Dopamine D3 receptors regulate reconsolidation of cocaine memory

Abstract

Memories of learned associations between the rewarding properties of drugs of abuse and environmental cues contribute to craving and relapse in humans. Disruption of reconsolidation dampens or even erases previous memories. Dopamine (DA) mediates the acquisition of reward memory and drugs of abuse can pathologically change related neuronal circuits in the mesolimbic DA system. Previous studies showed that DA D3 receptors are involved in cocaine-conditioned place preference (CPP) and reinstatement of cocaine-seeking behavior. However, the role of D3 receptors in reconsolidation of cocaine-induced reward memory remains unclear. In the present study, we combined genetic and pharmacological approaches to investigate the role of D3 receptors in reconsolidation of cocaine-induced CPP. We found that the mutation of the D3 receptor gene weakened reconsolidation of cocaine-induced CPP in mice triggered by a 3-min (min) retrieval. Furthermore, treatment of a selective D3 receptor antagonist PG01037 immediately following the 3-min retrieval disrupted reconsolidation of cocaine-induced CPP in wild-type mice and such disruption remained at least 1 week after the 3-min retrieval. These results suggest that D3 receptors play a key role in reconsolidation of cocaine-induced CPP in mice, and that pharmacological blockade of these receptors may be therapeutic for the treatment of cocaine craving and relapse in clinical settings.

Fig. 1

A genetic mutation of the D3 receptor gene weakened reconsolidation of cocaine-induced CPP in mice. A indicates the experimental timeline. B indicates effects of the mutation of D3 receptors on reconsolidation of cocaine-induced CPP in mice. Two groups of either D3 receptor mutant (D3−/−) or wild-type (WT) mice received either cocaine (Coc at 20 mg/kg) (n=27 for D3−/− and 26 for WT) or saline (n=6 for D3−/− and 5 for WT) for place conditioning. #p<0.05 compared between the two genotypes at a dose of 20 mg/kg of cocaine on day 13 or 14. A subset of D3−/− Coc 20 mg/kg and WT Coc 20 mg/kg groups (N=10 each) were tested once again for the reconsolidation on day 14 (reconsolidation test 2), Reconso1: reconsolidation test 1; reconso2: reconsolidation test 2.

Fig. 2

The genetic mutation of the D3 receptor gene had no effects on reconsolidation of cocaine-induced CPP without the 3-min retrieval. A indicates the experimental timeline. B indicates that there was no significant difference in expression of cocaine-induced CPP betweenD3 receptor mutant mice (D3−/−) and WT littermates on day 13 without the 3-min retrieval on day 12. Two groups of D3−/− or WT mice received either cocaine (Coc at 20 mg/kg) or saline for place conditioning. N=6 for each group.

Fig. 3

The D3 receptor antagonist PG01037 attenuated reconsolidation of cocaine-induced CPP in wild-type mice. A indicates the experimental timeline and PG01037 treatment for studying effects of pharmacological blockade of D3 receptors on reconsolidation of cocaine-induced CPP in WT mice. B indicates effects of the D3 receptor antagonist PG01037 on 3-min retrieval-triggered reconsolidation of cocaine-induced CPP in WT mice. Four different groups of WT mice were trained to acquire CPP. On day 12, three groups received PG01037 injections at different doses and one group received vehicle injections. PG01037 or vehicle were administered i.p. immediately after the 3-min retrieval [N=12 for vehicle (Veh), N=8 for 3 (PG01037-3), N=10 for 10 (PG01037-10), and N=11 for 30 mg/kg (PG01037-30)]. Reconsolidation testing was performed on either day 13 (24 h after), day 14 (48 h after) or day 20 (one week after either vehicle or PG01037 treatment). #p<0.05 compared with vehicle group during the same reconsolidation testing. C: cocaine; S: saline; Reconso1: reconsolidation test 1; reconso2: reconsolidation test 2; reconso3: reconsolidation test 3.

Fig. 4

The D3 receptor antagonist PG01037 did not affect reconsolidation of cocaine-induced CPP in wild-type mice without the 3-min retrieval. A indicates the experimental timeline. B indicates effects of PG01037 treatment at 30 mg/kg on reconsolidation of cocaine-induced CPP in WT mice without the 3-min retrieval. Two different groups of WT mice were trained to acquire CPP. On day 12, one group received PG01037 injections and the other group received vehicle injections. PG01037 or vehicle were administered i.p. and mice were not subjected to the 3-min retrieval [N=12 for vehicle (Veh) and N=10 for 30 mg/kg (PG01037-30)]. Reconsolidation testing (Reconso) was performed on day 13, which was 24 h after either vehicle or PG01037 treatment. C: cocaine; S: saline.