University of Louisiana at
Lafayette-New Iberia Research Center, Louisiana,
USA
Abstract:
The effects of two serotonergic
agents--fluoxetine, a serotonin (5-HT) reuptake
inhibitor, and buspirone, a 5-HT 1a agonist--on
rates of self-injurious and stereotypic behavior
were examined in 15 adult male Macaca mulatta.
All animals received a placebo for 2 weeks
followed by either buspirone or fluoxetine for
12 weeks. Behavior was monitored using a focal
sampling technique throughout the study and for
2 weeks post-study. Cerebrospinal fluid (CSF)
samples and body weights were obtained
pre-study, at the ends of placebo and treatment
phases, and post-study.
Fluoxetine and buspirone were significantly
effective in reducing rates of self-biting
during treatment weeks 1 to 8 and self-directed
stereotypic behavior during weeks 5 to 12 and
post-treatment. No significant effect of either
treatment on hair-plucking, stereotypic pacing,
saluting, or head tossing was identified. The
duration of neutral behavior increased, and
rates of scratching and yawning decreased in the
buspirone-treated condition.
In the fluoxetine-treated condition, rates
of yawning, scratching, and self-directed
grooming were higher overall compared with those
of buspirone-treated animals, and rates of
scratching increased significantly (P < 0.05)
in weeks 9 to 12; these findings suggest that
animals in the fluoxetine-treated condition
experienced higher levels of anxiety throughout
the study. In both treatment conditions,
concentrations of CSF 5-HIAA (5-HT metabolite)
were significantly lower (P < 0.05) than
placebo concentrations. Fluoxetine and buspirone
may be efficacious for treatment of
self-injurious and self-directed stereotypic
behavior in macaques. Further studies are
required to determine the optimal dosages and
treatment length
Studies have shown that self-injurious
behavior (SIB) is a serious problem in adult
rhesus macaques socially deprived in infancy and
individually housed in captivity. Jorgensen and
colleagues found that the incidence of
self-injury may be as high as 14% in captive
populations of rhesus monkeys, the vast majority
of which are males, with selfbiting being the
most prevalent form of ixur Severe cases of
self-biting require prolonged veterinary care
and often result in the removal of animals from
research protocols. The most severe forms of
self-injury may require digit or limb amputation
and in the worst cases, in which currently known
treatments fail, euthanasia becomes the only
option.
Current research has focused on identifying
an etiology of SIB with the ultimate goal of
prevention. It appears that compared with
others, some monkeys have an increased
vulnerability that is associated with stressful
social experiences in the first 2 years of life,
such as early weaning. In susceptible adult
animals, the disorder may be triggered by the
separation of sexual partners, separation from
social groups, contact with fearprovoking
personnel, or disruption of daily routines. Once
the condition develops, manipulation of the
environment by increasing cage space or
providing toys, puzzle-feeders, or forage boards
appears to have little effect. The results of
these studies suggest that pharmacological
intervention would be highly useful if it was
found to be an effective means to alleviate
SIB.
Although several neurotransmitters systems
may be involved in the initiation and
maintenance of SIB, most studies to date suggest
the central serotonergic system. Decreased
serotonine (5-HT) function is associated with
depression, suicide, and obsessive-compulsive
disorder (OCD) in humans. In rhesus macaques,
low central 5-HT concentration is associated
with impulsive and aggressive behavior. Further,
exposure of adult cynomolgus macaques to chronic
social stress is associated with low precortical
5-HT concentrations. In rhesus monkeys, early
social deprivation (e.g., early weaning or
social isolation) results in decreased 5-HT
function and increased rates of stereotypic
behavior and SIB. Many adult rhesus monkeys
display, in addition to SIB, a repertoire of
self-directed stereotypic behaviors. The
association between low 5-HT function and rates
of SIB is less clear in adult monkeys that have
not been socially deprived. Concentrations of
5-hydroxyindole acetic acid (5HIAA) in
cerebrospinal fluid (CSF) were measured in an
attempt to identify alterations in pre-synaptic
5-HT function among adult rhesus monkeys with
SIB. Although no significant differences in CSF
5-HIAA were associated with SIB compared with
levels in controls, Weld and coworkers found
that treatment with tryptophan, the amino-acid
precursor to SHT, decreased the duration of
self-biting and increased CSF 5-HIAA
concentrations in adult rhesus macaques with a
history of SIB. Interestingly, after receiving
the saine dose as the SIB subjects, the control
animals showed no changes in CSF 5-HIAA.
The overall aim of the present study was to
assess the acute effects of fluoxetine, a
selective 5-HT reuptake inhibitor (SSRI) and
buspirone (a 5-HT agonist) on SIB and
stereotypic behavior in rhesus macaques.
Although their mechanisms of action differ, both
compounds have demonstrated clinical efficacy in
the treatment of disorders associated with
alterations in serotonergic function (e.g.,
depression, obsessive-compulsive disorder, panic
disorder, and post-traumatic stress disorder) in
human. Self-mutilation or SIB in humans is
associated with psychopathology such as
depression, anxiety, and obsessive-compulsive
behavior. Fluoxetine is useful for treatment of
OCI) and dominance aggression in dogs. Buspirone
has been used effectively in treating canine
dominance aggression, canine and feline
stereotypic behavior, self-mutilation, OCD,
phobias, and inappropriate feline spraying.
