Dopamine D3 receptor deletion or blockade attenuates cocaine-induced conditioned place preference in mice

Abstract

The dopamine (DA) D3 receptor (D3R) has received much attention in medication development for treatment of addiction. However, the functional role of the D3R in drug reward and addiction has been a matter of debate. We recently reported that D3 receptor-knockout (D3−/−) mice display increased vulnerability to cocaine self-administration, which we interpret as a compensatory response to attenuated cocaine reward after D3R deletion. Here we report that D3−/− mice displayed attenuated cocaine-induced conditioned place response (CPP) compared to wild-type mice. Similarly, blockade of brain D3Rs by YQA-14, a novel DA D3 receptor antagonist, significantly and dose-dependently inhibits acquisition and expression of cocaine-induced CPP in WT mice, but not in D3−/− mice. These findings suggest that: 1) D3Rs play an important role in mediating cocaine’s rewarding effects; and 2) YQA-14 is a highly potent and selective D3R antagonist in vivo, which deserves further study as a candidate for treatment of cocaine addiction.

A selective D3 receptor antagonist YQA14 attenuates methamphetamine-induced behavioral sensitization and conditioned place preference in mice

“…These results suggest that D 3 Rs play a more important role in the expression of conditioned behaviors than in their acquisition [47,50] . Regardless of the mechanisms underlying the ineffectiveness of YQA14 at combatting the acquisition of METH-induced CPP, the present finding that YQA14 inhibits the expression of METH-induced CPP is consistent with previous reports that have shown that the blockade of D 3 Rs by SB-277011A, YQA14 or SR21502 inhibits cocaine-induced CPP [14,22,51] , cocaine and METH self-administration [12,18,21,31] , and cocaine-and METHinduced enhancement of electrical brain stimulation rewards [21,33,35] . Importantly, YQA14 itself does not induce CPP or CPA [22] .…”

“…In this study, we used cue-exposure therapy protocols combined with the use of selective D 3 R antagonists such as YQA14. The results are similar to those in previous studies showing that the chronic administration of YQA14 inhibits morphineinduced reinstatement of CPP and that the acute administration of YQA14 inhibits cocaine-or cue-induced relapse to cocaine-seeking behavior [12,21,22,58] . The neuronal mechanisms underlying these effects are unclear.…”

“…This is consistent with the significantly attenuated acute locomotor responses observed following administration of METH in D 3 R −/− mice compared with the effects observed in wild-type mice [30] . These results are also consistent with the ability of YQA14 and other D 3 R antagonists, such as SB-277011A, NGB2904, and PG-01037, to significantly inhibit METH or cocaine selfadministration [12,13,18,21,22,[31][32][33][34] and METH-or cocaine-enhanced electrical brain stimulation rewards, two of the other most common animal models used to evaluate drug reward systems [14-16, 22, 33, 35] . Behavioral sensitization has been proposed as a useful paradigm for investigating the mechanisms involved in addiction to psychostimulants.…”

“…Moreover, pharmacokinetic assays demonstrate that YQA14 has improved oral bioavailability (~20%) in vivo in dogs and a longer half-life (>1.5 h in human liver microsome enzymes) compared with SB-277011A (~20 min) in vitro [20] . YQA14 appears to have no rewarding or addictive potential because it does not sustain self-administration in rats that previously self-administered cocaine [21] or induce conditioned place preference (CPP) or conditioned place aversion (CPA) [22] . Furthermore, YQA14 has no effect on locomotor activity when administered acutely or chronically [21] .…”

P-Glycoprotein (ABCB1) Limits the Brain Distribution of YQA-14, a Novel Dopamine D₃ Receptor Antagonist

“…2,3) The pharmacological actions of YQA-14 on the central nervous system (CNS) have been reported in several animal models, including in self-administration, drug seeking behavior and behavior sensitization. [2][3][4][5] To date, SB-277011 A has been the most extensively-studied D 3 receptor antagonist in multiple animal models of addiction. But further development of SB-277011 A has been terminated due to problematic pharmacokinetics.…”