Dopamine D₃Receptor Antagonism Inhibits Cocaine-Seeking and Cocaine-Enhanced Brain Reward in Rats

Abstract

dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.

The Novel Dopamine D3 Receptor Antagonist NGB 2904 Inhibits Cocaine's Rewarding Effects and Cocaine-Induced Reinstatement of Drug-Seeking Behavior in Rats

“…Using this animal relapse model, we found that pretreatment with NGB 2904 (0.1, 1, and 5 mg/kg) significantly attenuated cocaine-triggered reinstatement of cocaineseeking behavior at doses that failed to reduce sucrose-plussucrose-cue-induced reinstatement of sucrose-seeking behavior, suggesting that NGB 2904-induced reduction in cocaine-seeking behavior is not caused by a generalized suppression of operant behavior. This finding is consistent with the previous finding that SB-277011A inhibits cocainetriggered reinstatement of cocaine-seeking, but not foodtriggered reinstatement of food-seeking (Vorel et al, 2002).…”

“…The general procedures for electrical BSR were the same as we have reported previously (Vorel et al, 2002;Hayes et al, 2003). Briefly, after 7 days of recovery from surgery, rats were allowed to self-train (autoshape) to lever-press for rewarding BSR.…”

“…Consequently, this raises the issue of whether the presently observed attenuating effects of NGB 2904 in these three behavioral paradigms might be attributable to D 1 or D 2 receptor-selective antagonism rather than to D 3 receptor-selective antagonism. We believe that is unlikely, because (1) multiple lines of in vitro evidence indicate that NGB 2904 is a highly selective D 3 receptor antagonist (Yuan et al, 1998;Robarge et al, 2001;Newman et al, 2003Newman et al, , 2005; see Introduction); (2) in the BSR paradigm, D 1 -and D 2 -preferring DA receptor antagonists inhibit brain reward functions, in a manner opposite to the brain reward enhancement produced by addictive drugs (Stein and Ray, 1960;Stein, 1962;Wise, 1982;Panagis and Spyraki, 1996;Gardner, 2005), while selective blockade of DA D 3 receptors by either NGB 2904 or SB-277011A does not alter electrical brain reward thresholds (Vorel et al, 2002;Campos et al, 2003Campos et al, , 2004; and finally (3) NGB 2904 does not significantly alter locomotor activity at the dose range tested in the present study (Newman et al, 2005), again unlike D 1 or D 2 receptor antagonists.…”

“…It significantly inhibits the rewarding effects of cocaine, heroin, and nicotine, as assessed by intravenous (i.v.) drug self-administration, intracranial brain stimulation reward (BSR), and conditioned place preference in rats (Vorel et al, 2002;Campos et al, 2003;Ashby et al, 2003;Gilbert et al, 2003). It also inhibits drug-seeking behavior as measured by secondorder reinforcement and by cocaine-, nicotine-, or stresstriggered relapse to drug-seeking in the reinstatement model (Vorel et al, 2002;Andreoli et al, 2003;Di Ciano et al, 2003;Cervo et al, 2003;Xi et al, 2004).…”

Nicotine-Associated Cues Maintain Nicotine-Seeking Behavior in Rats Several Weeks after Nicotine Withdrawal: Reversal by the Cannabinoid (CB1) Receptor Antagonist, Rimonabant (SR141716)

“…Presentation of cocainepaired stimuli increased dopamine release in the nucleus accumbens and amygdala in rats (Weiss et al, 2000;Ito et al, 2000). Moreover, pretreatment with dopamine receptor antagonists prevented cue-induced cocaine-and ethanolseeking behavior (Pilla et al, 1999;Ciccocioppo et al, 2001;Liu and Weiss, 2002;Vorel et al, 2002). Although the importance of conditioned cues in the acquisition of nicotine self-administration has been demonstrated (Goldberg et al, 1981;Caggiula et al, 2001Caggiula et al, , 2002, the mechanisms underlying nicotine-seeking behavior induced by drug-associated stimuli have not yet been investigated.…”