14 inhibits cocaine's rewarding effects and relapse to drug-seeking behavior in rats

Abstract

Preclinical studies suggest that dopamine D3 receptor (D3R) antagonists are promising for the treatment of drug abuse and addiction. However, few D3R antagonists have potential to be tested in humans due to short half-life, toxicity or limited preclinical research into pharmacotherapeutic efficacy. Here, we report on a novel D3R antagonist YQA14, which has improved half-life and pharmacokinetic profile and which displays potent pharmacotherapeutic efficacy in attenuating cocaine reward and relapse to drug-seeking behavior. Electrical brain-stimulation reward (BSR) in laboratory animals is a highly sensitive experimental approach to evaluate a drug's rewarding effects. We found that cocaine (2 mg/kg) significantly enhanced electrical BSR in rats (i.e., decreased stimulation threshold for BSR), while YQA14 alone had no effect on BSR. Pretreatment with YQA14 significantly and dose-dependently attenuated cocaine-enhanced BSR. YQA14 also facilitated extinction from drug-seeking behavior in rats during early behavioral extinction, and attenuated cocaine- or contextual cue-induced relapse to drug-seeking behavior. YQA14 alone did not maintain self-administration in either naïve rats or in rats experienced at cocaine self-administration. YQA14 also inhibited expression of repeated cocaine-induced behavioral sensitization. These findings suggest that YQA14 may have pharmacotherapeutic potential in attenuating cocaine-taking and cocaine-seeking behavior. Thus, YQA14 deserves further investigation as a promising agent for treatment of cocaine addiction.

Keywords: Cocaine; D3 receptors; Dopamine; Reinstatement; Reward; YQA14.

Figure 1

Effects of YQA14 on cocaine-enhanced BSR in rats. A: A representative rate-frequency function curve for BSR, illustrating BSR stimulation threshold (θ₀), M₅₀ and Ymax; B: Representative rate-frequency function curves for BSR, illustrating that cocaine (2 mg/kg, i.p.) shifted the rate-frequency function curve to the left, lowering the BSR threshold θ ₀ value (i.e., enhancing BSR), without a change in the Ymax level. C: Systemic administration of YQA14 dose-dependently decreased cocaine-enhanced BSR. D: Systemic administration of YQA14 alone had no effect on basal BSR. ^**p<0.01 compared to vehicle control group.

Figure 2

Cocaine and YQA14 self-administration. Intravenous administration of cocaine, but not YQA14, induced self-administration in drug naïve rats (A). YQA14 substitution for cocaine failed to maintain drug self-administration behavior in rats previously self-administering cocaine. ^***p<0.001 compared to vehicle control group.

Figure 3

Effects of YQA14 on drug-seeking behavior during extinction. Systemic administration of YQA14 dose-dependently decreased active lever presses (A), but not inactive lever presses (B), in rats during extinction conditions in which cocaine or cocaine-associated cue-light and tone were not available. ^*p<0.05, ^**p<0.01, ^***p<0.001 compared to vehicle control group.

Figure 4

Effects of YQA14 on cocaine-triggered reinstatement of drug-seeking behavior. Systemic administration of YQA14 (12.5 or 25 mg/kg i.p., 20 min prior to test) significantly inhibited cocaine-triggered reinstatement of drug-seeking behavior in rats extinguished from daily cocaine self-administration. ^***p<0.001, when compared with the vehicle pretreatment group.

Figure 5

Effects of YQA14 on contextual cue-triggered cocaine-seeking behavior. Systemic administration of YQA14 (12.5 or 25 mg/kg, i.p., 20 min prior to test) significantly inhibited contextual cue-triggered drug-seeking behavior in rats after 14 days of withdrawal from previous cocaine self-administration. ^*p<0.05, when compared with the vehicle pretreatment group.

Figure 6

Effects of YQA14 on basal level of locomotion and cocaine-induced behavioral sensitization. A: Pretreatment of YQA14 (12.5, 25 mg/kg, i.p., 20 min prior to each cocaine injection) did not produce a statistically significant inhibition on acquisition of cocaine-induced locomotor sensitization. Repeated administration of YQA14 (25 mg/kg) alone also failed to alter basal levels of locomotion. B: A single injection of YQA 14 (12.5, 25 mg/kg, i.p.) significantly inhibited expression of cocaine-induced locomotor sensitization in rats 7 days after the last cocaine injection.