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

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.

Comparison of the Time-Dependent Changes in Immediate Early Gene Labeling and Spine Density Following Abstinence From Contingent or Non-contingent Chocolate Pellet Delivery

“…Following acquisition, self-administration studies often test for reward seeking by utilizing different testing procedures which can include extinction without cues, extinction with cues, or a combination of both, thus focusing on extinction and forced abstinence models (Venniro et al, 2016 ). A study by Nugent et al ( 2017 ) investigated cue-induced reinstatement of cocaine or sucrose pellet seeking in C57BL/6J mice (Nugent et al, 2017 ). Self-administration was 2 h/day for 3 weeks (5 days/week) and an extinction session without cues test (6 h) occurred prior to a responding for cues test.…”

Evaluating Time-Dependent Changes in Food Seeking Following Periods of Forced Abstinence and Associated Changes in the Nucleus Accumbens

“…Following acquisition, self-administration studies often test for reward seeking by utilizing different testing procedures which can include extinction without cues, extinction with cues, or a combination of both, thus focusing on extinction and forced abstinence models (Venniro et al, 2016). A study by Nugent and colleagues (2017) investigated cue-induced reinstatement of cocaine or sucrose pellet seeking in C57BL/6J mice (Nugent et al, 2017). Self-administration was 2 hrs./day for 3 weeks (5 days/week) and an extinction session without cues test (6 hr.)…”

“…occurred prior to a responding for cues test. Following the extinction session, an incubation effect for cocaine, but not sucrose, was seen following 28 days of withdrawal (Nugent et al, 2017). Grimm and colleagues (2005) administered liquid sucrose for 6h/day for 10 days and used testing procedures that began with extinction without cues (6 hr.)…”

“…An increase in responding for cues was observed following 30 days of forced abstinence compared to 1 day (Grimm et al, 2005). The main difference between these two sucrose studies was that one used liquid sucrose/rats (Grimm et al, 2005) and the other used sucrose pellets/mice (Nugent et al, 2017). In the absence of extinction without cues, incubation of palatable food (administered 9 hr./day for 14 days) and liquid sucrose (6 hr./day for 10 days) craving has been demonstrated following 21 days of forced abstinence (Krasnova et al, 2014a;Uejima et al, 2007).…”

“…Our studies were undertaken during the light phase of the day/night cycle rather than a reversed cycle. Testing for the incubation of craving has been undertaken in the light phase (Ma et al, 2014;Nugent et al, 2017) and dark phase of the light cycle (Grimm et al, 2003;Krasnova et al, 2014a) both of which have resulted in an incubation effect. While this could be a contributing factor (Roedel et al, 2006), it is likely not as important as the design of the behavioral training and testing conditions or choice of reward.…”