Abuse of prescription opioid analgesics (such as oxycodone) has become a major health concern in the United States and occurs mostly in adolescents and young adults. The goal of this application is to determine in mice the behavioral and neurobiological consequences of re-exposure to oxycodone after withdrawal from an initial adolescent oxycodone self administration, and to compare these consequences to those in animals in which initial exposure occurred in adulthood. The current application will focus on adolescent oxycodone self administration-induced alterations in rewarding and locomotor effects of oxycodone, changes in the endogenous opioid systems in the mesocorticolimbic and nigrostriatal dopaminergic pathways, and how blocking of such changes affects oxycodone self-administration behavior in adulthood. We hypothesize that changes of endogenous opioid systems in the dopaminergic pathways resulting from initial opioid exposures during adolescence play an important role in the development of opioid dependence and opioid addiction upon later re-exposure.
The specific aims of this application are: 1. To determine whether and how adolescent oxycodone self-administration enhances the behavioral effect of oxycodone upon subsequent re-exposure during adulthood, in terms of development of rewarding effects and to determine whether these effects are more pronounced in adolescent than in adult mice. 2. To determine whether and how adolescent oxycodone self-administration alters mRNA levels of Pdyn, Penk1, MOP-r and KOP-r, MOP-r and KOP-r receptor density in specific brain regions of the mesocorticolimbic and nigrostriatal dopaminergic pathways, and to compare the effect in adolescent mice to those in adult mice. 3. To determine whether increased striatal MOP-r levels in the mouse brain following adolescent oxycodone self-administration underlie the greater abuse potential of oxycodone, observed upon adult re-exposure. Significance: These studies will model the early phase of prescription opioid abuse in adolescence, which has been understudied. These studies should produce important insight into the effects of adolescent oxycodone self administration on neurobiological and behavioral adaptations persisting into early adulthood. The studies could therefore eventually lead to strategies to prevent or minimize the severity of early onset prescription opioid abuse, through the identification of specific molecular and neuroanatomical substrates affected by adolescent exposure.
These will be the first studies on the effects of adolescent mouse oxycodone self administration on the endogenous opioid peptides in the mesocorticolimbic and nigrostriatal dopaminergic pathways, brain regions involved in rewarding properties of drug of abuse, and how such changes could lead to enhanced behavioral responses upon later re-exposure. Elucidation of behavioral and neurobiological changes induced by adolescent oxycodone self administration could enhance our understanding of the mechanisms leading to oxycodone addiction, and may lead to better strategies for prevention and treatment of abuse and addiction to prescription opioids in young human abusers.
|Yuferov, Vadim; Zhang, Yong; Liang, Yupu et al. (2018) Oxycodone Self-Administration Induces Alterations in Expression of Integrin, Semaphorin and Ephrin Genes in the Mouse Striatum. Front Psychiatry 9:257|
|Zhang, Yong; Liang, Yupu; Levran, Orna et al. (2017) Alterations of expression of inflammation/immune-related genes in the dorsal and ventral striatum of adult C57BL/6J mice following chronic oxycodone self-administration: a RNA sequencing study. Psychopharmacology (Berl) 234:2259-2275|
|Zhang, Yong; Windisch, Kyle; Altschuler, Joshua et al. (2016) Adolescent oxycodone self administration alters subsequent oxycodone-induced conditioned place preference and anti-nociceptive effect in C57BL/6J mice in adulthood. Neuropharmacology 111:314-322|
|Zhang, Y; Brownstein, A J; Buonora, M et al. (2015) Self administration of oxycodone alters synaptic plasticity gene expression in the hippocampus differentially in male adolescent and adult mice. Neuroscience 285:34-46|
|Zhang, Yong; Picetti, Roberto; Butelman, Eduardo R et al. (2015) Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice. Neuropsychopharmacology 40:1091-100|
|Zhang, Yong; Mayer-Blackwell, Brandan; Schlussman, Stefan D et al. (2014) Extended access oxycodone self-administration and neurotransmitter receptor gene expression in the dorsal striatum of adult C57BL/6 J mice. Psychopharmacology (Berl) 231:1277-87|
|Mayer-Blackwell, B; Schlussman, S D; Butelman, E R et al. (2014) Self administration of oxycodone by adolescent and adult mice affects striatal neurotransmitter receptor gene expression. Neuroscience 258:280-91|
|Niikura, Keiichi; Ho, Ann; Kreek, Mary Jeanne et al. (2013) Oxycodone-induced conditioned place preference and sensitization of locomotor activity in adolescent and adult mice. Pharmacol Biochem Behav 110:112-6|
|Zhang, Yong; Schlussman, Stefan D; Rabkin, Jacqui et al. (2013) Chronic escalating cocaine exposure, abstinence/withdrawal, and chronic re-exposure: effects on striatal dopamine and opioid systems in C57BL/6J mice. Neuropharmacology 67:259-66|