Wired to run: Exercise-induced endocannabinoid signaling in humans and cursorial mammals with implications for the 'runner's high'

Abstract

Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as the 'runner's high', which may function to encourage habitual aerobic exercise. Endocannabinoids (eCBs) are endogenous neurotransmitters that appear to play a major role in generating these rewards by activating cannabinoid receptors in brain reward regions during and after exercise. Other species also regularly engage in endurance exercise (cursorial mammals), and as humans share many morphological traits with these taxa, it is possible that exercise-induced eCB signaling motivates habitual high-intensity locomotor behaviors in cursorial mammals. If true, then neurobiological rewards may explain variation in habitual locomotor activity and performance across mammals. We measured circulating eCBs in humans, dogs (a cursorial mammal) and ferrets (a non-cursorial mammal) before and after treadmill exercise to test the hypothesis that neurobiological rewards are linked to high-intensity exercise in cursorial mammals. We show that humans and dogs share significantly increased exercise-induced eCB signaling following high-intensity endurance running. eCB signaling does not significantly increase following low-intensity walking in these taxa, and eCB signaling does not significantly increase in the non-cursorial ferrets following exercise at any intensity. This study provides the first evidence that inter-specific variation in neurotransmitter signaling may explain differences in locomotor behavior among mammals. Thus, a neurobiological reward for endurance exercise may explain why humans and other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks, and why non-cursorial mammals avoid such locomotor behaviors.

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INTRODUCTION
Goal-oriented behaviors that impose risks or high energy costs are
often motivated by neurobiological rewards, which are thought to
condition fitness-enhancing activities (Panksepp et al., 2002).
Humans frequently report such neurobiological rewards (commonly
termed the ‘runner’s high’) during and after distance running that
include both central effects (improved affect, sense of well being,
anxiety reduction, post-exercise calm) and peripheral effects
(reduced pain sensation) (Dietrich and McDaniel, 2004; Ogles and
Masters, 2003; Sachs and Pargman, 1979). Central and peripheral
rewards likely play a major role in humans’ motivation to run (Ogles
and Masters, 2003), and increase their ability to sustain high aerobic
intensities over long distances (Dietrich and McDaniel, 2004). A
neurobiological reward to encourage exercise may be especially
important because high levels of aerobic activity are more
energetically costly than walking (Cotes and Meade, 1960; Margaria
et al., 1963; Menier and Pugh, 1968) and have a higher potential
for both traumatic and overuse injuries (Johnson et al., 2000;
Pinchbeck et al., 2004; Prole, 1976).
The hypothesis that neurobiological rewards motivate human
endurance exercise (Ekkekakis et al., 2005; Sher, 1998) is consistent
with evidence that humans are highly adept endurance athletes
(Bramble and Lieberman, 2004; Carrier, 1984). For example,
humans possess anatomical specializations and demonstrate
endurance athletic performance (e.g. speed and distance traveled at
aerobic intensities) that are similar to those of other mammals that
habitually engage in endurance exercise, including long-distance
running (i.e. cursorial mammals) (Bramble and Lieberman, 2004;
Carrier, 1984). However, to date, no studies have examined the
possibility that other cursorial mammals receive these same
neurobiological rewards. This study tests the hypothesis that high
levels of aerobic activity in humans and other cursorial mammals
lead to neurotransmitter signaling associated with central and
peripheral rewards. Additionally, we explore the possibility that
inter-specific variation in exercise-induced rewards may play a role
in the non-cursorial behaviors of some taxa.
