The mu-opioid receptor (MOR) is essential for the rewarding and analgesic properties of opiate drugs, such as heroin and morphine. Furthermore, the importance of MOR systems for reward and reinforcement processes, more broadly, are evident from the fact that MOR knockout mice show reduced reward for many different drugs of abuse (nicotine, cocaine, alcohol and cannabinoids) and also for natural rewards such as social interactions and food. A key question that will be addressed in this Component is how MOR subpopulations that are expressed in distinct cell-types and circuits contribute to opioid reinforcement behaviors, specifically self-administration of the opioid receptor agonist, remifentanil. Components I and II have created and fully described genetically modified mice (BACs, knockins and knockouts) that either express MOR only in discrete brain regions (testing "sufficiency" for addiction behaviors) or mice with deletions of MOR in specific brain areas (testing "necessity" for addiction behaviors). We will initially determine if there are specific alterations in the acquisition and incubation of remifentanil self-administration as a result of restricted MOR expression. We will test if striatal expression of MOR predominantly confined to the striosome or patch compartment of the striatum is "sufficient" for opioid addictive behaviors. Conversely, mice that lack MOR in the striatal neurons will be evaluated to test for the "necessity" of striatal receptors for these same behaviors. We will then focus on the cellular and molecular adaptations within striatal specific cell-types as a consequence of opioid self-administration. Approaches will use optogenetics, electrophysiology and a very novel application of single cell transcriptome analysis developed by Dr. Yi Sun within the E/T-Core. Together this information will provide phenotypic profiles of discrete striatal cell-types (D1 and D2) within specific striatal compartments (ventral/dorsal, striosome/matrix) with the view of identifying novel adaptive mechanisms that could lead to therapeutic strategies for amelioration of drug abuse behaviors.

Public Health Relevance

Many addiction behaviors are mediated by opioid systems. The studies outlined in this CSORDA Component will determine which opioid neural circuits mediate different behaviors associated with opioid addiction. The research will identify cellular and molecular adaptations to self-administered opioid within individual cells associated with reward. The long-term goal will be toward discovering new therapeutic targets for substance abuse disorders.

National Institute of Health (NIH)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZDA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Los Angeles
United States
Zip Code
Erbs, Eric; Faget, Lauren; Scherrer, Gregory et al. (2015) A mu-delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks. Brain Struct Funct 220:677-702
Wang, Nan; Gray, Michelle; Lu, Xiao-Hong et al. (2014) Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease. Nat Med 20:536-41
Wassum, Kate M; Greenfield, Venuz Y; Linker, Kay E et al. (2014) Inflated reward value in early opiate withdrawal. Addict Biol :
Ivanov, Iliyan; Liu, Xun; Clerkin, Suzanne et al. (2014) Methylphenidate and brain activity in a reward/conflict paradigm: role of the insula in task performance. Eur Neuropsychopharmacol 24:897-906
Tsoa, Rosemarie W; Coskun, Volkan; Ho, Chi K et al. (2014) Spatiotemporally different origins of NG2 progenitors produce cortical interneurons versus glia in the mammalian forebrain. Proc Natl Acad Sci U S A 111:7444-9
Taylor, Anna M W; Murphy, Niall P; Evans, Christopher J et al. (2014) Correlation between ventral striatal catecholamine content and nociceptive thresholds in neuropathic mice. J Pain 15:878-85
Ostlund, Sean B; Kosheleff, Alisa R; Maidment, Nigel T (2014) Differential effects of systemic cholinergic receptor blockade on Pavlovian incentive motivation and goal-directed action selection. Neuropsychopharmacology 39:1490-7
Becker, Jérôme A J; Clesse, Daniel; Spiegelhalter, Coralie et al. (2014) Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity. Neuropsychopharmacology 39:2049-60
Pradhan, Amynah A; Smith, Monique L; McGuire, Brenna et al. (2014) Characterization of a novel model of chronic migraine. Pain 155:269-74
Liu, Hailiang; Chen, Yongchang; Niu, Yuyu et al. (2014) TALEN-mediated gene mutagenesis in rhesus and cynomolgus monkeys. Cell Stem Cell 14:323-8

Showing the most recent 10 out of 36 publications