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Research Center

Shirley and Stefan Hatos Center for Neuropharmacology

Leadership

Christopher Evans, PhD, Stefan Hatos Professor
Director

Contact Info

Hatos Center for Neuropharmacology Website

675 Charles E. Young Drive South
MRL 2762
Los Angeles, CA
aelias@mednet.ucla.edu
(310) 794-7011

About

The Shirley and Stefan Hatos Center for Neuropharmacology focuses on clinical and pre-clinical research concerned with drugs that can lead to substance use disorders, including opioids, alcohol, cannabinoids and psychostimulants. The center uses various models including rodents, flies, hagfish and human stem cell cultures to identify circuitry and processes involved in drug actions and during withdrawal from addictive drugs. Translational programs investigate the interaction of addictive drugs with other disorders such as chronic pain and mood disorders with the aim of identifying novel therapeutic strategies.

Research

The Shirley and Stefan Hatos Center is home to the NIDA-supported UCLA Opioid Research Center which investigates opioid systems at the molecular, cellular and behavioral levels. Although the collaborative research of the Center is primarily concerned with the action of opioids, individual faculty have research programs investigating:

Who We Are

  • Christopher J. Evans, Ph.D.

    Professor, Hatos Center Director

  • Anne. M. Andrews, Ph.D.

    Professor

  • David E. Krantz, M.D., Ph.D.

    Professor

  • Catherine M Cahill, Ph.D.

    Professor

  • Brigitte Kieffer, Ph.D.

    Scientific Director, Douglas Institute ; Professor, Department of Psychiatry, McGill University Molecular psychiatry, addiction and mood disorders, pain, development disorders.

  • Nigel T. Maidment, Ph.D.

    Professor, Department of Psychiatry & Biobehavioral Sciences

  • Lara Ray, Ph.D.

    Associate Professor, Department of Psychology

  • X. Willam Yang, M.D, Ph.D.

    Professor, Center for Neurobehavioral Genetics; Department of Psychiatry & Biobehavioral Sciences In the Hatos Center

  • Zhan Shu, Ph.D.

    Postdoctoral Scholar

  • Hoa Lam

    Senior Research Associate

  • Lindsay Lueptow, Ph.D.

    Postdoctoral Scholar

  • Ana Elias

    Senior Administrator

  • La Tasha Atkins

    Administrative Assistant

  • Patrick O’Neill

    Assistant Researcher

  • Courtney Cameron

    Project Scientist

  • Cherka Kibaly

    Lab manager

Center for Study of Opioid Receptors and Drugs of Abuse (CSORDA)

The research objectives of CSORDA are to gain insights into the mechanisms of action of endogenous opioids and opioid drugs at their cognate receptors with the goal of discerning fundamental processes contributing to behaviors such as analgesia, addiction, tolerance and withdrawal. The current focus is on the circuitry and cell-specific adaptations underlying addiction-related behaviors mediated by mu opioid receptors. The center will focus on the circuitry of reward processing with the renewal emphasizing study of the circuitry regulating dysphoric states and relapse following abstinence of opiate drugs including in different susceptibility models including neuropathic pain and PTSD.

RESEARCH PROJECTS

CSORDA funds four Research Projects that are highly interactive both thematically and technically use shared models, reagents and methodologies. Projects will focus on different brain circuitry associated with reward/aversion and employ mouse genetics and behavioral analysis combined with electrophysiology, optogenetics, transcript analysis and brain imaging. The four projects are:

  • Project I: Genetic Dissection of Striatal Indirect-Pathway in Opioid Withdrawal Aversion (Leads – Nigel Maidment and William Yang). This Project focuses on the D2-MSN cell type of the indirect pathway from the nucleus accumbens to the ventral pallidum,that both published and preliminary data indicate is critical in mediating both the aversive effects of opioid withdrawal and basal MOR-hedonic tone.
  • Project II: Mu Opioid receptors in Habenular Networks: Reward and/or Aversion? (Lead – Brigitte Kieffer). Project II is focused on habenula circuitry.
  • Project III: Impact of Chronic Pain on Circuitry Involved in Opioid Self-Administration Behaviors (Lead – Chris Evans; Co-investigator Catherine Cahill). This Project uses iv self-administration of the opioids, remifentanil, oxycodone and morphine, combined with genetic manipulations, to determine phases in self administration influenced by MOR in different neural populations, and how this impacts self-administration in chronic pain. 
  • Project IV: Bidirectional Comorbidity Between Fear Sensitization and Opioid Reward (Lead – Michael Fanselow). Component IV will use a rodent stress-induced PTSD model (Stress-Enhanced Fear Learning – SEFL) developed in Dr Fanselow’s laboratory to begin to explore the circuitry that may underlie the co-morbidity of PTSD and opioid abuse, and other drugs of abuse.