Discussion
Fluoxetine and buspirone were effective in
decreasing rates of self-biting during the first
8 weeks of treatment. Duration of selfdirected
stereotypic behavior decreased during weeks 5 to
12 and Post-Rx. However, rates of non -injurious
self. biting were not significantly different
from Pre-Rx levels during weeks 9 to 12. Rates
of hair-plucking, while low, did not decrease
with either treatment. We found no significant
effect of either treatment on stereotypic
pacing, saluting, or head tossing. The effects
of treatment on self-biting and stereotypic
behavior were not related to an overall lethargy
as evidenced by the lack of significant changes
in locomotion, scanning, play and only
short-term effects on resting.
The behavioral effects of fluoxetine
observed here are consistent with those of Weld
and colleagues who found that oral
supplementation of the 5-HT precursor tryptophan
decreased the duration of self-biting in adult
rhesus monkeys. As in Weld and colleagues
fluoxetine treatment did not have a significant
effect on some forms stereotypic behavior (i.e.
pacing, saluting). Direct comparison of the
effects of fluoxetine on stereotypic behavior is
difficult due to differences in categorization
of abnormal behavior between stwlies. These
differences are likely due to the idiosyncratic
nature of the stereotypies. The behavioral
effects of buspirone found in this study are
consistent with those of Kraemer and Clarke, who
found that buspirone reduced "self aggression"
(e.g., sell-bite, head slap, and head bang) in
mother- and peer-deprived juvenile rhesus
monkeys. Overall, the most significant decreases
in self-biting occurred during the mifiai 8
weeks of treatment. The lack of significant
treatment effects on these behaviors during
weeks 9 to 12 may reflect the need for dosage
adjustment or may in part be related to
compliance failures. Evaluation of serum drug
concentrations, which were not obtained in the
current study, would be required to dari1' these
issues.
While both compounds have demonstrated
anti-anxiety effects, the results of this study
suggest that only buspirone had significant
anti-anxiety effects as evidenced by an increase
in neutral behavior as well as a significant
decrease in rates of scratching and
yawning throughout the treatment period.
In the fluoxetine-treated animals rates of
yawning, scratching and self directed
grooming were higher overall compared to
buspirone treated animals and rates of
scratching increased significantly in Rx weeks 9
to 12, which suggests that animals in the
fluoxetine-treated condition experienced higher
levels of anxiety throughout the study compared
to the buspirone condition. It is unclear why
rates of self-directed grooming increased in
both conditions during Ra weeks 9 to 12 but may
indicate an increased level of anxiety in both
groups.
Combination therapy with a beuzodiazepine
such as diazepam may be an appropriate means of
reducing anxiety in the first 3 to 4 weeks of
treatment. For cases that present with severe
wounding, treatment is initiated with diazepam
(1.0 mg/kg orally twice daily) in conjunction
with fluoxetine for several weeks with empirical
success. In humans, combination therapy with
buspirone and fluoxetine has been used to treat
refractory depression. While synergistic effects
have been reported, the combination has been
associated in rare instances with increased
incidence of extrapyramidal effects and 5-HT
syndrome characterized by hyperpyrexia,
convulsions and coma. Further research is
ongoing to determine the efficacy of combination
therapies for SIB.
As shown in previous studies, concentrations
of CSF 5-HIAA were significantly decreased by
both treatments. In the fluoxetine-treated
condition, decreased CSF-5-HIAA may result from
reductions in the metabolism of 5-HT secondary
to reuptake inhibition. Fluoxetine blocks the
reuptake of 5-HT at dendritic synapses and axon
terminals. The resultant in crease in 5-HT
causes somatodendritic autoreceptors to
downregulate which results in increased impulse
flow release of 5-HT at the axon terminals. In
response to the increase in 5-HT, postsynaptic
receptors down-regulate. Downregulation of
postsynaptic receptors or regulation of
receptor-coupled intracellular signal
transduction pathways may require weeks of
therapy and is thought to underlie the clinical
effects.
Buspirone has mixed CNS effects in that it
is a potent 5-HT receptor agonist and a moderate
D2-dopamine receptor agonist and antagonist. It
is proposed that buspirone first slows neuronal
firing, helping the system to replenish 5-HT. In
the buspirone-treated condition, reductions in
CSF 5-HIAA may result from decreased 5-HT
turnover secondary to blockade of 5HT
autoreceptors. Buspirone acts as a partial
agonist of somatodendritic autoreceptors
directly, which may allow desensitization to
occur with smaller amounts of available 5-HT.
Over time post-synaptic receptors are
desensitized and downregulated, which is
associated with SSRI treatment. Research is
ongoing to determine whether the therapeutic
effects of 5-HT1a agonists are related to the
modulation of second messenger systems. The
actions of both treatments were specific to the
5-HT system as evidenced by the lack of
significant effects on CSF HVA and MHPG
concentrations in the present study. Decreases
in self-biting were apparent in both treatment
conditions within 4 weeks of treatment.
Upon discontinuation of treatment, rates of
self-biting and hair -plucking increased
significantly over Pre-Rx levels in our animals.
These results suggest that the drugs, although
efficacious during dosing do not induce
long-lasting changes or that treatment for 12
weeks is insufficient to sustain the effects. It
is recommended that human patients receive 4 to
9 months of treatment after remission of
clinical symptoms of depression and at least 6
months for generalized anxiety disorders.
Further research is required to determine
optimal treatment length for SIB.
Overall, the results of the present study
suggest that fluoxetine and buspirone may be
effective pharmacological agents for treatment
of SIB in adult macaques. However, optimal
dosages and treatment length require further
study. In the absence of appropriate blood
levels, we extrapolated from dosages used in
humans and canines. Although metabolite blood
levels are generally not associated with
clinical response in humans , this information
may nonetheless be useful in titrating dosages
in the future.
