Searles, C. T. | bioRxiv Science

bioRxiv2024

Disrupted Maternal Behavior in Morphine-Dependent Pregnant Rats and Anhedonia in their Offspring

It is currently estimated that every 15 minutes an infant is born with opioid use disorder and undergoes intense early life trauma due to opioid withdrawal. Clinical research on the long-term consequences of gestational opioid exposure reports increased rates of social, conduct, and emotional disorders in these children. Here, we investigate the impact of perinatal opioid exposure (POE) on behaviors associated with anhedonia and stress in male and female Sprague Dawley rats. Young adult female rats were administered morphine via programmable, subcutaneous micro-infusion pumps before, during, and through one week post gestation. Maternal behavior was examined for fragmentation and entropy for the first two postnatal weeks; offspring were assessed for sucrose preference, social behavior, and stress responsivity. Overall, dams that received morphine across gestation displayed significantly less pup-directed behavior with increased fragmentation for nursing and higher entropy scores. In adolescence, male and female rat offspring exposed to morphine displayed reduced sucrose preference and, as adults, spent significantly less time socially interacting with familiar conspecifics. Changes in social behaviors were linked to increased activity in nondopaminergic mesolimbic reward brain regions. Although no treatment effects were observed in forced swim test performance, corticosterone levels were significantly increased in POE adult males. Together, these results suggest that perinatal morphine exposure results in anhedonic behavior, possibly due to fragmented and unpredictable maternal behavior in opioid-dependent dams. Significance StatementClinical and preclinical research has shown that early life stress can produce lifelong depression-like symptoms. Here, we show that maternal opioid use during pregnancy produces depression-like symptoms in the offspring. We also observed disrupted maternal behavior in morphine-exposed dams that is similar to the changes in maternal behavior reported following other forms of early life stress. We propose that the stress of opioid exposure and suboptimal rearing leads to reduced sucrose preference, increased stress reactivity, and social avoidance behavior in the offspring, all of which are characteristics of anhedonia.

neuroscience↗

bioRxiv2023

Perigestational Opioid Exposure Alters Alcohol-Driven Reward Behaviors in Adolescent Rats

Every fifteen minutes, a baby is born in the U.S. experiencing neonatal opioid withdrawal syndrome (NOWS). Since 2004, the rate of NOWS has increased 7-fold. Clinical studies have established intrauterine exposure to drugs of abuse as a risk factor for adverse health outcomes in adult life, including the propensity for future illicit drug use. Despite extensive knowledge about common mechanisms of action in the neural circuitry that drives opioid and alcohol reward, there is little data on the risks that those born with NOWS face regarding alcohol use later in life. Here, we investigate the impact of perigestational opioid exposure (POE) on the mesolimbic reward system of male and female Sprague Dawley rats at postnatal and adolescent ages. Our laboratory has developed a clinically relevant model for morphine exposure spanning pre-conception to the first week of life. Using this model, we found that POE increased alcohol consumption in female rats under noncontingent conditions, and inversely, reduced alcohol consumption in both male and female rats during operant conditioning sessions. Operant responding was also reduced for sucrose, suggesting that the impact of POE on reward-seeking behaviors is not limited to drugs of abuse. Expression of {micro}-opioid receptors was also significantly altered in the nucleus accumbens and medial habenula, regions previously shown to play a significant role in reward/aversion circuitry. Significance StatementEarly life exposure to opioids is known to alter future drug behavior in rats. In the present study, female rats exposed to morphine via their mothers throughout and after pregnancy exhibited increased alcohol consumption when allowed to consume freely. During operant conditioning, however, male and female rats exposed to gestational morphine decreased consumption of alcohol as well as sucrose. We also observed that gestational morphine exposure altered {micro}-opioid receptor expression in reward-related brain regions. Our study provides the first evidence of changes in alcohol-directed reward behavior in a gestational opioid exposure rat model.

neuroscience↗