Experimental research into these rewards is often hampered by
the overall concept of the runner’s high (see Dietrich and McDaniel,
2004), as it is often equated with generalized euphoric sensations
in the popular press. Dietrich and McDaniel suggested a definition
more amenable to hypothesis testing, where the runner’s high is a
change in any of the following observable phenomena: pain
sensation, anxiolysis, sedation or feelings of well being (Dietrich
and McDaniel, 2004). This definition includes quantifiable
outcomes, allowing researchers to explore the neurobiological
mechanisms that may be responsible for the runner’s high. Recent
work has supported a strong role for endocannabinoid (eCB)
signaling in the rewards associated with endurance exercise (Dietrich
and McDaniel, 2004). The two recognized eCBs, anandamide (AEA)
and 2-arachidonylglycerol (2-AG), are endogenous ligands for the
The Journal of Experimental Biology 215, 1331-1336
© 2012. Published by The Company of Biologists Ltd
doi:10.1242/jeb.063677
RESEARCH ARTICLE
Wired to run: exercise-induced endocannabinoid signaling in humans and cursorial
mammals with implications for the ʻrunnerʼs highʼ
David A. Raichlen1,*, Adam D. Foster1, Gregory L. Gerdeman2, Alexandre Seillier3and Andrea Giuffrida3
1School of Anthropology, University of Arizona, Tucson, AZ 85721, USA, 2Department of Biology, Eckerd College, St Petersburg,
FL 33711, USA and 3Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229, USA
*Author for correspondence (raichlen@email.arizona.edu)
Accepted 21 December 2011
SUMMARY
Humans report a wide range of neurobiological rewards following moderate and intense aerobic activity, popularly referred to as
the ʻrunnerʼs highʼ, which may function to encourage habitual aerobic exercise. Endocannabinoids (eCBs) are endogenous
neurotransmitters that appear to play a major role in generating these rewards by activating cannabinoid receptors in brain
reward regions during and after exercise. Other species also regularly engage in endurance exercise (cursorial mammals), and as
humans share many morphological traits with these taxa, it is possible that exercise-induced eCB signaling motivates habitual
high-intensity locomotor behaviors in cursorial mammals. If true, then neurobiological rewards may explain variation in habitual
locomotor activity and performance across mammals. We measured circulating eCBs in humans, dogs (a cursorial mammal) and
ferrets (a non-cursorial mammal) before and after treadmill exercise to test the hypothesis that neurobiological rewards are linked
to high-intensity exercise in cursorial mammals. We show that humans and dogs share significantly increased exercise-induced
eCB signaling following high-intensity endurance running. eCB signaling does not significantly increase following low-intensity
walking in these taxa, and eCB signaling does not significantly increase in the non-cursorial ferrets following exercise at any
intensity. This study provides the first evidence that inter-specific variation in neurotransmitter signaling may explain differences
in locomotor behavior among mammals. Thus, a neurobiological reward for endurance exercise may explain why humans and
other cursorial mammals habitually engage in aerobic exercise despite the higher associated energy costs and injury risks, and
why non-cursorial mammals avoid such locomotor behaviors.
Key words: AEA, 2-AG, positive affect, running, walking, locomotion, Homo, exercise, endogenous cannabinoid.
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CB1and CB2cannabinoid receptors, which were originally identified
as the pharmacological targets of the principal psychoactive
ingredient of marijuana, D9-tetrahydrocannabinol (THC) (Piomelli,
2003). Because of high expression levels in brain regions relevant
to affective processing, activation of CB receptors produces
psychological rewards such as reduced anxiety, euphoria and a
general feeling of well being (Piomelli, 2003).
The two eCBs (AEA and 2-AG) are released both centrally and
peripherally in an activity-dependent manner to modulate the
release of classical neurotransmitters (Piomelli, 2003). As a key
example, eCBs released within the mesolimbic dopamine system
lead to overall activation of dopamine neurons by relieving the
influence of inhibitory, CB1-expressing GABAergic terminals onto
those neurons (Lupica and Riegel, 2005). This leads to enhanced
dopamine release in target areas, such as the nucleus accumbens
(NAc), a major brain area involved in behavioral reward (Cheer et
al., 2007). Through this and perhaps other mechanisms intrinsic to
the NAc, eCBs are thought to act as a ‘hedonic’ signal (Mahler et
al., 2007), triggering neurobiological rewards that are similar to those
described by runners (Dietrich and McDaniel, 2004), and which
likely contribute to the development of habitual reward-directed
behaviors (Gerdeman et al., 2003; Lupica and Riegel, 2005). In
addition to these effects on neural systems of incentive within the
brain, analgesic effects of eCBs occur both within the CNS and in
the periphery, via CB receptors expressed on peripheral nerve fibers
(Agarwal et al., 2007; Dietrich and McDaniel, 2004). Exercise-
induced reductions in pain sensation lead to feelings of effortlessness
associated with the strict definition of the runner’s high and improve
exercise performance by allowing individuals to run longer distances
(Dietrich and McDaniel, 2004). Both the psychological and analgesic
effects of CB receptor activation mirror athletes’ descriptions of the
neurobiological rewards associated with exercise (Dietrich and
McDaniel, 2004).
