mise à jour du
24 décembre 2006
Comp Med
The effects of fluoxetine and buspirone on self-injurious and stereotypic behavior in adult male rhesus macaques
Fontenot MB, Padgett EE, Dupuy AM, Lynch CR, De Petrillo PB, Higley JD.
University of Louisiana at Lafayette-New Iberia Research Center, Louisiana, USA


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.
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.
Tous les travaux de B. Deputte

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