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BEHAVIORAL PHARMACOLOGY
Department of Psychology, Behavioral Neuroscience Program, University of Florida, Gainesville, Florida
Received July 5, 2007; accepted October 4, 2007.
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Abstract |
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). It is also common in schizophrenia, borderline personality disorder, obsessive-compulsive disorder (OCD), and Tourette's syndrome (Primeau and Fontaine, 1987; Robertson et al., 1989; Burgess, 1991). In all of these groups, the self-injurious actions include head-banging, self-biting, skin-picking, self-punching, and many other forms (Rojahn and Esbensen, 2002). These behaviors can interfere with normal educational and socializing activities, and they can produce severe medical complications. Furthermore, the expression of SIB is extremely destructive for families and caretakers of the self-injurer, and the economic burden is staggering.
Although little is known about the neurochemical basis of SIB, a variety of studies have implicated dysregulation of dopaminergic, serotonergic, GABAergic, and opioid neurotransmission (for review, see Winchel and Stanley, 1991). Accordingly, clinical trials have been conducted with classical neuroleptics (e.g., haloperidol), selective serotonin reuptake inhibitors (SSRIs), and the opioid antagonist naltrexone (Sandman et al., 1990; Janowsky et al., 2005a,b). Although beneficial effects have been reported in many of these trials, nonresponders have been identified for each of these drug classes, and there are contradictory reports that these drugs did not have positive therapeutic effects (e.g., Willemsen-Swinkels et al., 1995).
More recent reports have described relatively consistent reductions in SIB during treatment with the atypical neuroleptic risperidone (Risperdol) (Masi, 2004). Positive outcomes have also been described during treatment with the antiepileptic and mood-stabilizing drug valproate (Depakote) (Ruedrich et al., 1999), and preliminary trials with the antiepileptic topiramate (Topamax) have been promising (Shapira et al., 2002). However, it should be noted that these three compounds have not been studied as extensively as the older drug classes have. Furthermore, interpretation of these clinical trials (and those of the older drugs) is hampered by the fact that most trials are conducted with uncontrolled open label designs because of the severe nature of the disorder. In addition, the effects of concomitant behavior therapy are generally not reported, and interactions with additional ongoing drug interventions may obscure the treatment outcomes. Precise monitoring of specific behaviors may also be difficult throughout the daily lives of patients, so many trials have relied upon more global impressions of the patients' progress, rather than specific counts of SIB (e.g., Caicedo and Williams, 2002).
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In one animal model of SIB, rodents exhibit self-biting behavior after administration of high doses of the indirect monoamine agonist pemoline (Mueller and Hsiao, 1980; Kies and Devine, 2004). The pemoline-induced SIB occurs in a dose orderly and stereotyped manner after three to five daily injections (Kies and Devine, 2004), and it can be blocked by coadministration of haloperidol, pimozide, or naltrexone (Mueller and Nyhan, 1982; King et al., 1993). Accordingly, the model seems to be responsive to classical interventions that have been at least partially successful in treatment of human self-injurers. However, the efficacy of atypical neuroleptics and antiepileptics has not been evaluated in the pemoline model of SIB.
Because risperidone and valproate each have established records of beneficial effects in human self-injurers, we examined the predictive validity of the pemoline model by investigating the effectiveness of these two drugs against pemoline-induced SIB. We also evaluated the pharmacotherapeutic potential of topiramate since there is preliminary evidence that it is effective in treatment of SIB in autism and Prader-Willi syndrome, and we have challenged the pemoline-induced SIB with tramadol (Ultram), an atypical opiate agonist that is thought to be beneficial in OCD and Tourette's syndrome (Shapira et al., 1997; Goldsmith et al., 1999) but has not been assessed previously for treatment of clinical SIB. In addition, we evaluated the impact of the experimental manipulations on regulation of the hypothalamic-pituitary-adrenal axis, and we investigated potential organotoxicity during pemoline administration.
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Materials and Methods |
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), and all experiments were pre-approved by the Institutional Animal Care and Use Committee at the University of Florida.
