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Principal Investigator: Jessica Tooley
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $34,908
Funding agency: National Institute on Drug Abuse
PROJECT SUMMARY
Opioid use disorder is an urgent public health crisis in the U.S. and roughly 30% of Americans prescribed opioids
misuse their medications. The overwhelming reason people with opioid use disorder continue taking opioids is
to avoid withdrawal. Opioid withdrawal is physically painful and emotionally exhausting. Despite the inherently
chronic relapsing nature of drug abuse and withdrawal, studies of how long-term opioid use alters the aversion
circuits of the brain are surprisingly limited compared to those studying the reward circuits. Dysfunction of
mesolimbic circuits, which includes the ventral pallidum (VP) and its downstream targets, has been implicated
in a wide range of substance abuse disorders, including opioid use disorder, but it is not known how opioid use-
induced adaptations arise in these brain areas. One hypothesis is that withdrawal from chronic use of opioids
may prompt adaptations in aversion-processing circuits that generate a higher sensitivity to aversive stimuli and
mediate the general negative affective state associated with withdrawal; thus leading to increased stress and
subsequent relapse. The VP is especially well-positioned to mediate adaptations of aversion circuits in opioid
use disorder. VP neurons receive input from reward and aversion encoding structures and modulate aversion
centers of the brain, a primary output being the lateral habenula (LHb). Furthermore, a recently discovered subset
of VP neurons (VPGlu) has been shown to encode aversion in reward-related contexts. In this proposal, I plan to
use a multi-faceted approach to investigate opioid use-induced adaptations of LHb-projecting VP (VPGluLHb)
neurons in mice. I hypothesize that VPGlu neurons are hyperactive and more responsive to noxious stimuli in
protracted opioid withdrawal, and that opioid withdrawal potentiates transmission at VPGluLHb synapses.
Lastly, I expect that VPGlu neuronal activity confers sensitivity to negative outcomes and that this response is
heighted following opioid withdrawal. I propose to test each of these hypotheses in specific aims using in vivo
and ex vivo electrophysiology, optogenetics, and behavioral techniques to evaluate VPGluLHb activity and
plasticity as potential mechanisms underlying enhanced sensitivity to aversive outcomes and events. Successful
completion of these aims will inform future therapeutic interventions to treat the negative affective state of opioid
withdrawal to allow for successful treatment of opioid use disorder.
Terms: <AMPA Receptors><Abstinence><Acute><Affective Symptoms><American><Anhedonia><Appetitive Behavior><Area><Automobile Driving><Aversive Stimulus><Behavior><Behavioral><Behavioral Assay><Brain><Brain Nervous System><Cell Body><Cells><Chronic><Coupled><Cues><Data><Dihydrohydroxycodeinone><Disease><Disorder><Drug abuse><Drugs><Dysfunction><Electrophysiology><Electrophysiology (science)><Emotional><Encephalon><Event><Exhibits><Functional disorder><Future><G-Proteins><GTP-Binding Proteins><GTP-Regulatory Proteins><Globus Pallidus><Glutamates><Goals><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Habenula><Height><Hyperactivity><Intake><L-Glutamate><Lateral><Longitudinal Studies><Measures><Mediating><Medication><Mice><Mice Mammals><Murine><Mus><N-Methyl-D-Aspartate Receptors><N-Methylaspartate Receptors><NMDA Receptor-Ionophore Complex><NMDA Receptors><Nature><Negative Valence><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Opiates><Opioid><Oral><Outcome><Output><Oxycodeinon><Oxycodone><Oxycodone SR><Oxycontin><Pain><Painful><Pattern><Persons><Pharmaceutical Preparations><Physiopathology><Population><Position><Positioning Attribute><Positive Valence><Preventative strategy><Prevention strategy><Preventive strategy><Probability><Property><Public Health><Punishment><Relapse><Rewards><Risk Behaviors><Risky Behavior><Role><Roxicodone><Self Administered><Self Administration><Stimulus><Stress><Structure><Substance abuse problem><Synapses><Synaptic><Techniques><Testing><Therapeutic Intervention><Transmission><Withdrawal><Withdrawal Symptom><Work><abuse of drugs><abuse of substances><abuses drugs><allostases><allostasis><at risk behavior><cell type><driving><drug withdrawal><drug/agent><electrophysiological><exhaust><experiment><experimental research><experimental study><experiments><glutamatergic><in vivo><intervention therapy><licit opioid><long-term study><longitudinal outcome studies><longterm study><mu opioid receptors><negative affect><negative affectivity><neural circuit><neural circuitry><neural mechanism><neurocircuitry><neuromechanism><neuronal><non-medical opioid use><nonmedical opioid use><opiate consumption><opiate drug use><opiate intake><opiate medication><opiate misuse><opiate use><opiate use disorder><opiate withdrawal><opioid consumption><opioid detox><opioid detoxification><opioid drug use><opioid intake><opioid medication><opioid misuse><opioid use><opioid use disorder><opioid withdrawal><optogenetics><oxycodone self-administration><pallidum><patch clamp><pathophysiology><pharmacologic><postsynaptic><prescribed opiate><prescribed opioid><prescription opiate><prescription opioid><recruit><relapse risk><response><reward processing><self-administer oxycodone><social role><substance abuse><synapse><synaptic circuit><synaptic circuitry><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><transmission process><treatment strategy><μ opioid receptors><μ-OR><μOR>