Selective antagonism at dopamine D3 receptors attenuates cocaine-seeking behaviour in the rat

Abstract

Dopamine (DA) D3 receptors have been suggested to play a role in mechanisms underlying the ability of drug-associated cues to induce drug-seeking behaviour. The present study investigated whether SB-277011-A, a selective DA D3 receptor antagonist, modulates reinstatement of cocaine-seeking behaviour induced by cocaine-associated stimuli. The study also explored whether or not this modulation is generable to seeking behaviours associated with a nutritive reinforcer such as sucrose. Separate groups of rats were trained to associate discriminative stimuli (SD) with the availability of cocaine or sucrose pellets vs. non-reward under a FR1 schedule of reinforcement. Each reinforced response was followed by a response-cue signalling a 20-s time-out (TO). After the self-administration training criterion was met, rats underwent extinction during which cocaine, sucrose pellets and SDs were withheld. Reinstatement tests, separated by 3 d during which rates of responding under extinction conditions remained at the criterion, were performed by presenting SDs non-contingently together with the contingent presentation of response-cues signalling a 20-s TO. Within- and between-subjects experimental designs revealed that 10 and 30 mg/kg SB-277011-A attenuated reinstatement of cocaine-seeking. SB-277011-A (10 mg/kg) did not modify conditioned reinstatement triggered by sucrose pellet-associated cues. These results, provided they can be extrapolated to abstinent human addicts, suggest the potential therapeutic use of selective DA D3 receptor antagonists for the prevention of cue-controlled cocaine-seeking and relapse.

The selective dopamine D3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats

“…It is also consistent with prior intravenous drug selfadministration experiments demonstrating that SB-277011A or NGB 2904 dose-dependently inhibits cocaine or nicotine self-administration under PR reinforcement schedules Ross et al 2007) and prevents reinstatement of drug-seeking behavior induced by cocaine or nicotine, drug-related cues, or stress (Vorel et al 2002;Xi et al 2004Xi et al , 2006Andreoli et al 2003;Cervo et al 2007). SB-277011A is a highly potent and selective D 3 receptor antagonist that has 80-to 100-fold selectivity for D 3 over other DA receptors and 100-fold selectivity over 180 other receptors, enzymes, ion channels, and transporters in the central nervous system (Reavill et al 2000;Stemp et al 2000;Micheli and Heidbreder 2006;Heidbreder et al, unpublished data).…”

“…Third, pharmacological studies demonstrate that DA D 3 receptors play an important role in emotion, motivation, and reinforcement, including the reinforcement produced by addictive drugs (Caine and Koob 1993;Duaux et al 1998;Sokoloff et al 2006). Growing evidence demonstrates that blockade of D 3 receptors by the selective D 3 receptor antagonists SB-277011A or NGB 2904 or by the putative partial D 3 receptor agonist BP-897 significantly inhibits reinstatement of drug-seeking behaviors triggered by addictive drugs, such as cocaine, nicotine, or alcohol, drug-associated cues or foot-shock stress (Vorel et al 2002;Andreoli et al 2003;Xi et al 2004Xi et al , 2006Cervo et al 2007), and also inhibits cocaine or nicotine self-administration under progressive-ratio (PR), second-order, or high-effort/low-payoff reinforcement schedules (Di Ciano et al 2003;Xi et al 2005Xi et al , 2006Ross et al 2007). These data support the potential use of selective D 3 receptor antagonists or partial agonists in the clinical treatment of drug craving and relapse to drug-taking or drug-seeking behavior (see reviews by Le Foll and Goldberg 2005;Heidbreder et al 2005;Xi and Gardner 2007).…”

Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists

“…While the MEDs for the inhibition of yawning by PG01037 and SB-277011A (32.0 mg/kg for both) are slightly higher than those reported for SB-277011A on a variety of operant behaviors (3.0 -24 mg/kg; Andreoli et al 2003;Di Ciano et al 2003;Xi et al 2004;Gilbert et al 2005;Xi et al 2005;Cervo et al 2007) and are likewise higher than might be expected based on in vitro D3 affinities of 0.7 nM and 10.7 nM respectively Grundt et al 2005) there is no evidence to suggest that the inhibition of yawning by these antagonists results from anything other than an antagonist activity at the D3 receptor. Not only did PG01037 and SB-277011A not inhibit sumanirole-induced hypothermia or increase yawning induced by high doses of PD-128,907 in the current studies at doses up to 56.0 mg/ kg, but SB-277011A also failed to induce catalepsy and increases plasma prolactin levels at doses up to 78.8 and 93 mg/kg; p.o.…”

The effects of two highly selective dopamine D3 receptor antagonists (SB-277011A and NGB-2904) on food self-administration in a rodent model of obesity

“…Upon meeting the vehicle baseline criteria, all the rats in Experiment 1 continued on the same protocol using a randomized Latin square design of SB-277011A administration (3 mg/kg; 10 mg/kg and 30 mg/kg for three consecutive sessions at each dose). The doses of SB-277011A were selected based on previous studies (Cervo et al, 2007;Heidbreder et al, 2007;Thanos et al, 2005). For Experiment 2, the similar randomized design was used for NGB-2904 after vehicle criteria was achieved (0.3 mg/kg; 1 mg/kg and 3 mg/kg).…”

“…In rats, SB-277011A has been reported to 1) attenuate cue-induced cocaine self-administration behavior Vorel et al, 2002); 2) block the expression of cocaine and heroin-induced conditioned place preference (CPP) (Ashby et al, 2003;Vorel et al, 2002); 3) attenuate alcohol intake in ethanol preferring rats Thanos et al, 2005) and 4) suppress alcohol self-administration, and prevent reinstatement of alcoholseeking in mice Thanos et al, 2005). In addition, SB-277011A significantly attenuated nicotine-triggered relapse to nicotine seeking (Andreoli et al, 2003;Pak et al, 2006) as well as sucrose-seeking behavior induced by sucrose-associated cue reintroduction (Cervo et al, 2007).…”