Drug abuse is a debilitating chronic disease characterized by compulsive drug seeking and use despite negative personal consequences. Repeated exposure to drugs of abuse is accompanied by persistent alterations in molecular processes. This includes alterations in transcription factors that regulate synaptic and structural plasticity molecules, which underlie the persistent behavioral responses to repeated drug exposure. Psychostimulant induced molecular alterations have been well characterized in critical reward brain regions, such as the nucleus accumbens (NAc). The two NAc medium spiny-projection neuron (MSN) subtypes display classically distinct projection outputs but recent studies demonstrate converging output from these neurons to the ventral pallidum (VP) in the actions of cocaine. Surprisingly, there is no information into psychostimulant induced molecular adaptations in VP, despite it being a main target of both NAc MSN subtypes and its critical role in behavioral responses to drugs of abuse. Our studies will investigate the underlying molecular processes occurring in VP after cocaine self-administration and determine how the two NAc MSN subtypes contribute to cocaine induced molecular alterations in the VP. We will focus on the transcription factor nuclear receptor subfamily 4 group A member 1 (Nr4a1) and the Nr4a1 transcriptional target, polo like kinase 2 (Plk2), which we identified to be upregulated in VP after cocaine self-administration using RNA-seq. Our studies will first identify which VP neuron subtype displays upregulation of these molecules after cocaine-self administration. We will then use genetic tools to overexpress or knockdown Nr4a1 and Plk2 in specific VP neuron subtypes during cocaine self-administration and relapse behavior. We will additionally determine if Nr4a1 transcriptionally regulates Plk2 in VP in these conditions. Next we will explore how VP neuron subtype structural and synaptic plasticity is regulated through Nr4a1 and Plk2. Finally, we will determine if the upstream NAc MSN subtypes can regulate these transcriptional and cellular adaptations in VP during cocaine self-administration. Our studies will for the first time provide information into the molecular adaptations that mediate cellular adaptations in VP neuron subtypes, which ultimately underlies drug self-administration or relapse behavior. Our studies can provide a foundation for molecular analysis in VP in addiction that in the future can be applied to other drugs of abuse. Finally, our studies have the ability to identify molecular targets for therapeutic intervention in addiction.
We propose to examine the molecular and cellular mechanisms occurring a major reward brain region, the ventral pallidum, in cocaine abuse. Our studies will provide new information into the molecular mechanisms occurring in a key reward brain region in cocaine abuse.
