Addiction to therapeutic opioid drugs and heroin has seen a marked increase in the US during the past two decades. In 2014, therapeutic opioid overdose and heroin were responsible for 18,893 and 10,574 deaths respectively. Opioid overdose is the primary driver for drug poisoning, being the leading cause of accidental death in the US, with 47,055 fatalities in 2014. The UCLA Center for Study of Opioid Receptors and Drugs of Abuse (CSORDA) has a focused multidisciplinary preclinical opioid research program with a broader educational and outreach mission in the area of addiction. Mu opioid receptors are targets for many addictive disorders since they are key components for mediating the rewarding effects of opiates, nicotine, cannabinoids, alcohol and food. CSORDA?s research program focuses on elucidating the circuitry and cell-specific adaptations underlying addiction-related behaviors mediated by mu opioid receptors. This CSORDA renewal application (years 31-36) focuses on understanding the circuitry regulating dysphoric states and investigates different opiate addiction susceptibility models, including neuropathic pain, opioid withdrawal and PTSD. The research plan will build upon progress during the past funding period by incorporating several CSORDA-developed innovative genetic mouse models, findings with regards to resting state fMRI imaging, as well as the elucidation of circuitry regulating opioid reward via neuroinflammation and perturbation of D2 enkephalinergic systems. The renewal will use a model of PTSD to examine the marked comorbidity of this disorder with addiction to drugs reliant on the endogenous opioid system for reward-related behaviors. To maintain CSORDA as a technically cutting edge and innovative Center, we have created a Technical Advancement Core (TA-Core) that will enable CSORDA?s research plan to incorporate new technologies optimized and vetted for CSORDA research. Four Research Projects are proposed that are highly interactive, both thematically and technically, and which use shared models, reagents and methods. Projects will focus on different brain circuitry associated with addiction, including the mesolimbic VTA striatal reward system (Projects I and III), the habenula (Projects II and III) and the amygdala (Project IV). Research Projects will explore the modulation of circuitry in models of chronic pain (Project III), withdrawal and depression (Projects I, II and III) and PTSD (Project IV). The research will employ mouse genetics and behavioral analysis combined with electrophysiology, optogenetics, transcript analysis and MRI imaging. In addition to the TA-Core, CSORDA will support an Animal Breeding Core (AB-Core) supplying all CSORDA Projects with mouse models and sharing reagents with the research community. The Administrative Core and CSORDA Advisory Board, consisting of Drs. Bernard Balleine, Antonello Bonci, Charles Chavkin, Pat Levitt, Eric Nestler and Peter Whybrow ex-officio, will provide programmatic oversight and coordinate training, outreach and a vigorous Pilot Program.

Public Health Relevance

Deaths resulting from overdose of opioid pain killers such as oxycodone as well as heroin have risen alarmingly over the past two decades. The Center for Opioid Receptors and Drugs of Abuse (CSORDA) is focused on preclinical research to understand the opioid-regulated brain circuits that mediate both the drug- induced euphoria as well as the depressive-like effects that occur during opioid withdrawal and to model the co-occurrence of opioid addiction with depression, anxiety and PTSD. The ultimate goal of this renewal of the Center is to identify therapeutic targets for alleviation of the depressive and stressful aspects of withdrawal that we consider are primary drivers for addiction to opioid drugs.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA005010-34
Application #
9964735
Study Section
Special Emphasis Panel (ZDA1)
Program Officer
Berton, Olivier Roland
Project Start
1987-09-30
Project End
2022-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
34
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Severino, Amie; Chen, Wenling; Hakimian, Joshua K et al. (2018) Mu-opioid receptors in nociceptive afferents produce a sustained suppression of hyperalgesia in chronic pain. Pain 159:1607-1620
Ben Hamida, Sami; Mendonça-Netto, Sueli; Arefin, Tanzil Mahmud et al. (2018) Increased Alcohol Seeking in Mice Lacking Gpr88 Involves Dysfunctional Mesocorticolimbic Networks. Biol Psychiatry 84:202-212
Lee, Kevin; Vuong, Helen E; Nusbaum, David J et al. (2018) The gut microbiota mediates reward and sensory responses associated with regimen-selective morphine dependence. Neuropsychopharmacology 43:2606-2614
Maroteaux, G; Arefin, T M; Harsan, L-A et al. (2018) Lack of anticipatory behavior in Gpr88 knockout mice showed by automatized home cage phenotyping. Genes Brain Behav 17:e12473
Ehrlich, Aliza T; Semache, Meriem; Bailly, Julie et al. (2018) Mapping GPR88-Venus illuminates a novel role for GPR88 in sensory processing. Brain Struct Funct 223:1275-1296
Becker, Jérôme A J; Kieffer, Brigitte L; Le Merrer, Julie (2017) Differential behavioral and molecular alterations upon protracted abstinence from cocaine versus morphine, nicotine, THC and alcohol. Addict Biol 22:1205-1217
Bakhurin, Konstantin I; Goudar, Vishwa; Shobe, Justin L et al. (2017) Differential Encoding of Time by Prefrontal and Striatal Network Dynamics. J Neurosci 37:854-870
Lalanne, L; Ayranci, G; Filliol, D et al. (2017) Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence. Addict Biol 22:1010-1021
Dagnew, Robel; Lin, Yin-Ying; Agatep, Jerikko et al. (2017) CerebraLux: a low-cost, open-source, wireless probe for optogenetic stimulation. Neurophotonics 4:045001
Boulos, Laura-Joy; Darcq, Emmanuel; Kieffer, Brigitte Lina (2017) Translating the Habenula-From Rodents to Humans. Biol Psychiatry 81:296-305

Showing the most recent 10 out of 117 publications