mise à jour du
1 mars 2010
Life Sci.
The anxiogenic drug FG7142 increases
self-injurious behavior in male rhesus monkeys
(Macaca mulatta)
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.
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.