Chronic Minocycline Treatment during Early Adolescence Ameliorates the Prenatal Ethanol Exposure-Induced Increase in Addiction Risk and Microglial Morphological Activation

Abstract

Abstract Prenatal ethanol exposure (PE) causes fetal alcohol spectrum disorders (FASD), which have a high prevalence in the United States. There are various cognitive and behavioral deficits in FASD, including increased addiction risk. The diagnosis of FASD is often delayed, and there are no effective pharmacological treatments available for FASD. Persistent neuroinflammation, driven by microglial activation, may underlie cognitive and behavioral deficits in FASD. In the present study, we investigated whether suppressing microglial activation by chronic minocycline treatment during preadolescence and early adolescence could ameliorate addiction risk in PE rats. Pregnant Sprague–Dawley rats received intragastric gavages of ethanol (6 g/kg/day; gestation days 8–20) to simulate heavy drinking during pregnancy in humans. Control rats received an isocaloric sucrose solution. We initiated chronic minocycline or vehicle treatment (33 mg/kg; i.p.; 5 days/week for 3 weeks) in female offspring between postnatal days 21 and 29. In rats treated with vehicle, PE led to increased amphetamine self-administration, indicating increased addiction risk. Chronic minocycline led to a reduction in amphetamine self-administration in PE rats but not in controls. Microglia morphology analysis in the ventral tegmental area showed that PE decreased the branch number of microglia, which was partially reversed by minocycline treatment, supporting that PE-induced addiction risk can be ameliorated by reducing PE-induced microglia activation. Minocycline is well tolerated in clinical settings. Our results inform a promising pharmacological treatment strategy for FASD.