Does Propranolol Attenuate Inflammatory Responses to a Psychological Stressor?

Psychological stress is implicated in the onset and progression of many common and costly
chronic diseases, including cardiovascular disease, chronic pain conditions, and major
depressive disorder (Cohen et al., 2007; Kendler et al., 1999; Steptoe and Kivimäki, 2012).
An emerging body of evidence suggests that inflammation, indexed via levels of
pro-inflammatory cytokines and reactive proteins, may be a key biological mechanism by which
stress affects health (Baker et al., 2012; Miller et al., 2009; Slavich et al., 2010).
Indeed, psychological stressors can induce increases in inflammation (Slavich and Irwin,
2014; Kiecolt-Glaser et al., 2003; Rohleder, 2014; Steptoe et al., 2007), and greater levels
of inflammation may contribute to the development of disease (Capuron and Miller, 2004; Choy
and Panayi, 2001; DellaGiola and Hannestad, 2010; Raison and Miller, 2013; The Emerging Risk
Factors Collaboration, 2010). Despite this growing literature linking stress, inflammation,
and poor health, little is known about the precise physiological mechanisms linking
psychological stress and increases in inflammation.

One hypothesized mechanism that may translate psychological stress into increases in levels
of inflammation is activation of the sympathetic nervous system (SNS). The SNS is part of the
autonomic nervous system and is primarily indexed by release of the catecholamines
epinephrine (adrenaline) and norepinephrine (noradrenaline). Prior research in non-human
animal models has shown that stress-induced SNS activation leads to increases in levels of
pro-inflammatory cytokines inflammation (Bierhaus et al., 2003; DeRijk et al., 1994; Kop et
al., 2008; van Gool et al., 1990), while pharmacologically blocking sympathetic activation
attenuates the inflammatory response to stress (Bierhaus et al., 2003). However, no known
human studies to date have examined the relationship between psychological stress, SNS
activation, and inflammation. The present study is designed to address this major gap in our
knowledge of the physiological mechanisms that may link stress and disease.

A potential reason for the lack of human research linking stress, SNS activation, and
inflammation is that SNS activity is difficult to measure. Indeed, adrenaline and
noradrenaline are released into the bloodstream very rapidly during a stressor, making their
kinetics difficult to capture during typical laboratory-based stress paradigms. Indirect
measures of SNS activity may be acquired using psychophysiological approaches that involve
peripheral measures of electrical activity and efficiency of the heart; however, these
methods provide only indirect indicators of SNS activity, making them subject to criticism in
the psychoneuroimmunology community.

To circumvent these issues with assessment of SNS activity, the present study will employ a
psychopharmacological approach to experimentally block SNS activity using the drug
propranolol. Propranolol is a beta-blocker medication that is very commonly prescribed by
physicians in the United States for the treatment of hypertension, given that it blocked
adrenergic receptors that lead to relaxation of the cardiac muscle and smooth muscle tissue.
Interestingly, propranolol is also sometimes prescribed to individuals who have performance
anxiety (i.e., public speaking anxiety), as reducing SNS activity (i.e., eliminating the
increased heart rate, blood pressure, sweaty palms, etc., that typically accompany
anxiety-provoking situations) has been anecdotally observed to decrease perceptions of stress
during these situations. Psychological scientists have recently become more interested in the
role SNS activity may play in the formation and reconsolidation of fear memories, and a
number of studies have now used propranolol to investigate if blocking SNS activity may help
treat individuals with Post-Traumatic Stress Disorder (PTSD; Pitman et al., 2002; Vaiva et
al., 2003). However, only one known study to date has investigated if propranolol reduces
stress-induced immune system activation (Benschop et al., 1994), and this (now dated) study
did not specifically explore if propranolol reduces inflammatory responses to stress.
Furthermore, no known studies have examined if blocking SNS activity with propranolol changes
individuals' appraisals of the stressful situation, or their affective responses to stress.
Results from this study will complement and extend the existing work on how SNS activity
affects fear memories and stress by focusing on how propranolol affects inflammatory and
psychological responses to a stressor.

In addition to these primary goals of the present study, the investigators will also explore
the role of SNS activation in a number of additional exploratory tasks that are hypothesized
to be affected by sympathetic arousal. More specifically, the investigators will examine if
exposure to propranolol eliminates implicit biases toward out-group members (in this case,
African Americans), given that a very large literature suggests that many White Americans
hold implicit biases against African Americans (Wittenbrink et al., 1997; Nosek et al.,
2002). While it has been hypothesized that sympathetic arousal based on cultural stereotypes
associating African Americans with negativity may be leading to these implicit biases, no
known studies have investigated this issue. The investigators will also explore of SNS
activation is critical for empathy, or individual's ability to understand the emotional
states of others, for avoiding risky decisions, and for moral judgments. Thus, this study
will also answer a number of exploratory, unanswered questions in social psychology regarding
the role that sympathetic arousal plays in some of our most fundamental psychological
processes.

In sum, this randomized, double-blind, placebo-controlled study of propranolol will shed
important light on how SNS activation influences our psychological and inflammatory responses
to stress. Results from this study will inform both the basic science literature that is
attempting to map the physiological mechanisms by which psychological stress may lead to poor
mental and physical health, and may also ultimately have therapeutic relevance for
individuals who are experiencing high levels of stress that is putting their health at risk.
By utilizing psychopharmacological approaches, the investigators will circumvent many of the
challenges of conducting this research in human populations. The investigators will also be
in a place to draw strong conclusions regarding causality, given that they will have
experimentally manipulated SNS activation, rather than relying on correlational measures of
SNS activity that are difficult to assess and are not appropriate for asking if SNS activity
causes changes in psychology and biology.

Inclusionary Criteria:

1. Healthy volunteers

2. Age 18-25

3. Fluent in English

Exclusionary Criteria:

1. presence or history of chronic physical illness (especially disorders with an
inflammatory component, such as rheumatoid arthritis, asthma, allergies, or issues
that can affect the heart, including low-blood pressure or other heart conditions)

2. presence or history of psychiatric illness (depression, anxiety)

3. any current prescription medication use

4. currently pregnant or planning to become pregnant

5. engagement in a number of health--compromising behaviors that may affect levels of
pro-inflammatory cytokines, including cigarette smoking, excessive caffeine intake and
sleep disturbance (e.g., working night shifts)

6. body mass index (BMI) greater than 30, given that adiposity is known to relate to
baseline levels of inflammation

7. anxiety about or previous history of problems with blood draws (e.g., fainting)

8. any reported heart conditions

9. history of fainting spells

10. low pulse, as measured at beginning of session I (below 60)

11. low blood pressure, as measured at beginning of session I (below 80)