Dopamine D3 and D2 Receptor Mechanisms in the Abuse-Related Behavioral Effects of Cocaine: Studies with Preferential Antagonists in Squirrel Monkeys

Abstract

Dopamine (DA) D3 and D2 receptor mechanisms are implicated in cocaine's abuse-related behavioral effects, but the relative contribution of the two receptor subtypes is only partially characterized. This study investigated the role of D3 and D2 subtype mechanisms by determining the degree to which the D3-preferr- were compared. In monkeys trained to discriminate cocaine from vehicle, both DA antagonists attenuated and both DA agonists partially reproduced cocaine's DS effects. PG01037 also selectively attenuated the cocaine-like DS effects of PD128907, whereas L-741626 attenuated the cocaine-like DS effects of both agonists. In self-administration studies, L-741626 nonselectively reduced cocaine-and food-maintained responding, whereas PG01037 was ineffective against either reinforcer. In studies involving reinstatement of extinguished cocaine seeking, both antagonists attenuated cocaine-induced reinstatement of responding, and both agonists induced at least partial reinstatement of cocaine seeking. L-741626 also attenuated sumanirole-induced, but not PD128907-induced, reinstatement of responding, whereas PG01037 was ineffective against either DA agonist. The results are consistent with a role for D3 and D2 receptor mechanisms in cocaine's DS effects and cocaine-induced reinstatement of drug seeking, but provide no evidence for a major role of D3 receptors in the direct reinforcing effects of cocaine.Cocaine inhibits the reuptake of DA into presynaptic terminals, resulting in stimulation of DA receptors primarily located in motor and limbic brain systems. Within the D2 family of DA receptors, there is substantial evidence for the role of the D2 receptor subtype in cocaine-induced behaviors; however, this research has not generated successful candidates for the treatment of cocaine addiction (see Xi and Gardner, 2008 for review). Considerably less is understood about the function of the D3 receptor subtype, primarily because of a lack of selective pharmacological probes that

Glycine Transporter-1 Inhibition Preceding Extinction Training Inhibits Reacquisition of Cocaine Seeking

“…Seven monkeys were trained to self-administer cocaine (0.18 mg/kg/injection) by pressing a lever under a secondorder fixed-interval 5-min fixed ratio 10, FI 5 (FR10 : S), schedule of intravenous drug injection similar to the schedule described by Achat-Mendes et al (2010). Rats were similarly trained to press a lever to self-administer cocaine (0.3 mg/ kg/injection) under an FI 5 (FR5 : S) schedule.…”

Dopamine D3Receptor Antagonist (GSK598809) Potentiates the Hypertensive Effects of Cocaine in Conscious, Freely-Moving Dogs

“…The dopamine D 3 receptor antagonist S33138 attenuated cocaine-enhanced brain stimulation reward and priming-induced relapse (Peng et al, 2009), and the dopamine D 3 receptor antagonist SR 21502 reduced cocaine-conditioned place preference (Hachimine et al, 2014), cue-induced relapse, and cocaine selfadministration (Galaj et al, 2014). The dopamine D 3 receptor antagonist PG01037 reduced cocaine-primed relapse in squirrel monkeys (Achat-Mendes et al, 2010), and the dopamine D 3 receptor antagonist YQA14 reduced cocaine-enhanced brain stimulation reward and attenuated cue-induced relapse (Song et al, 2014), as well as cocaine self-administration (Song et al, 2012) in rats. There is anatomic evidence for the dopamine D 3 receptor as a target also.…”

Dopamine D1 and D3 receptors mediate reconsolidation of cocaine memories in mouse models of drug self-administration

“…Both D1 and D3 receptors are expressed in mesolimbic DA projection areas. We and others have shown that D1 (Xu et al, 1994a; 1994b; 2000; Anderson et al, 2003; Bachtell et al, 2005; Alleweireldt et al, 2006; Berglind et al, 2006; Caine et al, 2007; Chen and Xu, 2010) and D3 receptors (Xu et al, 1997; Pilla et al., 1999; Vorel et al, 2002; Di Ciano et al, 2003; Neisewander et al, 2004; Xi et al, 2004; 2005; 2006; Martelle et al, 2007; Micheli and Heidbreder, 2008; Heidbreder and Newman, 2010; Achat-Mendes, et al, 2010; Chen and Xu, 2010; Kong et al, 2011; Song et al, 2012a, b) mediate locomotor-stimulant and positive reinforcing effects of cocaine, as well as cue-induced reinstatement of cocaine-seeking.…”

“…Many D3 receptor agonists and antagonists have been developed and tested and several D3 receptor antagonists show promise for attenuating reinstatement of drug-seeking in preclinical studies (Micheli and Heidbreder, 2008; Heidbreder and Newman, 2010; Newman et al, 2012). Among the many D3 receptor-preferring antagonists that have been developed and evaluated, PG01037 ( N -{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]- trans -but-2-enyl}-4-pyridine-2-yl-benzamide) selectively blocked D3-agonist induced yawning and attenuates reinstatement of drug-seeking via pharmacological antagonism of D3 receptors (Collins et al, 2005; 2007; Xi et al, 2006; Martelle et al, 2007, Achat-Mendes et al, 2010; Higley et al, 2011). We previously used both a D3 receptor mutant mouse model and PG01037 and found that D3 receptors play a key role in reconsolidation of cocaine-induced conditioned place preference (CPP) (Yan et al, 2013), implying the involvement of DA signaling in reconsolidation of cocaine memory.…”