The effects of morphine withdrawal and conditioned withdrawal on memory consolidation and c‐Fos expression in the central amygdala

Abstract

The current study tested the hypothesis that drug withdrawal contributes to the addiction cycle in part because of an action on memory consolidation. Hence, four experiments in male Sprague–Dawley rats compared the effects of precipitated morphine withdrawal and conditioned morphine withdrawal on the consolidation of object memory and on activation of c‐Fos in the central nucleus of the amygdala (CeA). It was found that immediate, but not 6 h delayed, post sample administration of 3 mg/kg of naltrexone significantly enhanced object memory in rats maintained, or previously maintained, on 10 mg/kg/day of morphine via osmotic minipumps. To establish whether conditioned withdrawal could also alter object memory, a contextual conditioning procedure was employed whereby morphine‐maintained (10 mg/kg/day) animals received naltrexone (3 mg/kg) in a distinctive context (CS+) and vehicle in a separate context (CS−) for 10 days. During conditioning in the CS+, naltrexone suppressed locomotor activity, caused a rapid body weight loss and increased frequency of wet dog shakes. Interestingly, confinement to this CS+ immediately, but not 6 h, after the sample phase, also enhanced object memory. Finally, posttraining naltrexone and exposure to the CS+ both induced significant expression of c‐Fos in the CeA. Therefore, this study reports for the first time that both acute precipitated withdrawal and conditioned withdrawal can facilitate memory consolidation, possibly through a common neural pathway that involves the central amygdala.

Cues conditioned to withdrawal and negative reinforcement: Neglected but key motivational elements driving opioid addiction

“…Precipitated withdrawal may enhance the learning of cues that are associated with withdrawal-evoked aversion and improve memory consolidation. Rats that were maintained on morphine with osmotic minipumps and injected with naltrexone immediately before novel object exploration exhibited an increase in object recognition memory 3 days later compared with morphine-naive and vehicle-treated animals (31).…”

Analysis of memory modulation by conditioned stimuli

“…Importantly, animals trained with 0 mA shock did not show a change in DR indicating that previous training with 0.8 mA was necessary for the effect of the CS complex on object memory. Although the experiment did not include a group of animals that received postsample exposure to the CS complex outside the window of consolidation (i.e., a delay group, exposed to the context/CS several hours after the sample phase), the observation that both Avoider and Non-Avoider subgroups displayed similarly elevated DRs during the choice phase, and that comparable effects have been observed in rats exposed to immediate postsample incentive (paired with nicotine, cocaine or heroin) ( Wolter et al 2019 , 2020 ) and other aversive (paired with precipitated opiate withdrawal) ( Baidoo et al 2020 ) CSs, suggest that the CS complex did, in fact, modulate the consolidation of object memory.…”

“…OR testing consisted of two phases: a sample phase and a choice phase, separated by a 72-h retention interval. This retention interval was chosen as a “suboptimal” condition in which treatment naïve rats do not typically express memory ( Wolter et al 2019 , 2020 ; Baidoo et al 2020 ). During the sample phase, two identical novel objects were placed into the Y-apparatus at the end of each exploration arm.…”

“…Interestingly, exposure to stimuli paired with both incentive ( Holahan and White 2013 ; Wolter et al 2019 , 2020 ; Baidoo et al 2020 ) and aversive ( Holahan and White 2002 , 2004 ; Leong et al 2015 ; Goode et al 2016 ) USs also enhances memory consolidation, presumably because of the conditioned emotional responses that they generate. For example, CSs that precede exposure to footshock elicit freezing ( Díaz-Mataix et al 2017 ), avoidance ( Dombrowski et al 2013 ), analgesia ( McNally et al 1999 ), as well as sympathetic stimulation such as increases in heart rate ( Zhang et al 2019 ), blood pressure ( Hsu et al 2012 ), and release of stress hormones ( Feenstra et al 1999 ), all reactions that are elicited by footshock itself ( Lim et al 1982 ; McCarty and Baucom 1982 ; Conti et al 1990 ; Galvez et al 1996 ; O'Doherty 2004 ; Lázaro-Muñoz et al 2010 ).…”

“…By capitalizing on these individual differences, the current study explored whether both the predictive and preparatory functions of aversive CSs play a role in modulating consolidation of object memory using the spontaneous object recognition (OR) task. OR relies on the natural tendency of rats to explore novel objects ( Winters et al 2008 ) and this task was selected because it has been found sensitive to enhancement by exposure to contextual CSs paired with both incentive and aversive stimuli ( Wolter et al 2019 , 2020 ; Baidoo et al 2020 ). Given the evidence reviewed above, it was predicted that exposure to the avoidance CS complex (the training chamber, the retractable gate, the warning tone, and the cue light) would impact consolidation of object memory equally in Avoider and Non-Avoider subgroups.…”