Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats

Abstract

Rationale-The dopamine (DA) D 3 receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D 3 receptor blockade by the novel D 3 antagonist SB-277011A inhibits cocaine's reinforcing action and cocaine-induced reinstatement of cocaineseeking behavior. © Springer-Verlag 2004Correspondence to: Zheng-Xiong Xi, zxi@intra.nida.nih.gov. NIH Public Access Author ManuscriptPsychopharmacology (Berl). Author manuscript; available in PMC 2013 July 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptObjective-In the present study, we investigated whether SB-277011A similarly inhibits stressinduced reinstatement of cocaine-seeking behavior.Methods-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.Results-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.Conclusions-The mesolimic DA D 3 receptor plays an important role in mediating stressinduced reinstatement.

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

“…This is consistent with previous studies demonstrating that haloperidol (a preferential D 2 vs D 3 receptor antagonist) and raclopride (a mixed D 2 /D 3 receptor antagonist) have dysphorigenic or aversive properties in both humans and laboratory animals (Singh et al 1996;Kita et al 1999;Baldo et al 1999; see review by Platt et al 2002). This is also consistent with previous studies demonstrating that BP-897 produces an aversive-like effect, as assessed in the BSR and conditioned place preference/aversion paradigms (Duarte et al 2003;Gyertyán and Gál 2003;Campos et al 2004). In addition, BP-897 also produces a compensatory increase in cocaine self-administration (Gyertyán and Gál 2003), and inhibits quinpirole (a mixed D 2 / D 3 receptor agonist)-induced inhibition of DA neuronal firing in the substantia nigra, similar to the D 2 receptor antagonist haloperidol (Wicke and Garcia-Ladona 2001).…”

“…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).…”

Dissociation of Psychomotor Sensitization from Compulsive Cocaine Consumption

“…Several procedural variables may explain this apparent discrepancy. First, in all previous studies except one (Deroche et al, 1999), daily access time to cocaine was longer than the minimum of the present study (ie 1 h) and ranged between 2 and 6 h (eg de Wit and Stewart, 1981;Erb et al, 1996;De Vries et al, 1998;Lynch and Carroll, 2000;Lu et al, 2004;Fuchs et al, 2004;Schenk and Partridge 1999;Neisewander et al, 1996;Xi et al, 2004;Sutton et al, 2003;Dias et al, 2004). Thus, together with the present findings, this difference may point to the existence of some threshold duration below which most individuals readily learn to take cocaine without becoming responsive to its motivational effects and above which they begin to respond to these effects.…”

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

“…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). These data strongly support the potential of SB-277011A in the treatment of drug addiction.…”