Major CA, Kelly BJ, Novak MA, Davenport MD,
Stonemetz KM, Meyer JS
New England Primate Research
Center, Harvard Medical School,
Southborough, MA,
USA
AIMS: Self-injurious behavior (SIB), which
is deliberate infliction of self-injury without
suicidal intent, is a significant human health
problem. SIB is not unique to humans but is also
manifested in a small percentage of captive
macaques, typically as self-directed biting.
Although the onset and maintenance of SIB have
been linked to increased anxiety in both humans
and nonhuman primates, no previous studies have
directly tested the anxiety-SIB hypothesis.
Here, we determined whether rhesus monkeys
increase their self-directed biting following a
challenge with the anxiogenic compound
N-methyl-beta-carboline-3-carboxamide
(FG7142).
MAIN METHODS: Ten rhesus monkeys (Macaca
mulatta) with a veterinary record of
self-wounding (SIB) as well as six age- and
weight-matched non-wounding control monkeys were
given intramuscular injections of 0.1, 0.3, or
1.0mg/kg FG7142. Behavior was observed following
drug administration with special attention to
displacement behaviors (scratching,
self-grooming, and yawning), locomotor
stereotypy, and self-directed biting. Plasma
cortisol and ACTH were also measured as
physiological indices of stress.
KEY FINDINGS: Self-directed biting rates
dose-dependently increased in a subset of SIB
monkeys, but did not change in control animals.
Furthermore, administration of FG7142 led to an
increase in scratching, yawning, and
locomotor stereotypy in all monkeys, but did not
affect the frequency self-grooming.
Additionally, there was a dose-dependent
increase in plasma cortisol concentrations, but
not ACTH, in all animals.
SIGNIFICANCE: The present findings indicate
that self-biting is anxiety-related in some but
not all SIB monkeys, suggesting that this
behavioral pathology is heterogeneous as has
previously been suggested for SIB in humans
Self-injurious behavior (SIB), which is the
deliberate infliction of self-injury without
suicidal intent, is a significant human health
problem. Common manifestations of SIB include
cutting or burning of the skin, other forms of
self-mutilation, and head-banging (Favazza
1998). One form of SIB, "impulsive" SIB, has
been related to heightened anxiety or tension
and may paradoxically serve to reduce negative
emotions (Simeon and Favazza 2001). Impulsive
SIB is often a symptom of anxiety-related and
personality disorders (e.g., posttraumatic
stress disorder (PTSD) and borderline
personality disorder (BPD) respectively).
Furthermore, patients with a co-occurrence of
these disorders and SIB report a reduction in
tension or anxiety immediately following an
episode of self-injury (Coid 1993; Herpertz
1995; Weaver et al. 2004; Weierich and Nock
2008).
Impulsive SIB appears to be functionally
different than other forms of SIB, such as
stereotypic or compulsive SIB (for an in-depth
discussion of the classification of SIB in
humans, see Simeon and Favazza 2001). SIB also
occurs spontaneously in macaque species and
mainly takes the form of self-directed biting,
which differs in form from most SIB in humans.
Nonetheless, these animals may provide a
valuable model to help us understand the causes
of and possible treatments for this condition in
humans. Self-inflicted wounding in individually
housed monkeys (as a result of self-directed
biting) has been reported in various macaque
species (Macaca sp.), at a prevalence rate of
about 5&endash;15% across research facilities
(Bayne et al. 1995; Bellanca and Crockett 2002;
Lutz et al. 2003).
Notably, these values fall within the range
of prevalence rates reported in non-clinical
human populations [4% (Briere and Gil 1998);
17% (Whitlock et al. 2006); and 35% (Gratz et
al. 2002)]. One major risk factor in the
development of SIB in monkeys is social
separation (i.e., permanent removal from a
stable social group) and placement into
individual housing at an early age, which is
likely to be a highly stressful event (Lutz et
al. 2003). Additional factors include prolonged
exposure to individual housing following social
separation and undergoing more minor veterinary
procedures than non-SIB animals (Baker 2002;
Bellanca and Crockett 2002; Lutz et al. 2003).
We have theorized that stressful events early in
development in conjunction with repeated
additional challenges later in life can lead to
the development of SIB as a coping strategy to
deal with stress and anxiety in both monkeys and
humans (Tiefenbacher et al. 2005b). Support for
this model comes from previous studies in our
laboratory showing that monkeys that engage in
SIB exhibit a persistent dysregulation of the
hypothalamic&endash;pituitary&endash;adrenal
(HPA) axis and a significant decrease in heart
rate immediately after self-biting (suggesting a
role for SIB in arousal reduction; Novak 2003;
Tiefenbacher et al. 2004).
Furthermore, we recently reported that
biting rates in monkeys with SIB persistently
increased as a consequence of an
administratively mandated relocation of the
animals to a new building (Davenport et al.
2008). Finally, self-biting rates were predicted
by cerebrospinal fluid levels of the anxiogenic
peptide corticotropin-releasing factor
(Tiefenbacher et al. 2002), and treatment with
the benzodiazepine (BDZ) diazepam significantly
reduced self-directed biting and wounding
frequency in 50% of the monkeys treated
(Tiefenbacher et al. 2005a). Although our
previous findings support a link between SIB and
anxiety in rhesus monkeys, these studies provide
correlational data only. In order to more fully
understand the relationship of SIB and anxiety,
it is important to determine whether increased
anxiety can serve as a trigger for SIB, a
question that has not previously been addressed
either in the primate or human literature.
