Molecular and long-term behavioral consequences of neonatal opioid exposure and withdrawal in mice

被引:14
作者
Dunn, Amelia D. D. [1 ]
Robinson, Shivon A. A. [1 ,2 ]
Nwokafor, Chiso [3 ]
Estill, Molly [4 ]
Ferrante, Julia [1 ]
Shen, Li [4 ]
Lemchi, Crystal O. O. [1 ]
Creus-Muncunill, Jordi [3 ]
Ramirez, Angie [3 ]
Mengaziol, Juliet [1 ]
Brynildsen, Julia K. K. [5 ]
Leggas, Mark [6 ]
Horn, Jamie [6 ]
Ehrlich, Michelle E. E. [3 ]
Blendy, Julie A. A. [1 ]
机构
[1] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA
[2] Williams Coll, Dept Psychol, Williamstown, MA USA
[3] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA
[4] Icahn Sch Med Mt Sinai, Dept Neurosci, New York, NY USA
[5] Univ Penn, Sch Engn & Appl Sci, Dept Bioengn, Philadelphia, PA USA
[6] St Jude Childrens Res Hosp, Dept Pharmaceut Sci, Memphis, TN USA
关键词
opioid; neonatal; withdrawal; brain transcriptome; mouse; behavior; IN-UTERO EXPOSURE; PRENATAL MORPHINE; ABSTINENCE SYNDROME; PRESCHOOL-CHILDREN; SOCIAL-BEHAVIOR; JUVENILE RATS; ALTERS; TOLERANCE; CORTEX; STRESS;
D O I
10.3389/fnbeh.2023.1202099
中图分类号
B84 [心理学]; C [社会科学总论]; Q98 [人类学];
学科分类号
03 ; 0303 ; 030303 ; 04 ; 0402 ;
摘要
IntroductionInfants 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. MethodsTo 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. ResultsOpioid 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. DiscussionDespite 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.
引用
收藏
页数:19
相关论文
共 103 条
[41]   Neurobiological bases of behavioral development in the second year [J].
Herschkowitz, N ;
Kagan, J ;
Zilles, K .
NEUROPEDIATRICS, 1999, 30 (05) :221-230
[42]   Neonatal Abstinence Syndrome and Maternal Opioid-Related Diagnoses in the US, 2010-2017 [J].
Hirai, Ashley H. ;
Ko, Jean Y. ;
Owens, Pamela L. ;
Stocks, Carol ;
Patrick, Stephen W. .
JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2021, 325 (02) :146-155
[43]   Prenatal exposure to morphine affects juvenile play behavior and adult social behavior in rats [J].
Hol, T ;
Niesink, M ;
vanRee, JM ;
Spruijt, BM .
PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR, 1996, 55 (04) :615-618
[44]  
HUTTENLOCHER PR, 1979, BRAIN RES, V163, P195
[45]   Morphine coordinates SST and PV interneurons in the prelimbic cortex to disinhibit pyramidal neurons and enhance reward [J].
Jiang, Changyou ;
Wang, Xueying ;
Le, Qiumin ;
Liu, Peipei ;
Liu, Cao ;
Wang, Zhilin ;
He, Guanhong ;
Zheng, Ping ;
Wang, Feifei ;
Ma, Lan .
MOLECULAR PSYCHIATRY, 2021, 26 (04) :1178-1193
[46]   Mitochondria as central regulators of neural stem cell fate and cognitive function [J].
Khacho, Mireille ;
Harris, Richard ;
Slack, Ruth S. .
NATURE REVIEWS NEUROSCIENCE, 2019, 20 (01) :34-48
[47]   Changes in adaptability following perinatal morphine exposure in juvenile and adult rats [J].
Klausz, Barbara ;
Pinter, Otto ;
Sobor, Melinda ;
Gyarmati, Zsuzsa ;
Fuerst, Zsuzsanna ;
Timar, Julia ;
Zelena, Dora .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2011, 654 (02) :166-172
[48]   Executive function in preschool children prenatally exposed to methadone or buprenorphine [J].
Konijnenberg, Carolien ;
Melinder, Annika .
CHILD NEUROPSYCHOLOGY, 2015, 21 (05) :570-585
[49]   DRUGS OF ABUSE - ANATOMY, PHARMACOLOGY AND FUNCTION OF REWARD PATHWAYS [J].
KOOB, GF .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1992, 13 (05) :177-184
[50]   lmerTest Package: Tests in Linear Mixed Effects Models [J].
Kuznetsova, Alexandra ;
Brockhoff, Per B. ;
Christensen, Rune H. B. .
JOURNAL OF STATISTICAL SOFTWARE, 2017, 82 (13) :1-26