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

Highlights

• Pharmacological blockade of D1 or D3 receptors disrupts reconsolidation of cocaine memory.

• Genetic mutations in D3 receptors attenuate reconsolidation of cocaine-induced reward memory.

• Dopamine D1 and D3 receptors may serve as new targets for combating cocaine abuse.

Abstract

Memories of drug experience and drug-associated environmental cues can elicit drug-seeking and taking behaviors in humans. Disruption of reconsolidation of drug memories dampens previous memories and therefore may provide a useful way to treat drug abuse. We and others previously demonstrated that dopamine D1 and D3 receptors play differential roles in acquiring cocaine-induced behaviors. Moreover, D3 receptors contribute to the reconsolidation of cocaine-induced conditioned place preference. In the present study, we examined effects of manipulating D1 or D3 receptors on reconsolidation of cocaine memories in mouse models of drug self-administration. We found that pharmacological blockade of D1 receptors or a genetic mutation of the D3 receptor gene attenuated reconsolidation that lasted for at least 1 week after the memory retrieval. In contrast, with no memory retrieval, pharmacological antagonism of D1 receptors or the D3 receptor gene mutation did not significantly affect reconsolidation of cocaine memories. Pharmacological blockade of D3 receptors also attenuated reconsolidation in wild-type mice that lasted for at least 1 week after the memory retrieval. These results suggest that D1 and D3 receptors and related signaling mechanisms play key roles in reconsolidation of cocaine memories in mice, and that these receptors may serve as novel targets for the treatment of cocaine abuse in humans.

Introduction

A central feature of drug addiction is the compulsive seeking and taking of drugs despite known negative consequences. Addicts experience drug craving after long periods of abstinence and are highly susceptible to relapse (O’Brien et al., 1998, Dackis and O’Brien, 2005). Memories of drug effects or learned associations between the rewarding properties of drugs and cues are thought to precipitate craving and relapse. Reconsolidation is a process in which memory undergoes a transiently labile stage after its retrieval and needs to be consolidated again in order to be maintained (Nader et al., 2000, Miller and Sweatt, 2006, Tronson and Taylor, 2007, Alberini, 2011). Pharmacological or molecular manipulations of reconsolidation of acquired drug memories have been shown to disrupt drug-seeking and relapsing behavior in animal models (Miller and Marshall, 2005, Lee et al., 2005, Lee et al., 2006, Valjent et al., 2006, Taylor et al., 2009, Sanchez et al., 2010, Yan et al., 2013) and in drug addicts (Xue et al., 2012). These studies suggest that understanding the molecular basis of reconsolidation of reward memory may help to develop new medications for the treatment of drug abuse (Sorg, 2012, Tronson and Taylor, 2013).

The mesolimbic dopamine (DA) projections are a major neural substrate for mediating actions of drugs of abuse that can increase synaptic levels of DA that is required for reward and reinforcement (Hyman et al., 2006, Kalivas and O’Brien, 2008, Koob and Volkow, 2010, Lüscher and Malenka, 2011). Recent studies suggest that DA is involved in reward learning and that drugs of abuse can change related neuronal circuits in the mesolimbic DA system (Ito et al., 2000, Stuber et al., 2005, Hyman et al., 2006, Wise, 2008, Volkow et al., 2009, Schultz, 2010, Torregrossa et al., 2011, Milton and Everitt, 2012). DA binds to DA receptors to trigger many molecular, physiological and behavioral changes. Five DA receptors have been identified and classified into two subfamilies (Beaulieu and Gainetdinov, 2011). The D1-like family includes D1 and D5 receptors that interact with G_s proteins. The D2-like family includes D2, D3 and D4 receptors that interact with G_i or G₀ proteins. Both D1 and D3 receptors are expressed in mesolimbic DA projection areas. We and others have shown that D1 (Xu et al., 1994a, Xu et al., 1994b, Xu et al., 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, Xi et al., 2005, Xi et al., 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, Song et al., 2012b) mediate locomotor-stimulant and positive reinforcing effects of cocaine, as well as cue-induced reinstatement of cocaine-seeking.

D1 receptor-based medications have been tried to reduce euphoric effects of cocaine in addicts, and despite the D1 receptor’s key role in mediating cocaine actions in preclinical studies, the results have not been consistent (Haney et al., 1999, Haney et al., 2001, Romach et al., 1999, Nann-Vernotica et al., 2001). Manipulating D1 receptor activity during reconsolidation may provide a new time window to treat cocaine abuse. 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, Caine et al., 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. The rodent model of intravenous drug self-administration mimics voluntary drug intake in humans and is arguably the best available preclinical model to study the neurobiological basis of drug-seeking and taking (O’Brien and Gardner, 2005, Epstein et al., 2006, Kalivas et al., 2006). In the current study, we have used both pharmacological and genetic approaches to investigate the role of D1 receptors, and to further study the role of D3 receptors in reconsolidation of cocaine memories in mouse models of drug self-administration.