Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist

Abstract

Environmental stimuli that are reliably associated with the effects of many abused drugs, especially stimulants such as cocaine, can produce craving and relapse in abstinent human substance abusers. In animals, such cues can induce and maintain drug-seeking behaviour and also reinstate drug-seeking after extinction. Reducing the motivational effects of drug-related cues might therefore be useful in the treatment of addiction. Converging pharmacological, human post-mortem and genetic studies implicate the dopamine D3 receptor in drug addiction. Here we have designed BP 897, the first D3-receptor-selective agonist, as assessed in vitro with recombinant receptors and in vivo with mice bearing disrupted D3-receptor genes. BP 897 is a partial agonist in vitro and acts in vivo as either an agonist or an antagonist. We show that BP 897 inhibits cocaine-seeking behaviour that depends upon the presentation of drug-associated cues, without having any intrinsic, primary rewarding effects. Our data indicate that compounds like BP 897 could be used for reducing the drug craving and vulnerability to relapse that are elicited by drug-associated environmental stimuli.

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

“…This suggestion is consistent with our findings that NGB 2904 or SB-277011A had no effect on cocaine self-administration under continuous FR reinforcement conditions in which a high cumulative dose is easily built up, but significantly inhibited cocaine self-administration under PR reinforcement conditions in which a high cumulative dose of drug is difficult to achieve (Di Ciano et al, 2003;Gilbert et al, 2003). Similarly, BP-897 (a D 3 partial agonist whose antagonist properties may predominate; see Wood et al, 2000;Wicke and Garcia-Ladona, 2001) also fails to inhibit cocaine self-administration under FR reinforcement conditions, but significantly inhibits cocaine-seeking behavior under second-order reinforcement conditions (Pilla et al, 1999), under which the brain's DA response to the cocaineassociated cues that drive second-order reinforced drugseeking behavior is substantially lower than to cocaine itself (ie approximately a 25% increase in accumbens DA produced by cocaine-associated cues (Gerasimov et al, 2001) vs approximately a 200-800% increase in accumbens DA produced by either exogenously or self-administered cocaine (Wise et al, 1995;Dewey et al, 1997)). …”

“…This compound has structural similarity to BP-897 (Pilla et al, 1999;Wood et al, 2000;Wicke and Garcia-Ladona, 2001), and binds with high affinity to cloned primate D 3 receptors (K i 1.4 nM) (Yuan et al, 1998;Robarge et al, 2001). NGB 2904 is reported to have 155-fold selectivity for primate D 3 over primate D 2 receptors, and 4800-fold selectivity for rat D 3 vs D 2 receptors (Yuan et al, 1998;Newman et al, 2003).…”

“…Recently, the D 3 partial agonist BP-897 (Pilla et al, 1999) and several D 3 -selective antagonists such as SB-277011A, S33084, A-437203, and NGB 2904 (N-(4-[4-{2, 3-dichlorophenyl}-1-piperazinyl]butyl)-3-fluorenylcarboxamide) have become available (Yuan et al, 1998;Stemp et al, 2000;Reavill et al, 2000;Millan et al, 2000), and some have been evaluated in animal models of addiction (for a review see Heidbreder et al, 2005). SB-277011A is the best characterized of these (see reviews by Le Foll et al, 2000;Schwartz et al, 2000;Remington and Kapur, 2001;Heidbreder et al, 2005).…”

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.…”

Effects of a Dopamine D3 Receptor Ligand, BP 897, on Acquisition and Expression of Food-, Morphine-, and Cocaine-induced Conditioned Place Preference, and Food-seeking Behavior in Rats

“…Interestingly, using BP 897, a ligand that displays a higher preference ratio for D 3 over D 2 receptors (B70-fold, as measured at recombinant human receptors, and B20-fold, in functional assays (Pilla et al, 1999)), recent studies gave more direct evidence for an involvement of D 3 R in rewardrelated processes. In vivo, BP 897 acts as a D 3 R partial agonist or antagonist, at low doses, and as a weak D 2 R antagonist at doses above 10 mg/kg (Pilla et al, 1999;Wood et al, 2000;Wicke and Garcia-Ladona, 2001).…”