Self-injurious behavior vs. nonsuicidal self-injury: the CNS stimulant pemoline as a model of self-destructive behavior.

BACKGROUND: Historically, the field of self-injury has distinguished between the behaviors exhibited among individuals with a developmental disability (self-injurious behaviors; SIB) and those present within a normative population (nonsuicidal self-injury; NSSI),which typically result as a response to perceived stress. More recently, however, conclusions about NSSI have been drawn from lines of animal research aimed at examining the neurobiological mechanisms of SIB. Despite some functional similarity between SIB and NSSI, no empirical investigation has provided precedent for the application of SIB-targeted animal research as justification for pharmacological interventions in populations demonstrating NSSI. AIMS: The present study examined this question directly, by simulating an animal model of SIB in rodents injected with pemoline and systematically manipulating stress conditions in order to monitor rates of self-injury. METHODS: Sham controls and experimental animals injected with pemoline (200 mg/kg) were assigned to either a low stress (discriminated positive reinforcement) or high stress (discriminated avoidance) group and compared on the dependent measures of self-inflicted injury prevalence and severity. RESULTS: The manipulation of stress conditions did not impact the rate of self-injury demonstrated by the rats. The results do not support a model of stress-induced SIB in rodents. CONCLUSIONS: Current findings provide evidence for caution in the development of pharmacotherapies of NSSI in human populations based on CNS stimulant models. Theoretical implications are discussed with respect to antecedent factors such as preinjury arousal level and environmental stress.

Animal models of self-injurious behaviour: an overview.

Self-injurious behaviour is highly prevalent in neurodevelopmental disorders. Interestingly, it is not restricted to any individual diagnostic group. Rather, it is exhibited in various forms across patient groups with distinct genetic defects and classifications of disorders. This suggests that there may be shared neuropathology that confers vulnerability. Convergent evidence from clinical pharmacotherapy, brain imaging studies, postmortem neurochemical analyses, and animal models indicates that dopaminergic insufficiency is a key culprit. This chapter provides an overview of studies in which animal models have been used to investigate the biochemical basis of self-injury, and highlights the convergence in findings between these models and expression of self-injury in humans.

The pemoline model of self-injurious behaviour.

Traditional models of neuropsychiatric disorders consist of attempts to replicate the broad spectrum of behavioural and neurochemical sequelae that characterize a specific disorder. However, these disorders comprise complex constellations of symptoms, including emotional instability, perseverative thoughts, and aberrant behaviours. Close examination often reveals heterogeneity of symptom expression within patient groups and homogeneity in expression of specific symptoms across diagnostic categories. Accordingly, it may not be possible to model the entire spectrum of characteristics for any one of these disorders in any single animal model. A focus on one or more specific behavioural characteristics (e.g. self-injury) may be a more fruitful strategy. Development of behaviourally focused models yields increased understanding of the genetic basis and biochemical abnormalities that underlie specific psychiatric dysfunctions. Furthermore, by revealing pathophysiology that underlies specific disease characteristics, behaviourally focused models improve translational power and help to identify targets for effective pharmacotherapies. One such behaviourally focused animal model is the pemoline model of self-injurious behaviour.

Polyamine pathway contributes to the pathogenesis of Parkinson disease.

The full complement of molecular pathways contributing to the pathogenesis of Parkinson disease (PD) remains unknown. Here we address this issue by taking a broad approach, beginning by using functional MRI to identify brainstem regions differentially affected and resistant to the disease. Relying on these imaging findings, we then profiled gene expression levels from postmortem brainstem regions, identifying a disease-related decrease in the expression of the catabolic polyamine enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1). Next, a range of studies were completed to support the pathogenicity of this finding. First, to test for a causal link between polyamines and α-synuclein toxicity, we investigated a yeast model expressing α-synuclein. Polyamines were found to enhance the toxicity of α-synuclein, and an unbiased genome-wide screen for modifiers of α-synuclein toxicity identified Tpo4, a member of a family of proteins responsible for polyamine transport. Second, to test for a causal link between SAT1 activity and PD histopathology, we investigated a mouse model expressing α-synuclein. DENSPM (N1, N11-diethylnorspermine), a polyamine analog that increases SAT1 activity, was found to reduce PD histopathology, whereas Berenil (diminazene aceturate), a pharmacological agent that reduces SAT1 activity, worsened the histopathology. Third, to test for a genetic link, we sequenced the SAT1 gene and a rare but unique disease-associated variant was identified. Taken together, the findings from human patients, yeast, and a mouse model implicate the polyamine pathway in PD pathogenesis.