CSORDA CORES:

The Administrative Core and CSORDA Advisory board, consisting of Drs Balleine, Chavkin, Bonci, Levitt, Nestler and Whybrow ex-officio, will provide programmatic oversight and coordinate training, outreach and a vigorous Pilot Program for the center. (Lead: Chris Evans) (CoI’s Nigel Maidment and Eydie London)

The Technical Advancement Core will maintain CSORDA as a technically cutting edge and innovative center which will enable CSORDA’s research plan to incorporate the very latest technologies in animal resting-state MRI, multilectrode array recording, transcript profiling, optogenetics and cellular calcium imaging with methodologies specifically optimized for CSORDA research. ((Leads: William Yang and Peyman Golshani) (Co-I’s Giovanni Coppola, Sotiris Mansmanidis and Brigitte Kieffer) 

The Animal Breeding Core will supply all CSORDA Projects with mouse models and extend facilities into the research community (Leads: William Yang) 

The Pilot Core will fund 4 Pilot Program grantees, each year to enhance the contribution of CSORDA to addiction research. 

CSORDA

Publications

2020

μ-Opioid Receptors on Distinct Neuronal Populations Mediate Different Aspects of Opioid Reward-Related Behaviors. 

Genetic and functional analysis of a Pacific hagfish opioid system.

Delta opioid receptor activation modulates affective pain and modality-specific pain hypersensitivity associated with chronic neuropathic pain. 

In vivo mapping of a GPCR interactome using knockin mice. 

Opioid dose regimen shapes mesolimbic adaptations. 

Sex differences in kappa opioid receptor antinociception is influenced by the number of X chromosomes in mouse. 

Chronic opioid pretreatment potentiates the sensitization of fear learning by trauma.

2019

Blockade of dopamine D1 receptors in male rats disrupts morphine reward in pain naïve but not in chronic pain states. 

Dietary Supplementation with Omega-3 Polyunsaturated Fatty Acids Reduces Opioid-Seeking Behaviors and Alters the Gut Microbiome. 

Pain-Induced Negative Affect Is Mediated via Recruitment of The Nucleus Accumbens Kappa Opioid System. 

Kappa Opioid Receptors Drive a Tonic Aversive Component of Chronic Pain.

Non-nociceptive roles of opioids in the CNS: opioids’ effects on neurogenesis, learning, memory and affect.

2018

Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment. 

Evidence and Function Relevance of Native DOR-MOR Heteromers.

Dissociation between morphine-induced spinal gliosis and analgesic tolerance by ultra-low-dose α2-adrenergic and cannabinoid CB1-receptor antagonists.

2017

Neuroinflammation-a co-occurring phenomenon linking chronic pain and opioid dependence. 

Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents. 

Mu opioid receptors in GABAergic neurons of the forebrain promote alcohol reward and drinking. 

Mu opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food.

2016

Mesolimbic dopamine signaling in acute and chronic pain: implications for motivation, analgesia, and addiction (in press)

Neurochips enable nanoscale devices for high resolution in vivo neurotransmitter sensing

Nicotine modifies corticostriatal plasticity and amphetamine rewarding behaviors in mice (in press)

Sustained Suppression of Hyperalgesia during Latent Sensitization by m, d and k-opioid receptors and a2A adrenergic receptors; Role of Constitutive Activity

Allostatic Mechanisms of Opioid Tolerance Beyond Desensitization and Downregulation. 

Topography of microglial activation in sensory- and affect-related brain regions in chronic pain. 

Neurobiology of opioid dependence in creating addiction vulnerability.