Accordingly, the present study was designed
to test the anxiety-SIB hypothesis by measuring
behavioral and physiological responses to an
anxietyprovoking pharmacological challenge.
Monkeys with a veterinary record of
self-wounding (SIB) along with age-matched
non-wounding controls were given injections of
N-methyl-?-carboline-3-carboxamide (FG7142), a
partial inverse agonist at the BDZ receptor.
FG7142 and other drugs in the ?-carboline family
have been shown to induce anxiety-related
behaviors in humans (Dorow et al. 1983) and
rhesus monkeys (Crawley et al. 1985; Takamatsu
et al. 2003; Kalin et al. 1992), and to
stimulate HPA axis activity (Takamatsu et al.
2003; for review of the pharmacology of FG7142,
see Evans and Lowry 2007). We predicted that
administration of FG7142 would result in
dosedependent increases in plasma
adrenocorticotropic hormone (ACTH) and cortisol
concentrations as well as increased frequencies
of anxiety-related behaviors in all animals.
Most importantly, we further predicted that the
frequency of self-directed biting would increase
in SIB monkeys following treatment with the
drug.
Discussion
To our knowledge, this is the first report
of increased SIB (selfdirected biting) in
monkeys following an experimentally-induced
state of anxiety. Previous research has shown
FG7142 to be an anxiogenic drug, and this notion
was supported in the present study by an
increase in displacement behaviors (scratching
and yawning) in both groups of subjects. Other
changes in behavior, such as the elevated
frequency of locomotor stereotypy, could
likewise indicate elevated levels of anxiety in
the monkeys as a result of the drug challenge.
Plasma cortisol concentrations were
significantly elevated in both SIB and control
animals following FG7142 administration, which
is consistent with previous work demonstrating a
stimulatory effect of this compound on the HPA
axis (Takamatsu et al. 2003).
Yet, despite this evidence that FG7142
produced a physiological stress response in all
monkeys, only SIB animals showed an increase in
self-biting. These results indicate that
self-biting behavior is a specific response of
some SIB monkeys (i.e., animals with a prior
history of self-wounding) to anxiety, not a
generalized reaction, for example increased
scratching or HPA activation that tends to be
shown by all animals. The present finding that
only 50% of the SIB monkeys increased their
self-directed biting following FG7142
administration suggests that (1) this behavioral
pathology is heterogeneous in monkeys, and (2)
that anxiety is a trigger for SIB only in one
form of the disorder.
Indeed, it is interesting to note that a
previous study from our laboratory involving
treatment of a largely separate group of monkeys
with diazepam (only one monkey was involved in
both studies) found that only half of the
animals responded positively (i.e., with
decreased SIB) to this compound (Tiefenbacher et
al. 2005a). Together, these findings implicate
the BDZ site on the ?-aminobutyric acidA (GABAA)
receptor as playing an important role in the
hypothesized anxietyrelated subtype of SIB.
Unfortunately, little is presently known about
the potential role of GABA and the GABAA
receptor in either the etiology or maintenance
of SIB. Indeed, it is possible that the
GABAergic system modulates SIB in a manner
independent of changes in anxiety. However,
given the known anxiolytic and anxiogenic
effects of diazepam and FG7142 respectively, we
propose that genetic polymorphisms of the GABAA
receptor or a functional dysregulation of the
GABA system may underlie anxiety-related forms
of SIB in both monkeys and humans. Additional
studies are needed to test this hypothesis.
In the present animal study, we were able to
perform a novel test of the anxiety-SIB
hypothesis by administering an anxiogenic
compound to our subjects. Although we found no
evidence for this kind of manipulation in the
human SIB literature, other findings support a
link between SIB and anxiety. First, one of the
most commonly reported reasons for engaging in
self-injury is to relieve negative affect in the
form of heightened tension or anxiety (reviewed
by Klonsky 2007). Second, several studies have
found elevated symptoms of anxiety in
non-clinical populations that exhibit SIB
(Gollust et al. 2008; Klonsky and Olino 2008;
Klonsky et al. 2003; Ross and Heath 2002).
Finally, consistent with the monkey study
cited earlier (Novak 2003), Haines et al. (1995)
found that changes in heart rate and other
psychophysiological measures support the notion
that SIB reduces tension in people that engage
in this behavior. These results provide strong
evidence for a relationship between SIB and
anxiety (sometimes labeled tension) in humans.
On the other hand, reasons other than tension
reduction are also offered by some individuals
who engage in SIB (Klonsky 2007). Thus, it will
be important in future research to elucidate the
relative importance of anxiety in the various
proposed categories of SIB in human populations
and to determine how these categories differ in
their underlying neurobiological mechanisms
(including potential involvement of the GABA
system).
Conclusions In conclusion, adult male rhesus
monkeys with a history of SIB as well as control
animals were administered several different
doses of the anxiogenic BDZ partial inverse
agonist FG7142. Drug treatment led to
dose-dependent increases in displacement
behaviors, locomotor stereotypy, and plasma
cortisol concentrations in both subject groups.
More importantly, there was a dose-dependent
increase in self-biting behavior in half of the
SIB monkeys but none of the controls. These
results suggest that SIB in rhesus monkeys is a
heterogeneous disorder, and that anxiety is an
important trigger for self-biting in some but
not all animals with the disorder.
