Patients suffering from opioid use disorder often relapse during periods of abstinence, which is posited to be caused by negative reinforcement driving motivated behaviors. Here, we explored whether opioid-seeking behaviors in mice were correlated with the negative affect of anxiety. To do this, we conditioned mice to associate a specific context with morphine, an opioid with strongly addictive properties, using a three compartment chamber. 24 h following five days of morphine (10 mg/kg, i.p.) conditioning, anxiety levels were tested by measuring time in the open arms of an elevated plus maze. The next day, mice were placed in the three compartment chamber to measure morphine-induced conditioned place preference (CPP). Our results show that following morphine conditioning, mice spent significantly less time in the open arm of the elevated plus maze, which was negatively correlated with the CPP score. Furthermore, we found that an acute treatment with (R,S)-ketamine (10 mg/kg, i.p.), a medication demonstrating promise for preventing anxiety-related phenotypes, 30 min. prior to testing on post conditioning day 1, increased time spent in the open arm of the elevated plus maze in morphine conditioned mice. Lastly, we found that a second injection of ketamine 30 min. prior to CPP tests on post conditioning day 2 attenuated morphine-induced CPP, which lasted for up to 28 d. Overall, our results suggest that morphine-induced CPP may be driven by negative reinforcement, which can be prevented by acute ketamine administration.
IntroductionChildhood adversity is pervasive and linked to numerous disadvantages in adulthood, including physical health problems, mental illness, and substance use disorders. Initial sensitivity to the rewarding effects of alcohol predicts the risk of developing an alcohol use disorder, and may be linked to developmental stress. The opioid peptide β-endorphin (β-E) regulates the stress response and is also implicated in the risk for excessive alcohol consumption.MethodsWe explored the influence of β-E in an animal model of early life adversity using controlled maternal separation by evaluating changes in locomotor activity, anxiety-like behavior, and the initial rewarding effects of alcohol in a single exposure conditioned place preference paradigm in control C57BL/6J and β-E deficient β-E +/+ 0.129S2-Pomc tm1Low/J; β-E −/− mice. Maternal separation (MS) occurred for 3 h each day from post-natal days (PND) 5–18 in approximately half the subjects.ResultsMaternal interactions increased following the separation protocol equally in both genotypes. MS and control subjects were tested as adolescents (PND 26–32) or adults (PND 58–72); the effects of MS were generally more pronounced in older subjects. Adults were more active than adolescents in the open field, and MS decreased activity in adolescent mice but increased it in adults. The increase in adult activity as a result of early life stress depended on both β-E and sex. β-E also influenced the effect of maternal separation on anxiety-like behavior in the Elevated Plus Maze. MS promoted rewarding effects of alcohol in male β-E deficient mice of either age, but had no effect in other groups.DiscussionTaken together, these results suggest that the effects of MS develop over time and are β-E and sex dependent and may aid understanding of how individual differences influence the impact of adverse childhood experiences.
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