Molecular Pharmacology of δ-Opioid Receptors. 

Neuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine.

Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta opioid Receptor Function.

Mu opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food. 

Interacting Cannabinoid and opioid Receptors in the Nucleus Accumbens Core Control Adolescent Social Play. 

BOLD Imaging in Awake Wild-Type and Mu- opioid Receptor Knock-Out Mice Reveals On-Target Activation Maps in Response to Oxycodone.

Deletion of the mu opioid receptor gene in mice reshapes the reward-aversion connectome. 

Drug discovery: Designing the ideal opioid . 

Agonist-Specific Recruitment of Arrestin Isoforms Differentially Modify Delta opioid Receptor Function.

Kappa opioid receptor antagonism and chronic antidepressant treatment have beneficial activities on social interactions and grooming deficits during heroin abstinence. 

Frontostriatal Circuit Dynamics Correlate with Cocaine Cue-Evoked Behavioral Arousal during Early Abstinence. 

Nicotine Modifies Corticostriatal Plasticity and Amphetamine Rewarding Behaviors in Mice(1,2,3).

2015

Anti-nociception mediated by a κ opioid receptor agonist is blocked by a δ receptor agonist

Neuroimmune Regulation of GABAergic Neurons Within the Ventral Tegmental Area During Withdrawal from Chronic Morphine

Microglia Disrupt Mesolimbic Reward Circuitry in Chronic Pain

Involvement of Endogenous Enkephalins and β-Endorphin in Feeding and Diet-Induced Obesity

Serotonin states and social anxiety

Sex- and SERT-associated differences in stimulated serotonin revealed by fast microdialysis

Perinatal vs. genetic programming of serotonin states associated with anxiety

Latent sensitization: a model for stress-sensitive chronic pain

Recent advances on the delta opioid receptor: from trafficking to function

Controlled DNA patterning by chemical lift-off lithography: matrix matters

Printable ultrathin metal oxide semiconductor-based conformal biosensors

2014

Targeted expression of mu-opioid receptors in a subset of striatal direct-pathway neurons restores opiate reward

Characterization of a novel model of chronic migraine

A mu–delta opioid receptor brain atlas reveals neuronal co-occurrence in subcortical networks

Drosophila melanogaster as a genetic model system to study neurotransmitter transporters

δ-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice

Correlation between ventral striatal catecholamine content and nociceptive thresholds in neuropathic mice

Maternal cigarette smoking during pregnancy predicts drug use via externalizing behavior in two-community-based samples of adolescents

The redistribution of Drosphila vesicular monoamine transporter mutants from synaptic vesicles to large dense-core vesicles impairs amine-dependent behavior

Synergistic effects on dopamine cell death in a Drosphila model of chronic toxin exposure

2013

Rethinking 5‑HT1A Receptors: Emerging Modes of Inhibitory Feedback of Relevance to Emotion-Related Behavior

Regulation of mu-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance

Chronic inflammatory injury results in increased coupling of delta opioid receptors tovoltage-gated Ca2+ channels

The real catecholamine content of secretory vesicles in the CNS revealed by electrochemical cytometry

Physiologically Relevant Changes in Serotonin Resolved by Fast Microdialysis

Phasic Mesolimbic Dopamine Release tracks reward seeking during expression of Pavlovian-to-Instrumental Transfer

Targeted Deletion of the Mouse Alpha2 Nicotinic Acetylcholine receptor Subunit Gene (Chma2) Potentiates Nicotine-Modulated Behaviors

Opioid self-administration results in cell-type specific adaptations of striatal medium spiny neurons

Drug-primed reinstatement of cocaine seeking in mice: increased excitability of medium-sized spiny neurons in the nucleus accumbens

Dispensable, Redundant, Complementary, and Cooperative Roles of Dopamine, Octopamine, and Serotonin in Drosophila melanogaster

Delta Opioid Receptors Regulate Temporoammonic-Activated Feed forward Inhibition to the Mouse CA1 Hippocampus

Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers

Select G-Protein-Coupled Receptors Modulate Agonist-Induced Signaling via a ROCK, LIMK, and ß-Arrestin 1 Pathway

