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Principal Investigator: Kanako Matsumura
Organization: UNIVERSITY OF TEXAS AT AUSTIN
Fiscal Year: 2024
Award: $45,771
Funding agency: National Institute on Drug Abuse
PROJECT ABSTRACT
40% of patients who are diagnosed with cocaine use disorder are considered to have a severe cocaine use
disorder meeting six or more criteria from the DSM-5. The lack of effective medication for cocaine use disorder
demonstrates an urgent need to better understand the effect of cocaine on neurobiology and behaviors. Cocaine-
induced increase in striatal dopamine release is essential for cocaine reinforcement, however, the mechanisms
of striatal circuit adaptations inducing cocaine seeking is not well established. The overall objective of this
proposal is to determine the mechanism by which cocaine affects striatopallidal circuit activity to facilitate cocaine
seeking and taking. My central hypothesis is that 1) cocaine-induced increases of the opioid peptide, enkephalin
in the striatum suppresses GABA transmission from striatal neurons via δ/µ opioid receptors and, as a result,
disinhibits VP GABA neurons, and 2) striatal enkephalin plays a key role in cocaine seeking.
Aim 1: Determine the necessity of striatal enkephalin in cocaine-induced adaptations in the
striatopallidal circuit: Based on our preliminary data and previous findings, I hypothesize that increase in
enkephalin in the striatum during withdrawal from a history of cocaine exposure leads to suppression of GABA
transmission from enkephalin-expressing striatal neurons, which increases excitability of the postsynaptic VP
GABA neurons. We will test this by performing whole-cell electrophysiology recordings in D2-MSN-selective
enkephalin knockouts with a history of cocaine exposure, and measure GABA transmission from striatal neurons
onto VP GABA neurons and VP neuron excitability. The use of exogenous enkephalin and opioid receptor
selective antagonists will confirm striatal enkephalin and determine the type of opioid receptor as a mechanism
for depression of GABA transmission and increased excitability. Immunohistochemistry will confirm the type of
recorded VP neurons.
Aim 2: Determine the role of striatal enkephalin in cocaine self-administration: Based on our preliminary
data, I hypothesize that striatal enkephalin facilitates self-administration and cocaine seeking. We will test this
by performing operant self-administration using striatal neuron-selective enkephalin knockouts and examine the
effect of striatal enkephalin deletion on cocaine seeking and taking and the motivation for cocaine.
Through completion of this proposal, and under the guidance of my sponsors, Drs. Lauren Dobbs and Robert
Messing, who are experts in substance use disorder research, I will receive extensive training to develop
professional skills, expand my laboratory skillset, and improve my communication skills for post-doctorate
research career in neuroscience. Combined with the training resources and expansive research expertise
available at University of Texas at Austin, I will be well-supported throughout this fellowship and make a
successful transition to a post-doctoral research position.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><Abstinence><Acceleration><Address><Affect><Aminalon><Aminalone><Attenuated><Automobile Driving><Behavior><Behavioral><Brain><Brain Nervous System><Catheters><Cell Body><Cells><Clampings><Closure by clamp><Cocaine><Cocaine use disorder><Cocaine withdrawal><Communication><Corpus Striatum><Corpus striatum structure><Cues><D2 receptor><DRD2 Receptor><DSM-5><DSM-V><DSM5><Data><Diagnosis><Diagnostic and Statistical Manual of Mental Disorders, 5th edition><Diagnostic and Statistical Manual of Mental Disorders-V><Disinhibition><Dopamine><Dopamine D2 Receptor><Dose><Drugs><Electrophysiology><Electrophysiology (science)><Encephalon><Enkephalin Receptors><Enkephalins><Exhibits><Extinction><FDA approved><Fellowship><GABA><Globus Pallidus><Goals><High Prevalence><History><Hydroxytyramine><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Implant><Injections><Intake><KO mice><Knock-out><Knock-out Mice><Knockout><Knockout Mice><Laboratories><Learning><Measures><Mediator><Medication><Mental Depression><Messenger RNA><Methods><Mice><Mice Mammals><Motivation><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Neurosciences><Nucleus Accumbens><Null Mouse><Opiate Peptides><Opiate Receptors><Opiates><Opioid><Opioid Peptide><Opioid Receptor><Patients><Pharmaceutical Preparations><Play><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Procedures><Psychological reinforcement><Receptor Protein><Recording of previous events><Reinforcement><Research><Research Associate><Research Resources><Resources><Rewards><Role><Saline><Saline Solution><Self Administered><Self Administration><Slice><Stimulus><Striate Body><Striatum><Substance Use Disorder><Synapses><Synaptic><System><Techniques><Testing><Texas><Training><Transmission><Universities><Whole-Cell Recordings><Withdrawal><antagonism><antagonist><attenuate><attenuates><behavior study><behavioral study><career><cocaine exposure><cocaine reward><cocaine seeking><cocaine self-administration><cocaine use><cocaine-exposed><conditioning><depression><driving><drug/agent><effective therapy><effective treatment><electrophysiological><endogenous opiate><endogenous opioids><exposed to cocaine><exposure to cocaine><gamma-Aminobutyric Acid><histories><improved><insight><mRNA><maladaptive behavior><meeting><meetings><motivated behavior><neural circuit><neural circuitry><neurobiological><neurobiological mechanism><neurocircuitry><neuronal><neuronal excitability><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><optogenetics><pallidum><pharmacologic><post-doc><post-doctoral><post-doctoral trainee><postsynaptic><preference><presynaptic><prevent><preventing><receptor><recruit><research associates><response><self-administer cocaine><skills><social role><striatal><substance use and disorder><synapse><synaptic circuit><synaptic circuitry><therapeutic target><transmission process><voltage><γ-Aminobutyric Acid>