Basic and clinical research suggests there are extensive bidirectional interactions between circadian rhythms and addiction. Disruptions to the circadian system, either by environmental or genetic perturbation, may increase the vulnerability to addiction, while chronic drug use leads to circadian disruptions that persist during abstinence and may contribute to relapse. Although these relationships are intriguing, very little is known about the molecular mechanisms underlying the relationship between the circadian system and the transition to addiction. Animal studies have demonstrated that chronic exposure to cocaine leads to alterations in the expression and function of specific circadian genes (i.e., components of the molecular clock) in the mesolimbic dopamine reward system. A major region of convergence for reward circuitry and a key substrate that regulates drug reward and motivation is the nucleus accumbens (NAc). The NAc is comprised of mostly two specific subtypes of medium spiny neurons (MSNs) that predominantly express either dopamine 1 or 2 receptors (D1+ or D2+). These two subtypes of MSNs have distinct roles in the regulation of cocaine reward behaviors, although the molecular mechanisms underlying these differences remain unclear. We have identified a novel role of the circadian transcription factor, neuronal PAS domain protein 2 (NPAS2) in the regulation of cocaine reward, potentially via its interactions with the transcription factor nuclear factor kappa B (NF?B) and its selective expression in D1+ MSNs of the NAc.
The aims of the K01 are as follows: 1) to investigate the functional role of NPAS2 in the regulation of different cocaine reward behaviors, (i.e., conditioned place preference and self-administration), via expression in D1+ or D2+ MSNs of the NAc; 2) to examine the effects of acute and chronic cocaine exposure on the expression of Npas2 and NF?B, along with the interactions between these transcription factors in the NAc; and 3) to investigate whether NPAS2 positively regulates NF?B-mediated transcription in D1+ and D2+ MSNs of the NAc. Therefore, the proposed K01 award will characterize the role of these novel cell type specific molecular mechanisms in the NAc that regulate cocaine reward. These studies will also further clarify the role of the molecular clock in the transition to addiction. These research goals are aligned with the strategic goals of NIDA and the NIH BRAIN Initiative to identify the functional significance of specific cell types in the brain by integrating innovative molecular and behavioral approaches. The candidate's long-term career goal is to develop an independent research program investigating the role of the circadian system in the regulation of reward circuitry that underlies the transition to drug addiction. The candidate has a strong background in circadian rhythms research and requires additional training to develop expertise in translational addiction research and the combination of advanced molecular approaches and complex behavioral assays. The proposed K01 Career Development Award will ensure the candidate's successful transition to an independent investigator by providing extensive conceptual and methodological training in the following areas: 1) conceptual expertise on the neurobiology of addiction for basic and translational research; 2) methodological proficiency in the combination of advanced molecular techniques, including protein immunoprecipitation, immunohistochemistry, and brain cell type specific viral-mediated gene transfer, with complex behavioral assays, including cocaine conditioned place preference and intravenous cocaine self-administration in mice; and 3) to integrate previous conceptual and research abilities with newly acquired neurobiological techniques and approaches, and conceptual expertise in addiction research, to become an independent investigator. The candidate will be mentored and advised by a team of faculty with expertise in the cellular and molecular mechanisms of addiction, reward neural circuitry and drug-induced neural plasticity, and circadian rhythms. The individualized career development plan includes a combination of regular meetings with mentors and consultants, grantsmanship skills training, formal coursework, conference attendance, formal research presentations, and technical and methodological training. The University of Pittsburgh and the Department of Psychiatry provides the necessary infrastructure to become a successful independent addiction researcher, including exceptional core and mentor research facilities, individualized career development programs and training opportunities, and a long-standing commitment by the institution and the departmental chair to develop promising young investigators.
Substance use and abuse disorders have a devastating impact on society, individuals and their families. Understanding the molecular neurobiology of addiction is critical for developing novel more effective treatments of the disease. Emerging evidence indicates the genes that regulate circadian rhythms are important contributors to the transition to addiction. This proposal will elucidate the molecular mechanisms in specific neural circuits that underlie addiction by determining the functional relevance of specific circadian genes in the regulation of drug reward. These studies could lead to novel treatments for addiction that stabilize circadian disruptions.