Recent work supports direct links between eCB signaling and
exercise in humans. Sparling and colleagues reported significant
increases in plasma levels of AEA (but not 2-AG) after moderate-
intensity aerobic activity (running or cycling at ~70–80% of
maximum heart rate) (Sparling et al., 2003). Although their study
measured plasma levels, eCBs are highly lipophilic, which allows
them to readily cross the blood–brain barrier (Dietrich and
McDaniel, 2004; Sparling et al., 2003). Thus, circulating levels of
AEA or 2-AG are thought to lead to central effects because eCBs
produced peripherally can cross the blood–brain barrier and activate
CB receptors in brain reward centers (Dietrich and McDaniel, 2004;
Solinas et al., 2006; Willoughby et al., 1997). Several studies have
demonstrated this by showing that intravenous injections of eCBs
(both AEA and 2-AG) activate CB receptors in the brain and lead
to reward-seeking behaviors (e.g. self-administered injections) in
animal models (Justinova et al., 2005; Justinova et al., 2011; Solinas
et al., 2006; Willoughby et al., 1997).
Recent work in experimental evolution (i.e. selection experiments
in rodents) suggests that eCB-induced rewards for exercise can be
a target of natural selection and may explain habitual engagement
in voluntary exercise in mammals. In female mice bred for high
levels of voluntary wheel running over 15years, administration of
rimonabant (a selective CB receptor antagonist) led to significantly
reduced levels of running compared with administration of a
placebo, as well as with control mice given rimonabant (Keeney et
al., 2008). Thus, selection used the eCB system to reward high
amounts of voluntary running in these mice (Keeney et al., 2008),
and these rewards encouraged increased levels of habitual voluntary
exercise. However, it is unknown whether this system is linked to
exercise in other mammals.
In this study, we measured plasma levels of eCBs in two cursorial
species [humans (Homo sapiens L.) and dogs (Canis familiaris L.)]
and one non-cursorial species [ferrets (Mustela putorius L.)]
following 30min of treadmill running to determine whether there
is variation in exercise-induced eCB activity among mammals. On
separate days, we measured plasma eCB levels in humans, dogs
and ferrets after 30min of low-intensity activity (treadmill walking
for humans and dogs, resting for ferrets; see Materials and methods)
to determine whether eCB signaling is intensity dependent. We
predicted eCB signaling would be strongest following running, and
should be stronger in humans and dogs than in ferrets.
MATERIALS AND METHODS
Our sample included recreationally fit humans (N10), mixed-breed
dogs (N8) and ferrets (N8) (see Table1). Non-human taxa were
chosen to match classical definitions of cursorial and non-cursorial
evolutionary history based on morphological adaptations to
endurance running (Jenkins, 1971). Humans and dogs were recruited
from the local community. Only human subjects who were
recreationally fit (i.e. could run 30min continuously) were included
in this study. Subjects received minimal treadmill training and
experiments were conducted when subjects could run continuously
at prescribed speeds for 30min. The period of training for both dogs
and ferrets ranged from one to three sessions and consisted only of
positive reinforcement methods. All methods were approved by the
University of Arizona IACUC and IRB.
Running speed for human subjects (see Table1) was selected to
elicit heart rates similar to those used previously (Sparling et al.,
2003). Walking speed in humans was selected to match preferred
walking speed as calculated by Froude number [velocity2/(hindlimb
length ⫻gravitational acceleration)≈0.25 at preferred walking
speed), a dimensionless speed that accounts for differences in body
size among subjects (see Table1) (Alexander and Jayes, 1983;
Minetti, 2001). While Froude numbers of 0.25 roughly correspond
to preferred walking speed (Minetti, 2001), we note that this was
not self-selected by subjects but was calculated based on each
subject’s anatomy. Heart rate for running speed averaged
72.5±2.54% (mean ± s.d.) of maximum heart rate and walking speed
corresponded to a mean (±s.d.) of 44.6±1.25% of maximum heart
rate [where maximum heart rate was calculated using the age-based
equation from Tanaka et al. (Tanaka et al., 2001)]. Heart rates for
running trials are well below the ventilatory threshold (the transition
from aerobic to anaerobic exercise) known to influence
D. A. Raichlen and others
Table 1. Subject data
Taxon Body mass (kg) Walking speed (ms–1) Running speed (ms–1) Walking Froude Running Froude
Humans 67.35±9.06 1.25 2.5 0.26±0.01 0.71±0.03
Dogs 28.11±7.68 1.10±0.047 1.83±0.8 0.25 0.70
Ferrets 1.12±0.15 0.50±0.01 0.84±0.01 0.25 0.70
Mean values are shown ±s.d.
