Gestational Buprenorphine Exposure Disrupts Dopamine Neuron Activity and Related Behaviors in Adulthood

Abstract

Opioid misuse among pregnant women is rapidly increasing in the United States. The number of maternal opioid-related diagnoses increased by 131% in the last 10 years, resulting in an increased number of infants exposed to opioids in utero and a subsequent increase in infants developing neonatal abstinence syndrome (NAS). The most prescribed treatment to combat maternal opioid use disorder is buprenorphine, a partial μ-opioid receptor agonist and κ-opioid receptor antagonist. Buprenorphine treatment effectively reduces NAS but has been associated with disrupted cortical development and neurodevelopmental consequences in childhood. Less is known about the long-term neurodevelopmental consequences following buprenorphine exposure in utero . Previous research has shown that gestational buprenorphine exposure can induce anxiety-like and depressive-like phenotypes in adult rats, suggesting that exposure to buprenorphine in utero may render individuals more susceptible to psychiatric illness in adulthood. A common pathology observed across multiple psychiatric illnesses is dopamine system dysfunction. Here, we administered the highly-abused opioid, oxycodone (10 mg/kg, i.p.) or a therapeutic used to treat opioid use disorder, buprenorphine (1 mg/kg, i.p) to pregnant Sprague Dawley rats from gestational day 11 through 21, then examined neurophysiological alterations in the mesolimbic dopamine system and dopamine-dependent behaviors in adult offspring. We found that gestational exposure to buprenorphine or oxycodone increases dopamine neuron activity in adulthood. Moreover, prenatal buprenorphine exposure disrupts the afferent regulation of dopamine neuron activity in the ventral tegmental area (VTA). Taken together, we posit that gestational buprenorphine or oxycodone exposure can have profound effects on the mesolimbic dopamine system in adulthood.

Abnormal morphology and synaptogenic signaling in astrocytes following prenatal opioid exposure

“…Despite the benefits of buprenorphine for the acute treatment of NAS [67], as well as preclinical evidence that shows less severe cognitive impairments with the use of buprenorphine versus morphine and methadone [68–70], there remains a concern of negative developmental outcomes. Recently, in utero buprenorphine exposure was shown to promote hyperactivity in the mesolimbic dopamine pathway and sensorimotor gating deficits in adult rats [71].…”

Abnormal Morphology and Synaptogenic Signaling in Astrocytes Following Prenatal Opioid Exposure

“…Despite the benefits of buprenorphine for the acute treatment of NAS [67], as well as preclinical evidence that shows less severe cognitive impairments with the use of buprenorphine versus morphine and methadone [68][69][70], there remains a concern of negative developmental outcomes. Recently, in utero buprenorphine exposure was shown to promote hyperactivity in the mesolimbic dopamine pathway and sensorimotor gating deficits in adult rats [71]. Furthermore, in humans, early school-age children who were exposed to MAT-prescribed buprenorphine performed significantly worse than a peer group on tests of hyperactivity, impulsivity, memory, and attention [72].…”

Developmental outcomes with perinatal exposure (DOPE) to prescription opioids

“…Furthermore, opioid-dependent alteration to NMDA receptors is pivotal in maintaining ion concentration at the postsynaptic terminal [ 9 ]. These changes were found to contribute to excitatory changes in the limbic system that are a part of the addictive properties, possibly influencing the impulsivity of users [ 10 ].…”