Acceleration tolerance at night with acute fatigue and stimulants.

INTRODUCTION: The impact of pharmacological agents on aviators concerns all flight surgeons. This study tested the related hypotheses that acute fatigue reduces +Gz tolerance and endurance, and that stimulants can partially reverse this impact. Additionally, the researchers attempted to develop a test battery sensitive enough to detect subtle differences in aviator cognition and performance among conditions. METHODS: To determine the effect of fatigue on +Gz tolerance and the impact of stimulant use, 10 male centrifuge subjects, mean age 32, from Brooks City-Base, TX, were tested in a repeated measures study under five nighttime conditions following an average of 22 h of sustained wakefulness during their circadian nadir. Using a within-subject design, subjects received placebo, dextroamphetamine 10 mg, modafinil 200 mg, methylphenidate 10 mg, and pemoline 37.5 mg at night, and were tested during a daytime control session. Cognitive/performance tests were administered before each centrifuge run. RESULTS: No difference in +Gz tolerance or endurance was detected among conditions. The cognitive/performance tests also did not detect any differences. Subject perception that anti-G straining maneuver (AGSM) difficulty was greater during the night placebo condition than during the daytime control, methylphenidate and modafinil night conditions reached statistical significance (P = 0.005, 0.012, 0.022, respectively). DISCUSSION: Physiological changes during the circadian nadir following acute sleep deprivation do not appear to negatively impact +Gz tolerance. A standardized protocol sufficiently sensitive to detect subtle behavioral and performance effects would be useful to test and compare the effect of other pharmacological agents on aviators.

Delusional parasitosis and the dopamine transporter. A new insight of etiology?

Delusional parasitosis (DP) is a psychotic condition in which a person has the unshakeable and mistaken belief (delusion) and/or aberrant perception (hallucination) of being infested with parasites. The disorder will be usually classified in a primary DP-group without a detectable cause (so-called pure forms), while secondary DP-groups are associated with general organic conditions, psychiatric illnesses and drugs (substance induced). Etiology and pathophysiology of DP remain however unknown. In the present paper we hypothesize for the first time a decreased striatal dopamine transporter (DAT)-functioning (corresponding with an increased extracellular dopamine-level) as etiologic condition for DP (primary and secondary groups). The DAT as key regulator of the dopamine-reuptake in the human brain is well known (regulation of the extracellular dopamine concentration). It is a presynaptic plasma membrane protein highly dense represented in the striatum. The hypothesis of a decreased DAT-functioning as etiologic condition by DP is revealed in case reports which show that DAT-inhibitors, such as cocaine, pemoline, methylphenidate and other amphetamine-derivatives can induce the clinical expression of DP. Several other associated causes of secondary DP-groups (medications, parkinson, chorea huntington, multiple system atrophy, diabetes, cerebrovascular diseases, alcoholism, traumatic brain injury, hyperuricemia, human immunodeficiency virus, iron deficiency, schizophrenia, depression) suggest that the clinical expression of DP may be related to a decreased striatal DAT-functioning (blocking, reduced ligand binding, reduced density, reduced activity). Our examined DP-cases (2-females) show means of magnetic resonance imaging a structurally damaged striatum. Furthermore, we presume that by the primary DP-group, the physiologically age-related decline of the DAT-density is pathologically elevated. Based on this hypothesis we show in the present paper the relation between DP and decreased striatal DAT-functioning, trying to give a new insight into the pathophysiologically mechanism involved. The hypothesis provides supporting evidence that increased levels of extracellular dopamine in the striatum of DP-patients is likely to be the result of decreased DAT-functioning and not increased rates of release. The hypothesis can be investigated simply by dopamine transporter imaging in patients with DP.

Assessing medication effects in the MTA study using neuropsychological outcomes.