Drugs
Pemoline (Spectrum Chemicals, New Brunswick, NJ) was suspended at a concentration of 50 mg/ml in warm peanut oil (held at approximately 36°C), with constant stirring. Risperidone (Sigma-Aldrich Co., St. Louis, MO) was dissolved in 45% (w/v) hydroxypropyl-β-cyclodextrin at concentrations of 0, 0.1, 0.5, and 1.0 mg/ml. Sodium valproate (Sigma-Aldrich Co.) was dissolved in 0.04% (w/v) Na2EDTA at concentrations of 0, 50, 100, and 200 mg/ml and was adjusted to a neutral pH of 7.4. Topiramate was provided by Johnson & Johnson (Raritan, NJ) and was dissolved in sterile saline at concentrations of 0, 1, 3, and 10 mg/ml. Tramadol hydrochloride (Sigma-Aldrich Co.) was dissolved in sterile saline at concentrations of 0, 0.1, 1.0, and 10 mg/ml.
Experimental Procedures
Drug Treatments. Twenty-nine of the rats were weighed and injected with pemoline (200 mg/kg s.c.) at approximately 8:00 AM on each of 5 consecutive days. These injections were administered at the nape of the neck or either flank on a rotating basis. The rats were also injected twice daily with risperidone (0, 0.1, 0.5, or 1.0 mg/kg i.p.; n = 6–8 per group) on each of the 5 days. The risperidone injections were administered at approximately 8:00 AM (immediately after the pemoline injection) and again at approximately 6:00 PM. The rest of the rats received daily pemoline injections at 200 mg/kg and twice daily injections of either valproate (0, 50, 100, or 200 mg/kg i.p.; n = 9 rats per group), topiramate (0, 1, 3, or 10 mg/kg, s.c.; n = 8–9 rats per group), or tramadol (0, 0.1, 1.0, or 10 mg/kg, s.c.; n = 18 rats per group) for 5 days, following the same procedures as in the risperidone experiment.
These doses of risperidone, valproate, topiramate, and tramadol were selected because they do not produce sedative effects in rats. Risperidone did not diminish any measure of activity after acute or chronic (once daily for 20 days) administration of doses ranging from 0.01 to 10 mg/kg (Drago et al., 1997). Valproate did not diminish locomotion or rearing when administered acutely or chronically (21 days) at doses ranging from 50 to 400 mg/kg (Fernandez et al., 1988). Topiramate did not diminish locomotion, and it did not affect any of a variety of measures of motor abilities when tested at 80 and 160 mg/kg (Alaverdashvili et al., 2005). Tramadol did not affect motor abilities at doses up to 30 mg/kg (Guneli et al., 2007).
Assays of Self-Injury. The rats were visually inspected each time they were injected (i.e., twice per day for 5 days), and the inspections were videotaped. For these inspections, each rat was held in front of a video camera and the head, forepaws, hindpaws, ventrum, and tail were manually turned toward the camera by the experimenter. The presence or absence of tissue injury (denuded skin, erythema, edema, or open lesion) was noted for each rat. Any rat with an open lesion was immediately euthanized. In addition, still photographs of the injured tissue were taken from the videotapes, outlines were drawn around the injured tissue, and MCID software (Imaging Research Inc., St. Catherines, ON, Canada) was used to calculate the area of tissue damage in millimeters squared.
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On the morning of the 6th day, each rat was visually inspected. Immediately after this inspection, the rat was terminated, and the thymus and adrenal glands were removed.
Health Status of the Rats. Thymus involution and adrenal hyperplasia are well known consequences of chronic stress exposure in rats. Accordingly, the thymus and adrenal glands were weighed to determine whether the stress of the experiment was substantial enough to affect the endocrine or immune status of the pemoline-treated rats.
An additional 30 rats (100–125 g; Harlan Inc.) were used to evaluate the potential that the pemoline regimen could induce organotoxicity in the rats. Rats received no treatment (n = 6), peanut oil injections (n = 6), or pemoline injections at 100 mg/kg/day for 14 days (n = 6), 200 mg/kg/day for 5 days (n = 6), or 300 mg/kg/day for 4 days (n = 6). The rats were rapidly decapitated the morning after the last injection. The trunk blood was collected, and plasma was isolated by centrifugation at 1000g for 5 min at 4°C. The plasma was frozen on dry ice and stored at –80 C. Organic toxicity was examined by assaying extinction of NADH by aspartate aminotransferase (AST), according to the procedure of Kus et al. (2004).
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All significant effects were further analyzed with least significant difference post-tests for all the analyses of variance and RM-ANOVA. Between-groups differences in all dependent measures were treated as statistically reliable when the p values were less than 0.05.
