A HISTORY OF ADOLESCENT OXYCODONE SELF-ADMINISTRATION: NEURAL MECHANISMS UNDERLYING NEUROCOGNITIVE IMPAIRMENTS

Abstract

Maturation of the prefrontal cortex and higher-order cognitive processes is ongoing through adolescence and young adulthood; developmental periods associated with the nonmedical use of prescription opioids. Initiation of oxycodone (OXY) self-administration during adolescence induces long-term dose-dependent impairments in neurobehavioral and neurocognitive development. To date, however, the neural mechanisms underlying neurocognitive impairments induced by adolescent prescription opioid use disorder (APOUD) have not been systematically evaluated. A DiOlistic labeling technique, in concert with sophisticated neuronal reconstruction software, revealed a prominent sex- and dose-dependent population shift in the morphological parameters of dendritic spines in pyramidal neurons in the anterior cingulate cortex (ACC) of rodents with a history of adolescent OXY self-administration relative to their control counterparts. Similarly, the biochemical mechanisms underlying dendritic spine dysmorphology, which were investigated using quantitative polymerase chain reaction, were dependent upon biological sex. In male rodents, a dose-dependent decrease in mRNA expression of GRIN1, a N-methyl-D-aspartate receptor, was observed in animals with a history of adolescent OXY self-administration relative to controls. In contrast, female rats with a history of adolescent OXY self-administration exhibited increased mRNA expression of cdk5, a protein kinase involved in the regulation of pre- and post-synaptic function; a transcriptional alteration that may result from excessive glutamate accumulation. Fundamentally, transcriptional dysregulation and dendritic spine dysmorphology mechanistically underlie, at least partly, APOUD-induced neurocognitive impairments. Collectively, results support that sex-dependent glutamatergic dysregulation may underlie dendritic spine dysmorphology in the ACC resulting in APOUD-induced neurocognitive impairments. Glutamatergic dysregulation, therefore, may afford a key target for the development of novel therapeutics. SIGNIFICANCE STATEMENTIndividuals with a history of adolescent prescription opioid use disorder (APOUD) are afflicted with profound neurocognitive impairments. Herein, sex-dependent glutamatergic dysregulation may underlie dendritic spine dysmorphology in the ACC resulting in APOUD-induced neurocognitive impairments, thereby affording a key target for the development of novel therapeutics.