Research articleIncubation of cue-induced reinstatement of cocaine, but not sucrose, seeking in C57BL/6J mice☆
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.
Section snippets
Animals
Male C57BL/6J mice were purchased from Jackson Laboratories (Bar Harbor, Maine) at 6–8 weeks of age. Mice weighed on average 25 ± 0.41 g at the beginning of the experiment. The mice were acclimated for 1 week prior to being placed in individual housing in a colony room maintained at 21 °C under a 12-hour light/dark cycle (lights on at 6:00 am). Mice had free access to water and rodent chow (2016 Harlan Teklad Global Diet) except during lever-press training for 25 mg sucrose pellets when mice were food
Self-administration
Groups of mice reliably self-administered cocaine starting with an initial average lever pressing of 46.7 ± 3.4 on the first day of self-administration. Over the three week period, all mice increased their lever pressing by approximately 57% to an average of 73.4 ± 2.0 presses/2 h session on the final day of self-administration. Mice were assigned into 3 withdrawal groups evenly matched for lever presses for the 15 days of training (Fig. 1a). A separate cohort of mice self-administered sucrose for 15
Discussion
This study found prominent and late forming incubation of discrete cue-induced reinstatement after 28, but not 1 or 7 days, following withdrawal from cocaine self-administration in C57BL6/J mice, one of the most commonly used genetic background strains for analysis of genetic deletion or transgenic over-expression. Our findings are consistent with previous studies in rats demonstrating that discrete cue-induced reinstatement of cocaine seeking incubates over time (Grimm et al., 2001). In
Disclosure/conflict of interest
ALN, EMA, EBL, and DWS have no disclosures/conflicts of interest to declare. This work was supported by NIH grant DA-10460, T32-DA7290, and by the Wesley Gilliland Professorship in Biomedical Research. Beyond this, the authors declare that, except for income received from the primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that
Acknowledgments
All experimental procedures were conducted in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals, and were approved by the UT Southwestern Medical Center Institutional Animal Care and Use Committee (IACUC). The National Institute on Drug Abuse generously provided cocaine.
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2021, Neuroscience and Biobehavioral ReviewsCitation Excerpt :One working hypothesis for why EE reduces craving is by creating a negative behavioral contrast between the EE and the self-administration context (Grimm et al., 2019). While the incubation of food caving is a robust phenomenon in several laboratories, there are reports of not finding incubation of food craving in rats (Jones et al., 2008; Noye Tuplin et al., 2018; Xi et al., 2013) and, as yet, incubation of food craving has not been observed in mice (Nugent et al., 2017). Several factors might contribute to this, requiring parametric evaluation within a laboratory.
Different periods of forced abstinence after instrumental learning for food reward of different macronutrient value on responding for conditioned cues and AMPAr subunit levels
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This work was supported by NIDA grants R01-DA026482 and T32-DA7290.
The authors report no conflicts of interest.
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Denotes co-first authorship.