2012

Phasic Mesolimbic Dopamine Signaling Precedes and Predicts Performance of a Self-Initiated Action Sequence Task

Differential serotonin transport is linked to the rh5-HTTLPR in peripheral blood cells

Transient Extracellular Glutamate Events in the Basolateral Amygdala Track Reward-Seeking Actions

A Single Administration of Low-Dose Varenicline Saturatesα4ß2* Nicotinic Acetylcholine Receptors in the Human Brain

Evidence that Behavioral Phenotypes of Morphine in ß-arr2_/_ Mice Are Due to the Unmasking of JNK Signaling

In VivoVisualization of Delta Opioid Receptors upon Physiological Activation Uncovers a Distinct Internalization Profile

Ligand-directed signaling within the opioid receptor family

Serotonin Uptake Is Largely Mediated by Platelets versus Lymphocytes in Peripheral Blood Cells

Electrochemically deposited iridium oxide reference electrode integrated with an electroenzymatic glutamate sensor on a multi- electrode array microprobe

From the bottom up: dimensional control and characterization in molecular monolayers

Virtual reality Cue exposure Therapy for The Treatment of tobacco dependence

2011

Effect of Bupropion Treatment on Brain Activation induced by Cigarette-Related Cues in Smokers

Mu-Opioid Receptor Activation in the Basolateral Amygdala Mediates the Learning of Increases But Not Decreases in the Incentive Value of a Food Reward

Analgesic tone conferred by constitutively active mu opioid receptors in mice lacking beta-arrestin 2

Elevated Tonic Extracellular Dopamine Concentration and Altered Dopamine Modulation of Synaptic Activity Precede Dopamine Loss in the Striatum of Mice Overexpressing Human a-Synuclein

Effect of Secondhand Smoke on Occupancy of Nicotinic Acetylcholine Receptors in Brain

Large Sample Group Independent Component Analysis of Functional Magnetic Resonance Imaging Using Anatomical Atlas-Based Reduction and Bootstrapped Clustering

Localization and Regulation of Fluorescently Labeled Delta Opioid Receptor, Expressed in Enteric Neurons of Mice

Differential dependence of Pavlovian incentive motivation and instrumental incentive learning processes on dopamine signaling

Presynaptic Control of Rapid Estrogen Fluctuations in the Songbird Auditory Forebrain

Manipulation of Cigarette Craving with Transcranial Magnetic Stimulation

A Putative Vesicular Transporter Expressed in Drosophila Mushroom Bodies that Mediates Sexual Behavior May Define a Neurotransmitter System

2010

Tyrosine-based Motif Localizes a Drosophila Vesicular Transporter to Synaptic Vesicles in Vivo

Opioid pharmaceuticals and addiction: The issues, and research directionsseeking solutions

Ligand-Directed Trafficking of thedelta-Opioid Receptor In Vivo: Two Paths Toward Analgesic Tolerance

2009

Opioid receptors: From binding sites to visible molecules in vivo

Neurokinin 1 Receptors Regulate Morphine-Induced Endocytosis and Desensitization of mu-Opioid Receptors in CNS Neurons

Delta Receptors Are Required for Full Inhibitory Coupling of mu-Receptors to Voltage-Dependent Ca2+ Channels in Dorsal Root Ganglion Neurons

Pavlovian conditioning of multiple opioid-like responses in mice

Disruption of endogenous opioid activity during instrumental learning enhances habit acquisition

Distinct opioid circuits determine the palatability and the desirability of rewarding events

Extracellular signal-regulated kinase activation in the amygdala mediates elevated plus maze behavior during opioid withdrawal

2008

Silicon Wafer-Based Platinum Microelectrode Array Biosensor for Near Real-Time Measurement of Glutamate in Vivo

Sex chromosome complement affects nociception in tests of acute and chronic exposure to morphine in mice

A Glial Variant of the Vesicular Monoamine Transporter Is Required To Store Histamine in the Drosophila Visual System

Drosophila Vesicular Monoamine Transporter Mutants Can Adapt to Reduced or Eliminated Vesicular Stores of Dopamine and Serotonin

2007

ß-Arrestin2 and c-Src Regulate the Constitutive Activity and Recycling of Mu Opioid Receptors in Dorsal Root Ganglion Neurons