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1333Exercise and endocannabinoid signaling
psychological responses to exercise (Ekkekakis et al., 2004). Speed
for non-human runners was chosen to match Froude numbers used
by human subjects, such that subjects all walked and ran at
dynamically similar speeds. All subjects (humans, dogs and ferrets)
ran at Froude numbers of ~0.70 for 30min (trotting gaits for ferrets
and dogs). Dogs and humans walked at Froude numbers of ~0.25
for 30min. Ferrets were unable to walk consistently on the treadmill
at any speed, so we compared data from running trials with data
collected after a 30min control trial where ferrets sat quietly in a
small cage.
Blood samples (0.5ml) were collected by venipuncture before
and after each of these trials using a syringe filled with 1ml of Krebs-
Tris buffer/EDTA (4.5mmoll–1). Samples were immediately
centrifuged in Accuspin tubes (Sigma, St Louis, MO, USA) at 800g,
for 10min. Methods for eCB extraction (both AEA and 2-AG) and
quantification by GC/MS isotope dilution are described in detail
elsewhere (Hardison et al., 2006).
Psychological state was assessed before and after all human trials
using a standard questionnaire that measures positive affect [positive
and negative affect schedule (PANAS) scale (Watson et al., 1988)].
Positive affect (PA) describes the enthusiasm, energy and
pleasurable engagement of an individual (Watson et al., 1988), and
is an important component of feelings of well being (Reed and Ones,
2006). As with many psychological instruments, there are limitations
to the PANAS that should be taken into account when interpreting
our results. For example, researchers have suggested that this scale
is limited to only the high activation ends of PA (e.g. excited or
enthused) (see Egloff, 1998; Mossholder et al., 1994; Russell and
Carroll, 1999). Thus, the low-activation ends of PA (e.g. calm or
serene) may not be fully captured using this instrument. Despite
this limitation, the PANAS has been used in many previous studies
to effectively capture exercise-related changes in affect (Reed and
Ones, 2006).
Subjects performed only one trial per day. Because day-to-day
fluctuations in baseline eCB levels are normal and known to occur
in healthy individuals (Vaughn et al., 2010; Zoerner et al., 2009),
we investigated the change in circulating eCBs from pre- to post-
exercise values on a given day only. Differences between AEA and
2-AG levels before and after exercise were assessed using paired
t-tests. A Pearson product-moment correlation was calculated
between the post- and pre-exercise difference in eCBs and the post-
and pre-exercise difference in PA.
RESULTS
Both humans and dogs showed a significant increase in plasma levels
of AEA following a 30min treadmill run; however, neither taxon
showed increased AEA levels following a lower intensity 30min
walk (dogs showed a significant decrease in AEA following walking
trials; see Fig.1 and Table2). In ferrets, plasma AEA levels were
unchanged following either a 30min run or a 30min rest period
(see Fig.1 and Table2, and Materials and methods). Similar to
Sparling and colleagues’ (Sparling et al., 2003) results in humans,
no taxon showed a significant change in levels of 2-AG following
any exercise trial (Table2). The difference between pre- and post-
exercise levels of AEA in humans was positively correlated with
the difference between pre- and post-exercise PA (r0.96, P<0.0001;
Fig.2). The correlation remained significant after removing the
possible outlier (highest AEA and PA change; r0.77, P<0.05).
DISCUSSION
This is the first study to show that there is inter-specific variation
in neurotransmitter signaling following exercise and that this
variation may explain differences in habitual locomotor behaviors
among mammals. In humans and dogs, but not ferrets, running
activates the eCB system, which likely improves aerobic exercise
performance and encourages a high frequency of aerobic activity
in these cursorial taxa. In humans, increased eCB signaling following
exercise is significantly correlated with improved PA, confirming
the role of eCBs in generating positive psychological effects. eCB
signaling does not increase following low-intensity activity in
humans and dogs, suggesting that these rewards are not simply
triggered by locomotion but are tied to higher exercise intensities.
