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Sex Differences in Behavioral and Brainstem Transcriptomic Neuroadaptations following Neonatal Opioid Exposure in Outbred Mice.

ABSTRACT: The opioid epidemic led to an increase in the number of neonatal opioid withdrawal syndrome (NOWS) cases in infants born to opioid-dependent mothers. Hallmark features of NOWS include weight loss, severe irritability, respiratory problems, and sleep fragmentation. Mouse models provide an opportunity to identify brain mechanisms that contribute to NOWS. Neonatal outbred Swiss Webster Cartworth Farms White (CFW) mice were administered morphine (15 mg/kg, s.c.) twice daily from postnatal day 1 (P1) to P14, an approximation of the third trimester of human gestation. Female and male mice underwent behavioral testing on P7 and P14 to determine the impact of opioid exposure on anxiety and pain sensitivity. Ultrasonic vocalizations (USVs) and daily body weights were also recorded. Brainstems containing pons and medulla were collected during morphine withdrawal on P14 for RNA sequencing. Morphine induced weight loss from P2 to P14, which persisted during adolescence (P21) and adulthood (P50). USVs markedly increased at P7 in females, emerging earlier than males. On P7 and P14, both morphine-exposed female and male mice displayed hyperalgesia on the hot plate and tail-flick assays, with females showing greater hyperalgesia than males. Morphine-exposed mice exhibited increased anxiety-like behavior in the open-field arena on P21. Transcriptome analysis of the brainstem, an area implicated in opioid withdrawal and NOWS, identified pathways enriched for noradrenergic signaling in females and males. We also found sex-specific pathways related to mitochondrial function and neurodevelopment in females and circadian entrainment in males. Sex-specific transcriptomic neuroadaptations implicate unique neurobiological mechanisms underlying NOWS-like behaviors.

SUBMITTER: Borrelli KN

PROVIDER: S-EPMC8454922 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionWomen have a shorter course from initial cocaine use to meeting the criteria for cocaine use disorder as compared to men. Preclinical findings similarly indicate that females develop key features of an addiction-like phenotype faster than males, including an enhanced motivation for cocaine and compulsive use, indicating that this phenomenon is biologically based. The goals of this study were to determine whether cocaine-craving, another key feature of addiction, also develops sooner during withdrawal in females than males and to determine whether there are sex differences in the molecular mechanisms associated with its development focusing on markers known to mediate cocaine-craving in males (i.e., dorsomedial prefrontal cortex, dmPFC, expression of brain-derived neurotrophic factor exon-IV, Bdnf-IV, and NMDA receptor subunits, Grin2a, Grin2b, and Grin1).MethodsCocaine-craving was assessed following extended-access cocaine self-administration and 2, 7, or 14 days of withdrawal using an extinction/cue-induced reinstatement procedure. Tissue was obtained from the dmPFC immediately after reinstatement testing and gene expression changes were analyzed using real-time qPCR.ResultsIn males, cocaine-craving (total extinction and cue-induced reinstatement responding) progressively increased from early to later withdrawal time-points whereas in females, cocaine-craving was already elevated during early withdrawal (after 2 days) and did not further increase at later withdrawal time-points. Levels of cocaine-craving, however, were similar between the sexes. Gene expression changes differed markedly between the sexes such that males showed the expected relapse- and withdrawal-associated changes in Bdnf-IV, Grin2a, Grin2b, and Grin1 expression, but females only showed a modest increase Grin1 expression at the intermediate withdrawal timepoint.DiscussionThese findings indicate that cocaine-craving is similarly expressed in males and females although the time-course for its incubation appears to be accelerated in females; the molecular mechanisms also likely differ in females versus males.

Project description:Background and aimsSeveral reports have documented risk factors for opioid use following treatment discharge, yet few have assessed sex differences, and no study has assessed risk using contemporary machine learning approaches. The goal of the present paper was to inform treatments for opioid use disorder (OUD) by exploring individual factors for each sex that are most strongly associated with opioid use following treatment.DesignSecondary analysis of Global Appraisal of Individual Needs (GAIN) database with follow-ups at 3, 6 and 12 months post-OUD treatment discharge, exploring demographic, psychological and behavioral variables that predict post-treatment opioid use.SettingOne hundred and thity-seven treatment sites across the United States.ParticipantsAdolescents (26.9%), young adults (40.8%) and adults (32.3%) in treatment for OUD. The sample (n = 1,126) was 54.9% male, 66.1% white, 20% Hispanic, 9.8% multi-race/ethnicity, 2.8% African American and 1.3% other.MeasurementPrimary outcome was latency to opioid use over 1 year following treatment admission.ResultsFor women, regularized Cox regression indicated that greater withdrawal symptoms [hazard ratio (HR) = 1.31], younger age (HR = 0.88), prior substance use disorder (SUD) treatment (HR = 1.11) and treatment resistance (HR = 1.11) presented the largest hazard for post-treatment opioid use, while a random survival forest identified and ranked substance use problems [variable importance (VI) = 0.007], criminal justice involvement (VI = 0.006), younger age (VI = 0.005) and greater withdrawal symptoms (VI = 0.004) as the greatest risk factors. For men, Cox regression indicated greater conduct disorder symptoms (HR = 1.34), younger age (HR = 0.76) and multiple SUDs (HR = 1.27) were most strongly associated with post-treatment opioid use, while a random survival forests ranked younger age (VI = 0.023), greater conduct disorder symptoms (VI = 0.010), having multiple substance use disorders (VI = 0.010) and criminal justice involvement (VI = 0.006) as the greatest risk factors.ConclusionRisk factors for relapse to opioid use following opioid use disorder treatment appear to be, for women, greater substance use problems and withdrawal symptoms and, for men, younger age and histories of conduct disorder and multiple substance use disorder.

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Sex Differences in Behavioral and Brainstem Transcriptomic Neuroadaptations following Neonatal Opioid Exposure in Outbred Mice.

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