Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats
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The dopamine (DA) D3 receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D3 receptor blockade by the novel D3 antagonist SB-277011A inhibits cocaine’s reinforcing action and cocaine-induced reinstatement of cocaine-seeking behavior.
In the present study, we investigated whether SB-277011A similarly inhibits stress-induced reinstatement of cocaine-seeking behavior.
Rats were allowed to self-administer cocaine (0.5 mg/kg per infusion, 3 h per session) for 10–14 days, followed by a once-daily extinction session for 7–14 days during which saline was substituted for cocaine. Extinction criteria were fewer than ten lever-presses per 3-h session for at least 3 consecutive days. After cocaine-seeking behavior was extinguished, each animal was tested twice for footshock-stress-induced reinstatement, once with vehicle (25% hydroxypropyl-β-cyclodextrin) and once with one of three doses of SB-277011A in counterbalanced fashion.
During the last 3 days of cocaine self-administration (SA), active lever-presses were approximately 100 per session under fixed-ratio 2 reinforcement (∼25 mg/kg cocaine per session). After extinction, intermittent footshock (10 min, 0.5 mA, 0.5 s on with a mean inter-shock interval of 40 s) robustly reinstated the cocaine-seeking behavior (8.4±3.6 active lever-presses in last extinction session to 35.3±5.2 in animals after footshock stress). Intraperitoneal (IP) injections of SB-277011A (3, 6, and 12 mg/kg) dose-dependently blocked stress-induced reinstatement of cocaine-seeking. Reinstatement was also blocked by microinjections of SB-277011A (1.5 μg/0.5 μl per side) bilaterally into the nucleus accumbens, but not into the dorsal striatum.
The mesolimic DA D3 receptor plays an important role in mediating stress-induced reinstatement.
KeywordsAccumbens Addiction Cocaine Dopamine D3 antagonist Reinstatement Relapse SB-277011A Self-administration Stress
The authors thank Yavin Shaham for advice on technical aspects of the footshock procedure and for insightful criticisms and suggestions regarding the manuscript, and Richard Taylor for assistance with the data analyses. This work was supported by the Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, US. Department of Health and Human Services, and by GlaxoSmithKline Pharmaceuticals. Equipment support was provided by the Aaron Diamond Foundation of New York, the Julia Sullivan Medical Research Fund, and the Old Stones Foundation.
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