Endogenous Opioid Mechanisms for Rejection Sensitivity

This project hypothesizes that the brain's opioid system determines rejection sensitivity, a personality trait that is a vulnerability factor and feature of several psychiatric disorders. This project will use positron emission tomography to measure the brain's opioid response to social rejection and acceptance in a nonclinical population with varying levels of rejection sensitivity. The results will provide the first major step towards understanding a neurotransmitter mechanism for rejection sensitivity, allowing for further investigation into predicting and treating its associated disorders.

Study Overview

• Status: Completed
• Conditions: Rejection Sensitivity

Detailed Description

Humans depend on acceptance into groups and intimate relationships for survival and emotional well-being. Actual or perceived threats to this need such as social rejection (when one is not wanted or liked) can lead to marked changes in mood and behavior such as sadness, social withdrawal, and impulsivity. The experience of severe or repeated social rejection in those who are rejection sensitive is a strong contributor to psychiatric disorders such as major depressive, social anxiety, and personality disorders. The neurotransmitter mechanisms underlying rejection sensitivity (RS) are not known.

It has been known for over 30 years in nonhuman animals that the endogenous opioid system, particularly the µ-opioid receptor (MOR) system, regulates social distress and social reward behaviors. Using positron emission tomography, we recently showed that social rejection and acceptance produced robust MOR-mediated neurotransmission in specific brain areas, which correlated with changes in mood and behavior. This study was the first to show that the endogenous opioid system responds to social cues in humans. The proposed project will examine the MOR system in the clinically important trait of RS. Since the neurotransmitter mechanisms of RS are unknown, we seek to first understand the basic neurobiology of RS in a healthy population, prior to studying clinical populations.

The overall hypothesis is that RS is associated with MOR function. Those with higher RS compared to lower RS are hypothesized to have overall lower MOR activation during social rejection and acceptance, leading to greater distress and dampened pro-social behavior. Numerous animal studies have also established that the MOR system is strongly influenced by harmful social environments. Therefore, we will also examine the role of childhood maltreatment (CM), a negative early life experience known to be one of the highest risk factors for developing depression and anxiety. The goal of this project is to determine how RS and CM interact to determine patterns of MOR binding during baseline, social rejection, and social acceptance in a healthy population. We will also examine how RS, mediated through MOR activation, influences mood and behavior.

The impact of this research is to provide the first major step towards understanding a neurotransmitter mechanism for RS, with the long-term goal of predicting and treating its associated disorders.

• Study Type: Observational
• Enrollment (Actual): 114

Contacts and Locations

Study Locations

• United States
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 25 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Healthy Controls

Description

Inclusion Criteria:

• Men and women age 18-25 (inclusive)
• Right-handed
• Native English speaker
• Not currently in a romantic relationship
• Willing and able to participate in a PET scan

Exclusion Criteria:

• Not on hormonal birth control
• Not pregnant
• Consume less than 5 cigarettes per week and less than 14 alcoholic drinks per week, on average
• No use of recreational or street drugs in the past two years (e.g. marijuana)
• Willing to abstain from alcohol and/or tobacco for 48 hours
• No major untreated medical problems
• Never diagnosed with a psychiatric or neurological disorder
• Potential problems with having an MRI scan (claustrophobia, metal objects, etc.)

Study Plan

How is the study designed?

Design Details

• Observational Models: Case-Only
• Time Perspectives: Cross-Sectional

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Healthy Controls; Healthy men and women ages 18-25 years

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mu-opioid binding potential	This study will measure levels of radiotracer (carbon-11-labeled carfentanil) binding to the mu-opioid receptor in the brain using positron-emission tomography (PET). Primary regions of interest include: the amygdala, anterior insular cortex, anterior cingulate cortex, nucleus accumbens, and thalamus. All structures will be examined bilaterally. Differences in binding potential (Bmax/Kd) for the radiotracer will be compared across different experimental conditions (e.g., neutral, positive, negative social feedback).	within 30 days of informed consent

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
fMRI blood-oxygen-level-dependent (BOLD) response	This study will measure brain activation in response to social feedback and monetary reward. Primary regions of interest include: the amygdala, anterior insular cortex, and the nucleus accumbens. All structures will be examined bilaterally. Arbitrary units for fMRI BOLD are used to compare activation during one condition (e.g., neutral, baseline) vs. another condition (e.g., positive social feedback, monetary reward).	within 30 days of informed consent
Plasma cortisol	This study will collect blood every 10 minutes during PET to measure changes in levels of plasma cortisol. Units are ug/dL.	within 30 days of informed consent

Collaborators and Investigators

• Sponsor: Stony Brook University
• Collaborators: National Institute of Mental Health (NIMH); University of Michigan
• Investigators: Principal Investigator: David T Hsu, Ph.D., Stony Brook University

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Actual): June 6, 2019
• Study Completion (Actual): June 6, 2019

Study Registration Dates

• First Submitted: July 11, 2014
• First Submitted That Met QC Criteria: July 11, 2014
• First Posted (Estimate): July 15, 2014

Study Record Updates

• Last Update Posted (Actual): October 22, 2020
• Last Update Submitted That Met QC Criteria: October 19, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: opioid; PET; fMRI; rejection; reward; social; exclusion; acceptance
• Additional Relevant MeSH Terms: Immune System Diseases; Hypersensitivity
• Other Study ID Numbers: R01MH102264 (U.S. NIH Grant/Contract)