Some rats were euthanized before the end of the experiment because they had an open lesion. In these cases, the missing data were replaced by repeating the final score that was attained for each dependent measure through the end of the experiment. This strategy was used to avoid the potential that the group means would underestimate the self-injurious oral contact and the area of tissue damage scores and to avoid the potential that the group means would over- or underestimate the locomotor, inactivity, and grooming scores when the most severe self-injurers had to be removed from any group. The numbers of rats that were terminated early in each group are summarized in Table 1.
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Interobserver Reliability. Interobserver reliability for the overnight behavioral scoring was assessed by two observers scoring the same 300 min of videotaped samples (60 clips lasting 5 min each with all concentrations of all drugs represented in this sampling each night). A quantitative measure of reliability was determined by taking the total number of seconds that each observer scored the same behavior in each time sample and dividing by the total number of seconds scored (i.e., 300 s).
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Results |
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Risperidone did not significantly affect the duration of time spent grooming (F12,100 = 1.253, p > 0.05; Fig. 2A). On the other hand, it did significantly increase the duration of inactivity overnight (F3,76 = 3.482, p < 0.05; Fig. 2B), although there were no significant time or group-by-time interaction effects. The amount of locomotion was initially high, and it decreased significantly across the days of treatment in all the groups (F4,100 = 8.709, p < 0.05; see Fig. 4C). Furthermore, the rats that were treated with the highest dose of risperidone exhibited higher rates of locomotion compared with the vehicle-treated rats (F3,100 = 3.874, p < 0.05; Fig. 2C), but there were no group-by-time interaction effects.
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Valproate administration did not significantly affect any of the other behaviors that were measured during the experiment. Although the time spent grooming (F4,128 = 5.286, p < 0.05; Fig. 4A), inactive (F4,128 = 4.753, p < 0.05; Fig. 4B), and the amount of locomotion recorded on videotapes overnight (F4,128 = 20.19, p < 0.05; Fig. 4C) each decreased significantly across the days of the experiment, there were no significant between-groups differences, and there were no group-by-time interaction effects.
Topiramate Experiment. All the rats that were treated with either vehicle or the low dose of topiramate and nearly all the rats that were treated with the two higher doses of topiramate exhibited pemoline-induced self-injury (Fig. 5A). Overall, the incidence and expression of SIB was greater in this experiment than it was in the other experiments, and more rats were euthanized because of severe SIB than in the other experiments (see Table 1). This is attributed to the fact that we used a new batch of pemoline, which was more potent than the batch that we used in the other experiments. This difference in potency was confirmed by a small difference in the drug purity (according to the drug supplier's certificate of analysis), and we have continued to observe differences in potency in additional experiments we recently conducted. Accordingly, we have reduced our working dose to 150 mg/kg in those subsequent experiments (A. M. Muehlmann and D. P. Devine, unpublished data). The rats that received the two higher doses of topiramate, however, displayed less self-injurious oral contact (F12,128 = 2.002, p < 0.05; Fig. 5B) and smaller areas of tissue damage (F30,320 = 1.569, p < 0.05; Fig. 5C), despite the high potency of the pemoline. The AUC for self-injurious oral contact and area of tissue damage were significantly correlated (r = 0.5513, p < 0.05; Fig. 5D) for all the vehicle- and topiramate-treated rats.
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Topiramate did not significantly affect the amount of time spent grooming. Topiramate-treated rats did exhibit more inactivity than vehicle-treated rats did (F12,120 = 1.9, p < 0.05; Fig. 6B), and this effect was most pronounced during the last 2 experimental nights. Locomotion decreased significantly throughout days of the experiment (F4,120 = 62.88, p < 0.05; Fig. 6C), but there were no between-group differences.
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), except for a slight thymus involution in the group of rats treated with the highest dose of valproate (data not shown). No sign of organic toxicity was found in the pemoline-treated rats. AST activity was consistently below 300 U/l (Table 2). In comparison, Kus et al. (2004) reported AST levels as high as 844 ± 125 U/l in rats with toxic liver damage and 295 ± 35 U/l in controls.
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Interobserver Reliability. The two observers' scores of the duration of overnight behaviors matched exactly 98.3% of the time.
