Abstract
Maternal drug abuse during pregnancy is a rapidly escalating societal problem. Psychostimulants, including amphetamine, cocaine, and methamphetamine, are amongst the illicit drugs most commonly consumed by pregnant women. Neuropharmacology concepts posit that psychostimulants affect monoamine signaling in the nervous system by their affinities to neurotransmitter reuptake and vesicular transporters to heighten neurotransmitter availability extracellularly. Exacerbated dopamine signaling is particularly considered as a key determinant of psychostimulant action. Much less is known about possible adverse effects of these drugs on peripheral organs, and if in utero exposure induces lifelong pathologies. Here, we addressed this question by combining human RNA‐seq data with cellular and mouse models of neuroendocrine development. We show that episodic maternal exposure to psychostimulants during pregnancy coincident with the intrauterine specification of pancreatic β cells permanently impairs their ability of insulin production, leading to glucose intolerance in adult female but not male offspring. We link psychostimulant action specifically to serotonin signaling and implicate the sex‐specific epigenetic reprogramming of serotonin‐related gene regulatory networks upstream from the transcription factor Pet1/Fev as determinants of reduced insulin production.
Highlights
The misuse of psychostimulants is a major socioeconomic burden, affecting up to 50 million people worldwide (Oliere et al, 2013)
Data were expressed as log counts per million mapped reads
We found that pancreatic insulin immunoreactivity was significantly reduced in female but not male neonates prenatally exposed to amphetamine (Fig 5A and A1)
Summary
The misuse of psychostimulants is a major socioeconomic burden, affecting up to 50 million people worldwide (Oliere et al, 2013). Amphetamine, cocaine, and methamphetamine are the most commonly consumed psychostimulants with their peripheral effects mimicking the activation of the sympathetic nervous system: increased heart rate and blood pressure, decreased digestion, and mobilization of glucose reserves (Favrod-Coune & Broers, 2010). Their mechanism of action centers on molecular interference with monoamine reuptake transporters (i.e., reversal of substrate flow) (Howell & Negus, 2014; Ross et al, 2015) and/or inhibition of monoamine oxidases. Extracellular concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) surge, which prolongs their action on respective receptor systems (Kitanaka et al, 2006; Ross et al, 2015; Liu et al, 2016).
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