Drug addiction remains a major public health issue. Addiction is characterized by lack of inhibitory control over drug seeking. Periods of remission, in which inhibitory control returns, are punctuated by relapses to active addiction. However, skills learned during behavioral therapies can protect against relapses. Investigation of the synaptic plasticity mechanisms underlying inhibitory learning may enable enhancement of inhibitory control by novel therapies. However, the relatively limited understanding of synaptic plasticity underlying extinction in drug seeking has precluded successful therapies to augment extinction learning. Hence, this proposal outlines a series of experiments that will determine the role of transient synaptic potentiation (t-LTP) in the infralimbic (IL) to accumbens shell (NAshell circuit in extinction from cocaine. Our preliminary data demonstrates t-LTP in dendritic spine head diameter in NAshell during an extinction session, meaning that spine head diameter rapidly (15 min) increases and then normalizes by 45 min. We hypothesize that electrophysiological t-LTP will be confined to NAshell during extinction and to NAcore during reinstatement. We further hypothesize that the IL to NAshell circuit is necessary and sufficient for extinction and associated t-LTP. These hypotheses, based upon preliminary data, will be tested through two specific aims.
Aim 1 will employ patch clamp electrophysiology to determine the time course of changes in AMPA:NMDA ratio during extinction and reinstatement in NAshell and NAcore.
Aim 2 will employ a DREADD (Designer Receptor Exclusively Activated by Designer Drug) strategy to determine the role of the IL to NAshell circuit in extinction-associated t-LTP. In addition to clarifying the role of transient corticostriatal synaptic plasticity in extintion from cocaine, this fellowship will train the applicant in modern techniques for manipulating neural circuits and assessing synaptic potentiation.

Public Health Relevance

Drug abuse remains a major public health issue, partly because periods of remission, in which inhibitory control is regained, are punctuated by relapse. These studies characterize synaptic plasticity underlying extinction from cocaine seeking, which is an animal model for inhibiting drug seeking. Knowledge gained from these studies will support development of a human therapy for enhancing inhibitory control and preventing relapse to drug seeking.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DA038893-03
Application #
9245637
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Babecki, Beth
Project Start
2015-04-01
Project End
2018-06-30
Budget Start
2017-04-01
Budget End
2018-03-31
Support Year
3
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Medical University of South Carolina
Department
Neurosciences
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29403
Roberts-Wolfe, Douglas; Bobadilla, Ana-Clara; Heinsbroek, Jasper A et al. (2018) Drug Refraining and Seeking Potentiate Synapses on Distinct Populations of Accumbens Medium Spiny Neurons. J Neurosci 38:7100-7107
Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2017) Accumbens nNOS Interneurons Regulate Cocaine Relapse. J Neurosci 37:742-756
Spencer, Sade; Garcia-Keller, Constanza; Roberts-Wolfe, Douglas et al. (2017) Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry 81:616-624
Smith, Alexander C W; Scofield, Michael D; Heinsbroek, Jasper A et al. (2016) Accumbens nNOS interneurons regulate cocaine relapse. J Neurosci :
Scofield, M D; Heinsbroek, J A; Gipson, C D et al. (2016) The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis. Pharmacol Rev 68:816-71
Garcia-Keller, C; Kupchik, Y M; Gipson, C D et al. (2016) Glutamatergic mechanisms of comorbidity between acute stress and cocaine self-administration. Mol Psychiatry 21:1063-9
Roberts-Wolfe, Douglas J; Kalivas, Peter W (2015) Glutamate Transporter GLT-1 as a Therapeutic Target for Substance Use Disorders. CNS Neurol Disord Drug Targets 14:745-56