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Discussion |
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The neurochemical mechanisms whereby pemoline causes SIB are not known. Pemoline is a long-lasting indirect monoamine agonist that blocks neuronal uptake of dopamine and norepinephrine after acute administration (Molina and Orsingher, 1981). Its effects on serotonergic uptake have been less well studied, and the impacts of the chronic high-dose pemoline regimen on neurochemical regulation have not been systematically characterized. The involvement of dopaminergic mechanisms in pemoline-induced SIB is suggested by the fact that the SIB is eliminated by coadministration of haloperidol or pimozide (Mueller and Nyhan, 1982). Furthermore, dopaminergic neurotransmission is often dysregulated in clinical populations that exhibit SIB (Turner and Lewis, 2002). Noradrenergic mechanisms are indirectly implicated in the pemoline model by the fact that isolated mice self-injure after clonidine administration (Razzak et al., 1977). Serotonergic mechanisms are implicated by the fact that coadministration of the SSRI paroxetine increases the expression of SIB in the pemoline model (Turner et al., 1999).
Risperidone Experiment. The dose orderly decreases that were observed in all the measures of self-injury are congruent with reports of risperidone's efficacy in clinical trials (Masi, 2004). Thus, the results of this study suggest convergence in the neurochemical mechanisms that contribute to the pathology of SIB in clinical subjects and in the pemoline model and generate support for the predictive validity of the pemoline model.
The robust effect of risperidone in the pemoline model also concurs with reports that risperidone attenuates SIB in the neonatal 6-hydroxydopamine model in rats (Allen et al., 1998) and in the amphetamine model in mice (Wagner et al., 2004). Risperidone is a benzisoxazole derivative that functions as an antagonist with high affinity at 5-HT2A receptors, moderate affinity at dopamine D2 receptors, and lower affinity at 
1 and 2 adrenoceptors (Leysen et al., 1988). Because risperidone blocks 5-HT2A receptors and is effective in these animal models and in clinical SIB, it appears that serotonergic neurotransmission may play an important role in the etiology of SIB. At the very least, therapies targeted at this system may have the potential to correct neurotransmitter dysregulation that contributes to the disorder. This also concurs with the negative effects of paroxetine in the pemoline model of SIB (Turner et al., 1999) and suggests that SSRIs may be contraindicated in SIB. Because risperidone also blocks D2 receptors, dopaminergic actions are also implicated in SIB. This suggestion is further supported by clinical observations (Turner and Lewis, 2002), by the effect of classical neuroleptics in the pemoline model (Mueller and Nyhan, 1982; King et al., 1993), and by the fact that the D1 receptor antagonist SCH 23390 blocks SIB in the neonatal 6-hydroxydopamine model (Allen et al., 1998).
Valproate Experiment. In the valproate challenge of pemoline-induced SIB, the beneficial effects were again consistent with the effectiveness in clinical self-injury (Ruedrich et al., 1999). However, valproate was less effective than was risperidone in the dose ranges that were evaluated. In fact, the lowest dose of valproate actually seemed to slightly increase the appearance of tissue injury, and valproate did not significantly reduce the amount of oral contact at any of the doses that were tested. Reductions in the incidence of self-injury and the amount of tissue damage were most apparent when the highest dose (200 mg/kg) was used. The discrepancy between the effectiveness of valproate in reducing the incidence and expression of tissue damage and its lack of effect on duration of self-injurious oral contact suggests that valproate did not reduce the overall expression of stereotyped oral behaviors but did reduce the severity of those behaviors.
Valproate inhibits neuronal excitability by increasing extracellular GABA concentrations (Nau and Loscher, 1982). This raises the possibility that valproate attenuates pemoline-induced SIB by inhibiting monoaminergic neurotransmission through GABAergic actions in the substantia nigra, ventral tegmental area, cortex, and/or striatum. This is consistent with a report that the GABA agonist baclofen reduced SIB in intellectually handicapped self-injurers (Primrose, 1979).
On the other hand, valproate also blocks voltage-gated Na+ and Ca2+ channels (McLean and MacDonald, 1986) and N-methyl-D-aspartate-mediated cellular depolarizations (Zeise et al., 1991). Accordingly, although the effects of valproate suggest interesting targets for investigation of the neurobiological basis of SIB, it is not clear at this time whether it reduces self-injury through GABAergic mechanisms, cation channel actions, or even alterations in intracellular signaling.
