R01DA058958

Cell type transcriptional mechanisms of polysubstance choice - project summary

In this new R01 application that is directly responsive to RFA-DA-23-015, our research team proposes to study the cell type specific molecular mechanisms regulated by FENTANYL and METHAMPHETAMINE polysubstance use at both the initiation and withdrawal stages of the substance use trajectory.

We propose to overcome current limitations in polysubstance research by utilizing preclinical assays of drug-vs.-food choice procedures in male and female rats, which more fully capture the severity of polysubstance use seen in humans by modeling the behavioral misallocation and decision making between concurrently available addictive drugs and alternative non-drug reinforcers.

We will combine these enhanced behavioral models with single nuclei RNA sequencing (SNRNASEQ) of the medial prefrontal cortex (PFC) and nucleus accumbens (NAC), key brain regions implicated in drug reinforcement and drug-taking, to capture and characterize the exact drug-induced molecular adaptations that occur in specific cell types, including non-neuronal cells.

We will directly test the hypothesis that the synergistic action of combined FENTANYL and METHAMPHETAMINE use produces enhanced drug use behaviors and brain molecular adaptations that are distinct from what is achieved by either FENTANYL or METHAMPHETAMINE use alone; that this polysubstance synergy involves unique transcriptional adaptations by brain region, accumulates as a function of drug experience, and contributes to the behavioral misallocation towards drug use over more beneficial rewarding activities that is the hallmark of drug addiction.

We will test this overarching hypothesis in two aims.

In Aim 1, we will uncover the impact of FENTANYL/METHAMPHETAMINE polysubstance use during the withdrawal phase of the substance use trajectory. We will use drug-vs.-food self-administration choice procedures for saline, FENTANYL alone, METHAMPHETAMINE alone, and FENTANYL/METHAMPHETAMINE combinations to uncover how an extended history of polysubstance use synergizes to increase somatic withdrawal effects and drug taking behavior while experiencing withdrawal. We will then perform SNRNASEQ in the PFC and NAC to interrogate the brain cell type specific transcriptional adaptations in these rats.

In Aim 2, we will similarly perform drug-vs.-food choice procedures and SNRNASEQ of these brain regions to explore the emergence of behavioral and transcriptional adaptations at the initiation of drug use experience. We will go on to compare our SNRNASEQ data from Aims 1 and 2 to understand how the FENTANYL/METHAMPHETAMINE polysubstance cell type transcriptional profile changes over the substance use trajectory.

This project will reveal how FENTANYL and METHAMPHETAMINE synergize to produce maladaptive drug choice behaviors and brain cell type specific transcriptional responses at distinct stages of the substance use trajectory that are common barriers to recovery. Results gained from this project will inform the discovery of novel and more efficacious pharmacological agents to treat the core decision making process that is uniquely disrupted by polysubstance use.

Virginia Commonwealth University

TO SUPPORT BASIC AND CLINICAL NEUROSCIENCE, BIOMEDICAL, BEHAVIORAL AND SOCIAL SCIENCE, EPIDEMIOLOGIC, HEALTH SERVICES AND HEALTH DISPARITY RESEARCH. TO DEVELOP NEW KNOWLEDGE AND APPROACHES RELATED TO THE PREVENTION, DIAGNOSIS, TREATMENT, ETIOLOGY, AND CONSEQUENCES OF DRUG ABUSE AND ADDICTION, INCLUDING HIV/AIDS. TO SUPPORT RESEARCH TRAINING AND RESEARCH SCIENTIST DEVELOPMENT. TO SUPPORT DISSEMINATION OF RESEARCH FINDINGS. SMALL BUSINESS INNOVATION RESEARCH (SBIR) LEGISLATION IS INTENDED TO EXPAND AND IMPROVE THE SBIR PROGRAMS TO EMPHASIZE AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF TECHNOLOGY DEVELOPED THROUGH FEDERAL SBIR RESEARCH AND DEVELOPMENT, INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN THE SBIR PROGRAM. THE LEGISLATION INTENDS THAT THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.279 - Drug Abuse and Addiction Research Programs

National Institute on Drug Abuse (NIDA) [HHS - NIH]

Richmond, Virginia 232191539 United States

Single Zip Code

Transformative Research on the Basic Mechanisms of Polysubstance use in Addiction (R01 - Clinical Trial Not Allowed) (RFA-DA-23-015)

Amendment Since initial award the total obligations have increased 211% from $443,135 to $1,376,550.