Incubation of cue-induced reinstatement of cocaine, but not sucrose, seeking in C57BL/6J mice

Highlights

• Incubation of cue-induced reinstatement of cocaine seeking in C57BL/6J mice

• Transient incubation of context-induced cocaine or sucrose seeking

• No incubation of cue-induced reinstatement of sucrose seeking

Abstract

Prior studies have shown that drug-seeking behaviors increase, rather than dissipate, over weeks to months after withdrawal from drug self-administration. This phenomenon - termed incubation - suggests that drug-craving responses elicited by conditioned environmental or discrete cues may intensify over pronged abstinence. While most of this work is conducted in rats with intravenous drug self-administration models, there is less evidence for incubation in mice that have greater utility for molecular genetic analysis and perturbation. We tested whether incubation of cocaine-seeking behavior is evident in C57BL/6J mice following 3 weeks (5 days/week) of cocaine self-administration in 2 h self-administration sessions. We compared cocaine-seeking (drug-paired lever) responses 1, 7, or 28 days after withdrawal from cocaine self-administration, and over similar times following sucrose pellet self-administration. We found that the initial re-exposure to the self-administration test chambers elicited increased reward-seeking behavior in both sucrose and cocaine self-administering mice, with maximal responses found at 7 days compared to 1 or 28 days after self-administration with either reinforcer. However, following extinction training, reinstatement of cocaine seeking reinforced by response-contingent presentation of reward-associated cues (tone/light) was significantly higher after 28 days compared to 1 or 7 days following cocaine self-administration. In contrast, cue-induced reinstatement of sucrose-paired lever pressing did not increase over this time frame, demonstrating a drug-specific incubation effect not seen with a natural reward. Thus, C57BL/6J mice display incubation of cue-induced reinstatement of cocaine seeking similar to findings with rats, but only show a transient incubation of context-induced cocaine seeking.

Introduction

Cocaine craving can be elicited by exposure to conditioned environmental cues associated with prior drug use, and drug craving has been shown to be highly predictive of the propensity for relapse after a period of abstinence (Rohsenow et al., 2007). Drug-associated cues also elicit marked electrophysiological responses in human cocaine abusers that intensify after prolonged periods of abstinence (Parvaz et al., 2016). In rats, a similar time-dependent intensification of cocaine-seeking behavior, often referred to as incubation, is observed following chronic intravenous cocaine self-administration (Tran-Nguyen et al., 1998, Crombag and Shaham, 2002, Alleweireldt et al., 2001, Di Ciano and Everitt, 2004, Katz and Higgins, 2003, Grimm et al., 2001, Grimm et al., 2003, Grimm et al., 2002, Pickens et al., 2011, Shaham et al., 2003, Lee et al., 2013). These rat studies often employ extinction/reinstatement procedures where cocaine seeking is measured by non-reinforced responding at a drug-paired lever after initial return to the self-administration test chambers. Following extinction of the lever-press behavior, exposing animals to the discrete injection cues associated with prior cocaine self-administration also is used to test the propensity for relapse, or reinstatement of cocaine seeking. Using these models, cocaine seeking elicited by both initial return to the self-administration context and cue-induced reinstatement of cocaine seeking progressively increases, rather than dissipates, over weeks to months after withdrawal from self-administration (Grimm et al., 2001, Koya et al., 2009, Lu et al., 2004a) very similarly to the increases in cue reactivity recently described in humans cocaine abusers (Parvaz et al., 2016). Given this time-dependent exacerbation in cue responsiveness, a delineation of the neurobiological mechanisms underlying the effect may lead to more effective treatments for cocaine addiction, especially over long-term abstinence.

A similar incubation of drug seeking has been shown for other abused drugs including heroin (Di Ciano and Everitt, 2004, Shalev et al., 2001), alcohol (Bienkowski et al., 2004), methamphetamine (Conrad et al., 2008, Shepard et al., 2004, Krasnova et al., 2014), and nicotine (Diergaarde et al., 2008, Funk et al., 2016), suggesting that incubation reflects a pathological process common to drug addiction in general. The incubation phenomenon also occurs with behavior motivated by natural rewards including sucrose, but the enhanced sucrose-seeking behavior fails to persist for more than a few weeks following self-administration training in rats (Di Ciano and Everitt, 2004, Grimm et al., 2002, Grimm et al., 2005). Thus, incubation may reflect a natural process of reward memory intensification over some discrete period that facilitates animal survival, but that drugs of abuse exacerbate and prolong this natural process leading to vulnerability to relapse long after cessation of drug use (Lu et al., 2004b).

Studies on the incubation of cocaine-seeking behavior are extensively performed using rat models (Tran-Nguyen et al., 1998, Crombag and Shaham, 2002, Alleweireldt et al., 2001, Di Ciano and Everitt, 2004, Katz and Higgins, 2003, Grimm et al., 2001, Grimm et al., 2003, Grimm et al., 2002, Pickens et al., 2011, Shaham et al., 2003), but relatively few have employed mouse models (Halbout et al., 2014, Mead et al., 2007, Terrier et al., 2016). Mouse models of intravenous cocaine self-administration are more difficult to perform, but allow for the use of transgenic and gene deletion models not readily accessible in rats. In this study, we tested whether the C57BL/6J mice display incubation of cocaine seeking over time in response to contextual and discrete injection cues using the extinction/reinstatement paradigm, and compared responses in cocaine-trained mice to responses in mice trained to self-administer sucrose pellets as a natural reward.