Prenatal opioid exposure impairs endocannabinoid and glutamate transmission in the dorsal striatum

Abstract

The opioid crisis has contributed to a growing population of children exposed to opioids during fetal development; however, many of the long-term effects of opioid exposure on development are unknown. We previously demonstrated that opioids have deleterious effects on endocannabinoid plasticity at glutamate synapses in the dorsal striatum of adolescent rodents, but it is unclear if prenatal opioid exposure produces similar neuroadaptations. Using a mouse model of prenatal methadone exposure (PME), we performed proteomics, phosphoproteomics, and patch-clamp electrophysiology in the dorsolateral and dorsomedial striatum (DLS & DMS, respectively) to examine synaptic functioning in adolescent PME offspring. PME impacted the proteome and phosphoproteome in a region- and sex-dependent manner. Many proteins and phosphorylated proteins associated with glutamate transmission were differentially abundant in PME offspring which was associated with reduced glutamate release in the DLS and altered the rise time of excitatory events in the DMS. Similarly, the intrinsic excitability properties of DMS neurons were significantly affected by PME. Lastly, pathway analyses revealed an enrichment in retrograde endocannabinoid signaling in the DLS, but not the DMS of males. Electrophysiology studies confirmed endocannabinoid-mediated synaptic depression was impaired in the DLS, but not DMS, of PME-males. These results indicate PME induces persistent neuroadaptations in the dorsal striatum and could contribute to the aberrant behavioral development described in offspring with prenatal opioid exposure.

Significance Statement

Rewarding drugs, including opioids, are known to disrupt endocannabinoid and glutamate signaling in the dorsal striatum of mature rodents which may underlie maladaptive behavioral processes associated with addiction. Given the growing population of children with prenatal opioid exposure, we sought to determine if prenatal opioid exposure produces similar neuroadaptations in the dorsal striatum of offspring. Using a mouse model of prenatal methadone exposure (PME), we discovered endocannabinoid-mediated synaptic depression was impaired in the dorsolateral striatum and glutamate signaling was disrupted in the dorsolateral and dorsomedial striatum of adolescent PME offspring. These neuroadaptations likely alter the functional output of the dorsal striatum which may contribute to the aberrant behavioral development and altered reward phenotype often associated with prenatal opioid exposure.