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Principal Investigator: Devan Marc Gomez
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2024
Award: $84,969
Funding agency: National Institute on Drug Abuse
DESCRIPTION (provided by applicant): Opioid abuse remains a costly epidemic in the US,
prompting research into new and effective interventions to curb addiction-like behavior. Amongst the
therapeutic characteristics of opioids, their associated withdrawal effects are substantial and
recognized to contribute to development of abuse and relapse. While acute somatic withdrawal
symptoms are relatively well characterized, their prolonged affective counterparts are less understood.
Regulating a broad array of affective behaviors, the mesolimbic dopamine (DA) system has been
demonstrated as both necessary and sufficient for reward-related behavior towards opioids and
withdrawal- related negative affect, with a canonical hypodopaminergic state following opioid
dependence at least partially responsible for drug craving and relapse vulnerability. Despite this,
limitations of previous studies concerning heterogeneity of mesolimbic circuitry and a shortage of
assessments of opioid-induced long-term changes to motivated behavior and subsequent drug intake
following dependence have stifled clear demonstrations of protracted motivational dysfunction and
detection of underlying mechanism for the associated hypodopaminergic state. Growing evidence
indicates that cannabinoid (CB) signaling is highly influential in regulating mesoaccumbal dopamine
and opioid systems, including dopamine and opioid control of reinforcement, and that CB-based
therapies may hold efficacy in treating negative affective states during acute/somatic withdrawal and
perhaps opioid intake. Despite these promising data, data regarding how CB signaling is altered during
opioid withdrawal and whether CB-therapies are efficacious in countering dependence-related changes
in motivation for and intake of opioids with more protracted withdrawal are almost non-existent. This
proposal builds off my research to date demonstrating that 1) morphine dependence promotes a long-lasting elevation in GABAA- mediated inhibitory tone specific to DA neurons in the lateral ventral
tegmental area projecting to the lateral nucleus accumbens shell (latVTA-latShell), 2) prior dependence
increases motivation for and intake of morphine, and 3) elevations in GABA signaling align with an
apparent tolerance to CB1-induced disinhibition of lateral VTA DA firing. In Aim2/Exp1, I will utilize ex
vivo slice electrophysiology to assess alterations in synaptic strength and CB-dependent regulation of
GABAergic afferents from the rostromedial tegmental nucleus (RMTg) to latVTA- latShell DA cells.
Behavior studies in Aim2/Exp2 will extend upon data demonstrating increased effort-based motivated
responding for morphine under protracted withdrawal conditions by measuring cannabinoid-induced
alteration of this effect. Completing these experiments will support my research development by adding
technical skills in more sophisticated electrophysiology and behavioral approaches. Further, results will
fill critical unknowns regarding mechanisms underlying ostensibly important changes in DA function and
behavior that drive OUD and characterize the longer-lasting benefits and limitations of CB-based
interventions.
Terms: <4-Aminobutanoic Acid><4-Aminobutyric Acid><4-amino-butanoic acid><Acute><Affective><Aminalon><Aminalone><Behavior><Behavioral><CB1><CB1 Receptor><CB1R><CNR1 gene><Cannabinoid Receptor CB1><Cannabinoids><Cell Body><Cell Communication and Signaling><Cell Nucleus><Cell Signaling><Cells><Characteristics><Code><Coding System><Corpus Striatum><Corpus striatum structure><DA Neuron><Data><Dependence><Detection><Development><Development and Research><Disinhibition><Dopamine><Dopamine neuron><Drug usage><Drugs><Dysfunction><Electrophysiology><Electrophysiology (science)><Epidemic><Functional disorder><GABA><Goals><Heterogeneity><Hydroxytyramine><Influentials><Infumorph><Intake><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Kadian><Lateral><MS Contin><MSir><Measures><Mediating><Medication><Morphia><Morphine><Morphine Addiction><Morphine Dependence><Motivation><Neurophysiology / Electrophysiology><Nucleus><Nucleus Accumbens><Opiate Addiction><Opiate Dependence><Opiates><Opioid><Oramorph><Oramorph SR><Patients><Pharmaceutical Preparations><Physiopathology><Psychological reinforcement><R & D><R&D><Regulation><Reinforcement><Relapse><Research><Rewards><Roxanol><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Statex SR><Striate Body><Striatum><Synapses><Synaptic><System><Technical Expertise><Therapeutic><Ventral Tegmental Area><Withdrawal><Withdrawal Symptom><Work><acute symptom><addiction><addictive disorder><behavior study><behavioral study><biological signal transduction><cannabinoid receptor 1><cannabinoid receptor type 1><cannabinoid therapeutics><cannabinoid therapy><cannabinoid treatment><cannabinoid type 1><cannabinoid-based therapeutic><cannabinoid-based therapy><cannabinoid-based treatment><cost><developmental><dopaminergic neuron><drug craving><drug efficacy><drug relapse><drug use><drug/agent><effective intervention><efficacious therapy><efficacious treatment><electrophysiological><experiment><experimental research><experimental study><experiments><gamma-Aminobutyric Acid><interventional strategy><mesolimbic dopamine system><mesolimbic system><motivated behavior><negative affect><negative affectivity><opiate abuse><opiate consumption><opiate drug abuse><opiate drug use><opiate intake><opiate use><opiate withdrawal><opioid abuse><opioid addiction><opioid consumption><opioid dependence><opioid dependent><opioid detox><opioid detoxification><opioid drug abuse><opioid drug use><opioid intake><opioid use><opioid withdrawal><pathophysiology><public health relevance><research and development><striatal><symptom treatment><symptomatic treatment><synapse><technical skills><treat symptom><ventral tegmentum><γ-Aminobutyric Acid>