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Principal Investigator: Sergio Dominguez Lopez
Organization: STATE UNIVERSITY OF NEW YORK AT BUFFALO
Fiscal Year: 2024
Award: $249,000
Funding agency: National Institute on Drug Abuse
Project Summary/Abstract
This proposal is being submitted to support the transition of Dr. Dominguez-Lopez from mentored trainee to
an independent investigator in the neurobiology of drug addiction, specifically studying the dopamine
microcircuits controlling drug-seeking behavior. Dr. Dominguez-Lopez works under the mentorship of Dr.
Michael Beckstead at the Oklahoma Medical Research Foundation (OMRF) investigating the role of
dopamine neurotransmission in the ventral tegmental area (VTA) in methamphetamine (METH) self-
administration behavior. Dr. Beckstead is a recognized expert in dopamine synaptic transmission in the fields
of addiction. Dr. Beckstead’s laboratory combines mouse models of drug self-administration with patch-clamp
electrophysiology 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 Dr. Holly Van Remmen,
Dr. Willard Freeman, Dr. Linda Thompson, members of OMRF, and Dr. Rajeshwar Awatramani from
Northwestern University in Chicago. The short-term objective of this application 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. Preliminary 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 that is resistant to mitochondrial oxidative
stress induced by chronic METH exposure. The proposed aims are 1) Identification of VTA dopamine
microcircuits encoding METH-seeking behavior, and 2) Metabolic characteristics of VTA dopamine neurons
encoding METH-seeking behavior. Identification of the specific brain circuits responsible for METH addictive
properties is a first step to develop therapeutic strategies to help addicts recover from METH addiction.
Terms: <Affect><Anatomic Sites><Anatomic structures><Anatomy><Antioxidants><Applications Grants><Autoregulation><Axon><Axon Terminals><Behavior><Behavioral><Bio-Informatics><Bioinformatics><Brain><Brain Nervous System><Cell Body><Cells><Censuses><Characteristics><Chemical Dependence><Chicago><Chronic><Classification><Collaborations><Crystal Meth><Crystal methamphetamine><DA Neuron><DNA Recombination><Data><Deoxyephedrine><Desoxyephedrine><Development Plans><Dopamine><Dopamine neuron><Drug Addiction><Drug Controls><Drug Dependence><Drug Dependency><Drug Modelings><Dysfunction><Educational Models><Electrophysiology><Electrophysiology (science)><Encephalon><Environment><Event><Expression Signature><Fluorescence Activated Cell Sorting Fractionation><Fluorescence-Activated Cell Sorting><Fluorescence-Activated Cell Sortings><Foundations><Functional disorder><GSSG><Gene Expression Profile><Gene Transcription><Genetic><Genetic Recombination><Genetic Transcription><Glutathione><Glutathione Disulfide><Grant><Grant Proposals><HPLC><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><Holly><Homeostasis><Hydroxytyramine><Injections><Instructional Models><Intake><Investigators><Knowledge><Label><Laboratories><Location><METH dependence><METH effect><Measures><Mediating><Medical Research><Mentors><Mentorship><Metabolic><Methamphetamine><Methamphetamine dependence><Methodology><Methylamphetamine><Mice><Mice Mammals><Mitochondria><Molecular><Murine><Mus><N-Methylamphetamine><Nerve Cells><Nerve Degeneration><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neural Transmission><Neurobiology><Neurocyte><Neuron Degeneration><Neuronal Transmission><Neurons><Neurophysiology / Electrophysiology><Oklahoma><Oxidation-Reduction><Oxidative Stress Induction><Oxidized Glutathione><Oxygen Consumption><Pathway interactions><Physiological Homeostasis><Physiopathology><Population><Predisposition><Preparation><Presynaptic Nerve Endings><Presynaptic Terminals><Property><QOL><Quality of life><RNA Expression><Recombination><Redox><Reporter><Research><Research Activity><Research Personnel><Research Proposals><Researchers><Resistance><Resolution><Respiration><Role><Scientist><Secure><Self Administered><Self Administration><Site><Spirometry><Staining method><Stains><Survival Rate><Susceptibility><Synaptic Boutons><Synaptic Terminals><Synaptic Transmission><System><Systematics><Tamoxifen><Technology><Testing><Theoretic Models><Theoretical model><Therapeutic><Time><Training><Training Activity><Transcription><Underrepresented Groups><Underrepresented Populations><Universities><Ventral Tegmental Area><Viral><Virus><Visualization><Work><Writing><addiction><addiction to methamphetamine><addictive disorder><axon signaling><axon-glial signaling><axonal signaling><brain research><career><career development><dopaminergic neuron><drug seeking behavior><educational methods><educational practices><educational principles><electrophysiological><experience><exposure to meth><exposure to methamphetamine><fighting><gamma-L-Glu-L-Cys-Gly><gamma-L-Glutamyl-L-Cysteinylglycine><gene expression pattern><gene expression signature><genetic profiling><glia signaling><glial signaling><immunocytochemistry><innovate><innovation><innovative><member><meth><meth addiction><meth exposure><methamphetamine addiction><methamphetamine effect><methamphetamine exposure><mitochondrial><mitochondrial metabolism><mouse model><murine model><nerve signaling><neural degeneration><neural signaling><neurobiological><neurodegeneration><neurodegenerative><neurological degeneration><neuronal><neuronal circuit><neuronal circuitry><neuronal degeneration><neuronal signaling><neurotransmission><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><oxidation reduction reaction><oxidative damage><oxidative injury><patch clamp><pathophysiology><pathway><preparations><programs><resistant><resolutions><respiratory mechanism><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skills><social role><tool><training module><transcriptional profile><transcriptional signature><transcriptomics><under representation of groups><under represented groups><under represented people><under represented populations><underrepresentation of groups><underrepresented people><ventral tegmentum>