Enkephalin release promotes homeostatic increases in Constitutively active mu opioid receptors during Morphine withdrawal

2006

Overexpression of the Drosophila vesicular monoamine transporter increases motor activity and courtship but decreases the behavioral response to cocaine

NMDA receptor antagonism disrupts the development of morphine analgesic tolerance in male, but not female C57BL/6J mice

Constitutively Active Mu Opioid Receptors Mediate the Enhanced Conditioned Aversive Effect of Naloxone in Morphine-Dependent Mice

Mu opioid receptor-effector coupling and trafficking In dorsal root ganglia neurons

Immunolocalization of orphanin FQ in rat cochlea

Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy

Morphine analgesic tolerance in 129P3/J and 129S6/SvEv mice

2005

Endogenous enkephalins, not endorphins, modulate basal hedonic state in mice

2004

Secrets of the opium poppy revealed

2003

Blockade of ventral pallidal opioid receptors induces a conditioned place aversion and attenuates acquisition of cocaine place preference in the rat

Brain Region-Specific Mechanisms for Acute Morphine-Induced Mitogen-Activated Protein Kinase Modulation and Distinct Patterns of Activation during Analgesic

Tolerance and Locomotor Sensitization

2002

Novel orphanin FQ/nociceptin transcripts are expressed in human immune cells

2001

Differential splicing of transcripts encoding the orphanin FQ/nociceptin precursor

Agonist-, Antagonist-, and Inverse Agonist-Regulated Trafficking of the Delta-Opioid Receptor Correlates with, but Does Not Require, G Protein Activation

Naloxone fails to produce conditioned place aversion in mu-opioid receptor knock-out mice

2000

Ligand-Induced Changes in Surface µ-Opioid Receptor Number: Relationship to G Protein Activation?

1998

Opioid Regulation of Pallidal Enkephalin Release:Bimodal Effects of Locally Administered Mu& Delta Opioid Agonists in Freely Moving Rats

mu-Opioid Receptor Internalization: Opiate Drugs Have Differential Effects on a Conserved Endocytic Mechanism In Vitro and in the Mammalian Brain

Repeated heroin administration increases extracellular opioid peptide-like immunoreactivity in the globus pallidus/ventral pallidumof freely moving rats

ORL-1 and Mu Opioid Receptor Antisera Label Different Fibers in Areas Involved in Pain Processing

1997

Presynaptic Versus Postsynaptic Localization of m and d Opioid Receptors in Dorsal and Ventral Striatopallidal Pathways

Functional Analysis of Cloned Opioid Receptors inTransfected Cell Lines

Orphanin FQ Inhibits Synaptic Transmission and Long-Term Potentiation in Rat Hippocampus

1996

Morphine Activates Opioid Receptors without Causing Their Rapid Internalization

Hatos Foundation Student and Faculty Programmatic Support

Hatos Faculty

Anne Andrews
Catherine Cahill
Arthur Brody
Christopher Evans
Brigitte Kieffer
David Krantz
Nigel Maidment
Lara Ray

Hatos postdoctoral Researchers

Martin Bjorstrom
Janet Byun
Onymachi Egbuta
Anna Grygoruk
Kim LeBlanc
Yaoying Ma
Matthew Maga
David pena
Rafael Romero
Anne Simon
Lindsay Lueptow

Hatos Undergraduate Students

Waleed Atallah
Nina Desai
Connor King
Alan Le
Sadaf Mehrabani
Ani Minasyan
Jasmin Olsson
Nicole Romaneschi
Maureen Sampson
Dylan Stone
pia Vayssiere
Elroy Vojdani
C. Yu

Postgraduate Students

Ghislaine Monteillet Agius
Benito Anton 
Shoshana Eitan 
p. D. Skoubis
J. Shoblock 
Tzu-ping Yu
Daniel Nachun
paulette A. Zaki 
Elemer T. piros
Jamshid Arjomand
M. Foster Olive
Alwin Klaassen

Hatos Technical

Elizabeth Brooks
Hoa Lam
Cynthia Lui
Neptune Mizrahi
Vanessa Tolosa
Hongyan Yang
Cherka Kibaly

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