In fact, eCB levels decreased in dogs following the 30min walking
trial. This result suggests that dogs may not have any specific
affective response to walking under these experimental conditions.
In ferrets, a taxon that does not generally engage in cursorial activity
(see King and Powell, 2007), and is not morphologically adapted
to endurance exercise behaviors (Jenkins, 1971), exercise does not
result in an increase in eCB signaling. This inter-specific variation
suggests that eCB signaling plays a functional role in the aerobic
behaviors of cursorial mammals.
eCBs can aid cursorial mammals by improving high-intensity
athletic performance through both central and peripheral actions.
Centrally, CB receptors are primarily expressed in presynaptic
terminals, where activation by eCBs leads to a decrease in the
synaptic release of classical neurotransmitters (Piomelli, 2003) and
produces psychological effects similar to those described by runners
in this study (Chaperon and Thiebot, 1999; Diaz, 1997; Piomelli,
2003). It is important to note that this study measured peripheral
eCB levels only, and thus we cannot be sure that our measurements
fully reflect changes in eCBs within the central nervous system.
However, the strong correlation between changes in AEA and
0
2
4
6
8
10
12
Humans Dogs Ferrets
AEA (pmol ml–1)
0
2
4
6
8
10
12
Humans Dogs Ferrets
B
*
*
A
*
Fig.1. Changes in anandamide (AEA) concentrations before and after
treadmill exercise. Pre-exercise levels are shown in white; post-exercise
levels are shown in black. (A)Plasma AEA levels before and after running
for 30min at a Froude number of 0.70. (B)Plasma AEA levels before and
after walking for 30min at a Froude number of 0.25. Asterisks indicate
significant differences at P<0.05. Error bars are s.e.m.
THE JOURNAL OF EXPERIMENTAL BIOLOGY

1334
changes in PA following exercise shown here (Fig.2) suggests that
post-running AEA levels measured peripherally in plasma are
reflective of increased AEA in the central nervous system (Dietrich
and McDaniel, 2004). This is possible because eCBs are highly
lipophilic and physiological studies suggest that they readily traverse
the blood–brain barrier (Dietrich and McDaniel, 2004; Glaser et al.,
2006; Willoughby et al., 1997). For example, peripheral intravenous
injection of AEA in rodents leads to increased AEA and dopamine
levels in brain reward regions (Solinas et al., 2006; Willoughby et
al., 1997). Additionally, intravenous injections of eCBs activate CB
receptors in the brain and lead to reward-seeking behaviors (e.g.
self-administered injections) in animal models (Justinova et al.,
2005; Justinova et al., 2011; Solinas et al., 2006; Willoughby et al.,
1997).
Improvements in PA such as those measured here are a major
factor in human runners’ motivation to habitually engage in aerobic
exercise (Bryan et al., 2007; Kwan and Bryan, 2010; Schneider et
al., 2009; Williams et al., 2008), suggesting that one role for eCB-
induced rewards is to encourage a high frequency of aerobic activity.
These effects are not limited to elite athletes. Many studies have
shown that aerobic exercise has a positive psychological effect in
healthy populations of non-athletes (Reed and Ones, 2006), and the
improvements in mood and PA play a role in how well individuals
adhere to exercise programs (Ekkekakis et al., 2005). Additionally,
exercise improves psychological well being in non-athletic
individuals with depressive or anxiety disorders (Scully et al., 1998).
Thus, these broadly felt rewards are likely essential for the enjoyment
of exercise and may explain why mammalian taxa engage in
cursorial behaviors despite the higher energy costs and associated
injury risks (Bramble and Lieberman, 2004; Johnson et al., 2000;
Pinchbeck et al., 2004; Prole, 1976).