Topiramate Experiment. The effects of topiramate on pemoline-induced SIB were also consistent with the clinical observations (Shapira et al., 2002), providing further support for the predictive validity of the pemoline model of SIB. These data are particularly interesting in relation to a study in which topiramate reduced the sizes and severity of wounds in subjects with Prader-Willi syndrome who exhibited severe skin picking (Shapira et al., 2002). Although the measures of wound expression in this open-label study were more precise than is typical of clinical studies of SIB, the findings are complicated by the fact that topiramate has been found to promote dermal healing (Shapira et al., 2003). In the current analysis with pemoline-induced SIB, topiramate not only decreased tissue damage, it also decreased the duration of self-injurious oral contact, suggesting that the clinical report accurately revealed a decrease in actual skin-picking behavior, rather than an unrelated dermal action of the drug.
Topiramate, like valproate exerts inhibitory effects on neuronal excitability. It enhances GABAergic neurotransmission by increasing GABA-mediated Cl– influx through GABAA receptors (White et al., 1997). It also inhibits Na+ and/or Ca2+ channels (DeLorenzo et al., 2000), and it decreases kainate-evoked current through -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (Gibbs et al., 2000). Accordingly, topiramate has the potential to interact with neurotransmission in multiple systems, and the specific mechanism(s) whereby it decreases SIB are unknown.
Tramadol Experiment. Although tramadol decreases compulsive behaviors in individuals with OCD and Tourette's syndrome (Shapira et al., 1997; Goldsmith et al., 1999), it did not significantly affect any dependent measure of SIB in the pemoline model. One possible interpretation of these results is that the pemoline-induced SIB is not a compulsive behavior. This interpretation contrasts with our observations that the rats focus on specific tissue sites (Kies and Devine, 2004) and are often difficult to distract when they are engaged in self-biting behavior. However, the clinical efficacy of tramadol as an anti-compulsive agent is not yet well established since the reports are based on open label trials with small sample sizes. Moreover, it is possible that the dosage or dosing regimen (b.i.d.) of tramadol that we used in this study may not have been aggressive enough. The potential that compulsions play an important role in pemoline-induced SIB merits further evaluation.
On the other hand, the pharmacological actions of tramadol may explain the outcome of this experiment. Tramadol is an opioid receptor agonist that exhibits moderate affinity to µ receptors (Raffa et al., 1992), an action that is consistent with its efficacy in clinical trials and animal models of compulsions. However, tramadol also blocks reuptake of norepinephrine and serotonin (Raffa et al., 1992). These actions (especially blockade of serotonin reuptake) may account for the lack of efficacy of tramadol in the pemoline model of SIB.
Summary and Conclusions. Although there is no universally effective pharmacological treatment for SIB, the results of the experiments with risperidone, valproate, and topiramate provide evidence of the predictive validity of the pemoline model of SIB. Thus, the pemoline model of SIB may be a valuable tool for prescreening potential pharmacotherapeutic interventions for SIB in a controlled laboratory setting with quantifiable dependent measures. The tramadol experiment suggests that this treatment does not hold therapeutic promise. It is not clear if the failure of tramadol to diminish pemoline-induced SIB might be due to its blockade of norepinephrine or serotonin uptake, but the results of this and other studies (Allen et al., 1998; Turner et al., 1999) suggest that drugs such as SSRIs that block monoamine uptake should be considered with caution.
Additional examinations of the therapeutic effects of pharmacological manipulations in the pemoline model may be useful to identify neurobiological factors that contribute to the etiology and expression of SIB. Although the specific pharmacological actions that underlie the efficacy of these drug challenges are currently unknown, comparisons of drug-induced neurochemical alterations that differentiate self-injurious pemoline-treated rats from noninjurious rats that are treated with these pharmacological challenges may help to reveal important neurochemical variables that underlie SIB.
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: SIB, self-injurious behavior; OCD, obsessive-compulsive disorder; SSRI, selective serotonin reuptake inhibitor; pemoline, 2-amino-5-phenyl-1,3-oxazol-4-one; AST, aspartate aminotransferase; RM-ANOVA, repeated measures analysis of variance; AUC, area(s) under the curve.
Address correspondence to: Darragh P. Devine, University of Florida, Department of Psychology, P.O. Box 112250, Gainesville, FL 32611-2250. E-mail: dpdevine{at}ufl.edu
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