The mu-opioid receptor (MOR) is required for the profound effects of opiate drugs, including analgesia and drug reward. A long-term objective of the opioid research field is to understand the cellular and molecular targets through which the MOR mediates such effects. The MOR expresses broadly in the brain, so the precise cell types in which MOR expression is responsible for opiate's physiological effects including reward-related behaviors remain unknown. In the striatum, a major subcortical region implicated in drug addiction, MOR is expressed at high levels in a subset of medium spiny neurons (MSNs) that defines a striatal compartment, the striosome/patch compartment;while the MOR negative MSNs constitute the matrix compartment. The functional significance of striosome compartment and its high level MOR expression remain elusive. In our preliminary study, using a novel BAC transgenic rescue strategy, we have demonstrated that targeted expression of MOR selectively in the striosome MSNs that project to the substantia nigra (striatonigral MSNs) is sufficient to restore opiate reward seeking behaviors (i.e. sensitization and CPP) in otherwise MOR null background. Furthermore, the rescue mice also restore opiate-induced dopamine release in the striatum. In the current project, we will further define the striatal subregions (dorsal vs ventral), cell types (striatonigral vs striatopallidal MSNs in the striosome), and cell-autonomous gene expression changes that are critical to opiate reward. We will further test the mono-synaptic connectivity between the striosome striatonigral MSNs and the dopaminergic neurons in substantia nigra and ventral tegmental areas. Finally, we will use optogenetic and functional MRI approaches to test whether light-induced stimulation or suppression of the striosome striatonigral MSNs could lead to bi-directional modulation of reward-seeking behaviors including opiate reward, and to visualize the neural circuits controlled by striosome striatognigral neurons.

Public Health Relevance

Opiate drugs require the mu-opioid receptor to elicit their behavioral effects, including analgesia, dependence and drug reward. In this research Component of CSORDA we will use novel transgenic mouse models to define the precise neuronal cell types in the mammalian striatum in which mu-opioid receptor expression is sufficient for opiate reward, and to explore the underlying cellular and molecular mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Specialized Center (P50)
Project #
5P50DA005010-27
Application #
8501398
Study Section
Special Emphasis Panel (ZDA1-EXL-T)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
27
Fiscal Year
2013
Total Cost
$282,907
Indirect Cost
$99,201
Name
University of California Los Angeles
Department
Type
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