In addition to central effects on psychological state, eCBs may
act at peripheral CB receptors to decrease nociceptor activity
(Agarwal et al., 2007) and produce exercise-induced analgesia
(Sparling et al., 2003). This reduction in pain sensitivity is an
important component of the runner’s high (i.e. feelings of
effortlessness) as defined by Dietrich and McDaniel (Dietrich and
McDaniel, 2004), and one that improves aerobic exercise
performance by allowing individuals to continue running for long
distances. Exercise-induced analgesia is a widespread phenomenon
that occurs in both athletes and non-athletes following moderate
and high-intensity exercise (Hoffman and Hoffman, 2007; Koltyn,
2002). eCBs reduce pain throughout the body because peripheral
nerves that are active in sensing pain pathways contain dense
concentrations of CB receptors (Dietrich and McDaniel, 2004),
which function to inhibit the release of neurotransmitters (Gerdeman,
2008; Piomelli, 2003). Peripheral analgesia by eCBs is also achieved
through the actions of CB receptors to inhibit the release of
inflammatory mediators (Hohmann and Suplita, 2006; Ibrahim et
al., 2003). In addition to acting at peripheral sites, CB receptors are
found at central sites implicated in pain modulation such as the dorsal
horn of the lumbar spinal cord and the rostral ventromedial medulla
of the brainstem (Hohmann et al., 1999; Meng et al., 1998),
suggesting that circulating eCBs may also lead to a central reduction
in pain perception.
Thus, the measured increases in AEA levels in the circulating
bloodstream likely produce both peripheral (i.e. analgesic) and
central effects that support their role in encouraging aerobic activity
and improving exercise performance (Dietrich and McDaniel,
2004). As eCBs function similarly across mammals (Chaperon and
Thiebot, 1999), our results suggest that both humans and dogs
achieve a psychological and physiological benefit from increased
AEA signaling during and after running. The intensity-dependent
nature of eCB activity in humans and dogs suggests that
neurobiological rewards function to encourage higher exercise
intensities than those required at walking speed.
CONCLUSIONS
Exercise-induced eCB signaling increases following higher intensity
aerobic activities in humans and dogs, but not in the non-cursorial
ferrets. This study is the first to explore inter-specific variation in
D. A. Raichlen and others
Table 2. Pre- and post-exercise values of AEA and 2-AG
AEA 2-AG
Pre-exercise Post-exercise Pre-exercise Post-exercise
Speed Taxon N(pmolml–1) (pmolml–1)P-value (nmolml–1) (nmolml–1)P-value
Walk/control Human 10 1.34±0.43 0.61±0.39 0.10 0.004±0.0001 0.021±0.002 0.16
Dog 8 6.48±2.7 1.61±0.83 0.04 0.039±0.019 0.124±0.055 0.10
Ferret 8 4.19±1.93 7.51±4.45 0.14 0.049±0.009 0.032±0.013 0.25
Run Human 10 2.38±0.76 6.13±2.63 0.03 0.007±0.005 0.029±0.022 0.19
Dog 8 2.44±0.92 8.01±2.66 0.03 0.056±0.018 0.268±0.201 0.17
Ferret 8 2.98±1.13 3.87±1.39 0.33 0.428±0.218 0.229±0.118 0.31
AEA, anandamide; 2-AG, 2-arachidonylglycerol.
Mean values are shown ±s.e.m.
Bold values are significant differences found using a paired t-test.
–1
1
3
5
7
9
11
13
15
17
19
–1 1 3 5 7 9 111315171921
Difference in PA (post – pre)
Difference in AEA (post – pre)
Fig.2. Correlation between positive affect (PA) and AEA in humans. Values
are the difference between pre- and post-exercise PA scores plotted
against the difference between pre- and post-exercise plasma levels of
AEA. Note that the values for two subjects were nearly identical (difference
in AEA0.89 and 0.90, difference in PA3 for both subjects), and they are
not differentiated on the figure.
THE JOURNAL OF EXPERIMENTAL BIOLOGY

1335Exercise and endocannabinoid signaling
exercise-induced neurotransmitter signaling and, thus, represents a
novel method for examining how and why mammals engage in
different types of locomotor behaviors. Our results show that
neurobiological differences among mammalian taxa may explain
variation in their habitual locomotor behaviors.
