Dopamine Neuronal Microcircuits Controlling Methamphetamine Seeking Behavior

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Project Summary/Abstract This proposal is submitted to support the transition of Dr. Dominguez-Lopez from a mentored trainee to an independent investigator in the neurobiology of drug addiction, specifically studying the dopamine microcircuits controlling drug-seeking behavior. Dr. Dominguez-Lopez will work under the mentorship of Dr. Mary Kay Lobo at the University of Maryland School of Medicine (UMSOM), investigating the role of dopamine neurotransmission in the ventral tegmental area (VTA) in methamphetamine (METH) self-administration behavior. Dr. Lobo is a recognized expert in motivated behavior and dopamine neurotransmission in the context of drug abuse. Dr. Lobo’s laboratory combines mouse models of drug self-administration with mitochondrial metabolism, molecular biology, genetics, and immunocytochemistry, providing a dynamic environment for Dr. Dominguez-Lopez to become an experienced scientist. The submitted proposal incorporates scientific training in methodologies to study mitochondrial metabolism, transcriptional analysis, bioinformatics, and genetic labeling of active neuronal populations. The applicant will be receiving training in educational methods, scientific writing, grant preparation, and other skills necessary to become an independent brain research scientist from an underrepresented group. The proposed program includes mentoring interactions with Drs. Joseph Cheer, Seth Ament, Brian Polster, faculty members of UMSOM, and Dr. Marisela Morales from NIDA IRP. In addition, Dr. Rajeshwar Awatramani from Northwestern University in Chicago will be a consultant in this project. The short-term objective of this proposal is to enhance Dr. Dominguez-Lopez’s knowledge of mitochondrial metabolism and single-cell transcriptomics applied to dopaminergic circuits. In the long-term, this will enable Dr. Dominguez-Lopez to secure protected time for training and research activities, establish new collaborations, and pursue his novel independent research resulting in competitive grant proposals. Data obtained by Dr. Dominguez-Lopez indicates that prolonged METH self-administration in mice produces a decrease of dopamine neurons in the VTA, decreases dopamine cell excitability, increases mitochondrial oxygen consumption rate, and decreases levels of glutathione. These observations are concurrent with increased drug-seeking behavior. This research proposal expands on those findings to identify metabolic and molecular characteristics in dopamine circuits that provide resistance or vulnerability to METH exposure. The central hypothesis is that a subpopulation of VTA dopamine neurons is responsible for METH-seeking behavior, forming a microcircuit resistant to mitochondrial oxidative stress induced by chronic METH exposure. The proposed aims are 1) Identifying VTA dopamine microcircuits encoding METH-seeking behavior and 2) Metabolic characteristics of VTA dopamine neurons encoding METH-seeking behavior. Identifying the specific brain circuits responsible for METH addictive properties is a first step to developing therapeutic strategies to help addicts recover from METH addiction.