Adolescent nicotine-induced enhancement of adult morphine reward: mediation by midbrain inhibitory circuits

项目总结

Project Summary Opioid abuse remains one of the leading causes of preventable death in the United States1. A number of elements contribute to this serious public health problem, with prior nicotine use being an important yet poorly understood risk factor2. Nicotine is the main addictive component of tobacco products, including electronic cigarettes, use of which is particularly prevalent among adolescents3. Despite compelling human epidemiological studies linking adolescent nicotine use with future opioid abuse4, the underlying brain mechanisms remain unclear. To address this scientific gap, this proposal investigates the neurobiological underpinnings linking adolescent nicotine use with adult opioid abuse. Consistent with the literature5, our pilot behavioral data demonstrate that mice treated with nicotine in adolescence show enhanced preference for a morphine-paired context in the conditioned place preference (CPP) paradigm. As a potential neural substrate of this behavioral interaction, the ventral tegmental area (VTA) is a heterogeneous midbrain nucleus, consisting of both dopamine and GABA neurons, that is essential for reward processing and drug-related behaviors6-9. Extending this literature, prior work from the Dani Lab demonstrated that nicotine exposure during the adolescent developmental window produces a persistent change in VTA GABA neuron function that drives enhanced drug seeking10. As evidence of such nicotine-induced neural adaptations in the VTA, our pilot electrophysiological results revealed that the pharmacological effect of morphine on VTA GABA neurons (i.e. inhibition) is paradoxically inverted (i.e. excitation) by adolescent nicotine treatment. How changes in GABA neuron function relate to morphine reward remain unknown. For these reasons, this proposal tests the overarching hypothesis that adolescent nicotine promotes adult morphine reward via altered morphine-induced excitability of VTA GABA neurons. To test this hypothesis, my proposed project integrates ex vivo electrophysiology, in vivo chemogenetic manipulations, and behavioral pharmacology to interrogate the role of VTA GABA neuron excitability in adolescent nicotine-induced heightened morphine reward. Specifically, Aim 1 characterizes the effect of adolescent nicotine on morphine-induced inhibitory signaling in the VTA. Aim 2 determines the role of aberrant VTA GABA neuron activity, arising from adolescent nicotine exposure, in driving heightened morphine CPP. Collectively, the results of this work will provide insight into the neural basis of nicotine-induced morphine abuse liability and will further inform our understanding of midbrain plasticity in drug reward processing. This grant will also provide crucial training for an aspiring independent scientist in an outstanding environment at the University of Pennsylvania. In particular, this proposal represents a critical step in attaining the applicant’s career goal of leading her own laboratory by combining a comprehensive, well-balanced training plan with an innovative program of research to investigate the role of VTA GABA neuron excitability in adolescent nicotine-induced adult opioid abuse.