AUTHOR=Dunn Amelia D. , Robinson Shivon A. , Nwokafor Chiso , Estill Molly , Ferrante Julia , Shen Li , Lemchi Crystal O. , Creus-Muncunill Jordi , Ramirez Angie , Mengaziol Juliet , Brynildsen Julia K. , Leggas Mark , Horn Jamie , Ehrlich Michelle E. , Blendy Julie A. TITLE=Molecular and long-term behavioral consequences of neonatal opioid exposure and withdrawal in mice JOURNAL=Frontiers in Behavioral Neuroscience VOLUME=17 YEAR=2023 URL=https://www.frontiersin.org/journals/behavioral-neuroscience/articles/10.3389/fnbeh.2023.1202099 DOI=10.3389/fnbeh.2023.1202099 ISSN=1662-5153 ABSTRACT=Introduction

Infants exposed to opioids in utero are at high risk of exhibiting Neonatal Opioid Withdrawal Syndrome (NOWS), a combination of somatic withdrawal symptoms including high pitched crying, sleeplessness, irritability, gastrointestinal distress, and in the worst cases, seizures. The heterogeneity of in utero opioid exposure, particularly exposure to polypharmacy, makes it difficult to investigate the underlying molecular mechanisms that could inform early diagnosis and treatment of NOWS, and challenging to investigate consequences later in life.

Methods

To address these issues, we developed a mouse model of NOWS that includes gestational and post-natal morphine exposure that encompasses the developmental equivalent of all three human trimesters and assessed both behavior and transcriptome alterations.

Results

Opioid exposure throughout all three human equivalent trimesters delayed developmental milestones and produced acute withdrawal phenotypes in mice reminiscent of those observed in infants. We also uncovered different patterns of gene expression depending on the duration and timing of opioid exposure (3-trimesters, in utero only, or the last trimester equivalent only). Opioid exposure and subsequent withdrawal affected social behavior and sleep in adulthood in a sex-dependent manner but did not affect adult behaviors related to anxiety, depression, or opioid response.

Discussion

Despite marked withdrawal and delays in development, long-term deficits in behaviors typically associated with substance use disorders were modest. Remarkably, transcriptomic analysis revealed an enrichment for genes with altered expression in published datasets for Autism Spectrum Disorders, which correlate well with the deficits in social affiliation seen in our model. The number of differentially expressed genes between the NOWS and saline groups varied markedly based on exposure protocol and sex, but common pathways included synapse development, the GABAergic and myelin systems, and mitochondrial function.