Although this study is based on a limited taxonomic sample, we
believe that our results point to a possible neurobiological
explanation for how different locomotor behaviors may evolve. The
shared exercise-induced eCB signaling pathway in humans and dogs,
but not in the non-cursorial ferrets, is consistent with anatomical
and biomechanical studies pointing to selection for increased levels
of aerobic activity in humans (Bramble and Lieberman, 2004;
Carrier, 1984). It is important to interpret the results of this study
in the context of previous work showing that human endurance
exercise performance matches that of mammals traditionally defined
as cursorial (Bramble and Lieberman, 2004; Carrier, 1984). For
example, humans can habitually run distances and at speeds
comparable to other cursorial mammals, and humans share many
anatomical traits with quadrupedal cursors that improve endurance
athletic performance (e.g. increased limb length, increased semi-
circular canal size, increased joint surface areas) (Bramble and
Lieberman, 2004; Carrier, 1984). Our results show that humans also
share a neurobiological trait with a cursorial mammal that improves
endurance exercise performance and may explain the known
psychological benefits and analgesic effects of exercise in humans
(Dietrich and McDaniel, 2004; Scully et al., 1998). Given evidence
from recent experiments that the eCB system is a target of selection
which encourages exercise in mammals that undergo experimental
evolution for high levels of voluntary running (Keeney et al., 2008),
we suggest that eCB signaling represents a possible evolutionary
explanation for the neurobiological rewards associated with exercise
in humans.
Our study does have some limitations that should be noted when
interpreting our results. First, we measured eCB signaling in a
relatively small number of taxa. Thus, we suggest that future studies
analyze a larger number of non-cursorial and cursorial taxa to fully
understand the variation in exercise-induced neurobiological rewards
across mammals. Second, our experiments did not test for a specific
mechanical trigger of eCB signaling. Although we used running
behaviors to determine exercise-induced eCB signaling across taxa,
Sparling and colleagues showed that eCBs are released in humans
following both cycling and running at moderate aerobic intensities
(Sparling et al., 2003). Neurobiological rewards are likely tied to
high levels of endurance activity, but may not be triggered by a
specific mechanical behavior per se. From an evolutionary
perspective, these levels of aerobic activity are likely achieved in
different taxa during high-intensity running behaviors, suggesting
selection may have acted to encourage these intensities during legged
locomotion. Third, our human sample was made up of recreationally
fit subjects; however, we do not know whether our results are
generalizable to more sedentary human populations. We suggest
that, for tests of evolutionary hypotheses, fit individuals make better
models of earlier human groups, as our ancestors lived active
hunter–gatherer lifestyles (Malina and Little, 2008). Nonetheless,
further research examining the role of fitness level in eCB activity
in humans is necessary. It is possible that more sedentary groups
cannot adequately exercise at the intensities required to elicit a
significant eCB elevation, and do not gain similar psychological
benefits from exercise at lower intensities. This possible intra-
specific variation in physical fitness may explain why some
individuals do not enjoy exercise. Finally, while we showed that
eCB activity is correlated with PA, and therefore feelings of well
being in our human sample, we did not measure other aspects of
the runner’s high as defined by Dietrich and McDaniel (Dietrich
and McDaniel, 2004). While eCB activity is linked to reductions
in pain sensitivity, anxiolysis and sedation (Piomelli, 2003; Dietrich
and McDaniel, 2004), future work should examine these traits in
more detail to determine whether exercise-induced eCBs lead to
changes in all aspects of the runner’s high.
Despite these limitations, our results lay the foundation for a more
thorough understanding of the psychological and physiological effects
of exercise in cursorial mammals, including humans. It is possible
that neurobiological rewards induced by eCB signaling are an ancient
human trait that evolved to encourage aerobic activity (Bramble and
Lieberman, 2004; Carrier, 1984; Malina and Little, 2008), and that
the rewards explain the evolution of differences in voluntary locomotor
activity more broadly across mammals. Future studies are needed to
fully support this evolutionary hypothesis; however, our results
provide the framework for a novel way to examine the evolution of
endurance exercise in humans and other mammals. The fact that
running, and endurance exercise in general, remains an enjoyable and
psychologically beneficial recreational activity for tens of millions of
humans today suggests that we still may respond to a neurobiological
trait that evolved early in our lineage.
ACKNOWLEDGEMENTS
We thank Sarah Daley, Michael Bernas, Michael Rand, Peter Gordon and Miguel
Diaz for their help with animal care and data collection, and Daniel Lieberman and
Herman Pontzer for discussions of the project and comments on the manuscript.
John Allen provided advice on psychological testing. We thank two anonymous
reviewers for constructive comments that greatly improved this manuscript. The
staff of the Clinical and Translational Science Research Center at the University of
Arizona assisted with human data collection.
FUNDING
This project was supported by the National Science Foundation [BCS 0820270]
and a Wenner Gren Foundation Hunt Fellowship to D.A.R.
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