BACKGROUND: While studies have increasingly investigated deficits in reaction time (RT) and RT variability in children with attention deficit/hyperactivity disorder (ADHD), few studies have examined the effects of stimulant medication on these important neuropsychological outcome measures. METHODS: 316 children who participated in the Multimodal Treatment Study of Children with ADHD (MTA) completed the Conners' Continuous Performance Test (CPT) at the 24-month assessment point. Outcome measures included standard CPT outcomes (e.g., errors of commission, mean hit reaction time (RT)) and RT indicators derived from an Ex-Gaussian distributional model (i.e., mu, sigma, and tau). RESULTS: Analyses revealed significant effects of medication across all neuropsychological outcome measures. Results on the Ex-Gaussian outcome measures revealed that stimulant medication slows RT and reduces RT variability. CONCLUSIONS: This demonstrates the importance of including analytic strategies that can accurately model the actual distributional pattern, including the positive skew. Further, the results of the study relate to several theoretical models of ADHD.

Effect of fluoxetine, pemoline and placebo on heart period and QT variability in normal humans.

OBJECTIVE: To measure the effects of fluoxetine and pemoline on heart period and QT variability. METHODS: Healthy volunteers were randomly assigned treatment with 20 mg daily of fluoxetine (n=7), 56.25 mg of pemoline (n=7) or placebo (n=9). Twenty-four-hour Holter ECGs were obtained before and after approximately 8 weeks of double-blind treatment. RESULTS: There were no significant changes in the fluoxetine group. Pemoline was associated with a significant decrease in the high frequency (HF) power (0.15-0.5 Hz, P=.02) and fractal dimension of RR time series (P=.03). QTvi, a measure of QT interval variability, increased in the pemoline group (P=.05). CONCLUSION: Pemoline, but not fluoxetine, decreases heart period variability (HPV) in the HF power, suggesting a vagolytic effect on cardiac autonomic function. Pemoline is also associated with an increase in QT interval variability, a measure that is sensitive to adrenergic agonists.

Pharmacologic thresholds for self-injurious behavior in a genetic mouse model of Lesch-Nyhan disease.

Congenital deficiency of hypoxanthine-guanine phosphoribosyl transferase (HPRT) causes Lesch-Nyhan disease in humans, which is associated with severe and recurrent self-injurious behavior (SIB). The HPRT-deficient knockout mouse model, however, does not display this unusual behavior. The present studies tested whether these mice might be more vulnerable to pharmacologic agents known to cause SIB in normal rodents, including clonidine, Bay K 8644, GBR 12909, methamphetamine, pemoline and caffeine. The results provided three conclusions. First, normal mice did not display SIB using some drugs known to provoke the behavior in rats (GBR 12909, caffeine), indicating important species differences in the expression of the behavior. Second, the C57BL/6J mice did not display SIB using drugs effective for other strains of mice (methamphetamine, pemoline), indicating important strain differences in expression of the behavior. Finally, there was no evidence that the HPRT-deficient mice were more susceptible to SIB when it occurred (clonidine, Bay K 8644).

Psychostimulants in supportive care.

Psychostimulant medications have been used clinically and investigated in psychiatric populations, the medically ill, cancer patients and healthy people. This article discusses the pharmacology of dextroamphetamine, methylphenidate, pemoline (and other psychostimulants such as caffeine and ephedrine), their use in general medicine and cancer care, side effects, and abuse potential. Therapeutic use in children is addressed only insofar as it illustrates facets of their use in adults.

A verification of psychostimulant-induced improvement in sustained attention in rats: effects of d-amphetamine, nicotine, and pemoline.

Previous studies from this laboratory have demonstrated that a variety of psychostimulant drugs can improve the performance of rats trained in a 2-choice stimulus detection task in which the correct responses are indicated by a briefly illuminated light. To enhance the construct validity of the task for assessing sustained attention, the procedure was modified so that the precue interval across trials varied unpredictably between 3, 7, and 11 s. After training rats (N = 17) so that their baseline accuracy levels stabilized between 75% and 88% correct, their performance was assessed after administration of d-amphetamine (0.125-0.75 mg/kg sc), nicotine (0.25-0.75 mg/kg sc), and pemoline (5.0-30.0 po). At certain doses all 3 drugs induced performance improvements in mean choice accuracy and choice response time. Because the precue intervals varied unpredictably and the cue durations used to maintain the rats' baseline accuracy levels were typically short (range = 70-500 ms), the task conforms to most conditions typically required for assessing sustained attention. Results verify the proposal that psychostimulant drugs can enhance the attentiveness of animals in a fashion similar to that documented in humans.

Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks.

Fluoxetine inhibits the reuptake of serotonin, and dextroamphetamine enhances presynaptic release of monoamines. Although the excitatory effect of both noradrenaline and dopamine on motor behavior generally is accepted, the role of serotonin on motor output is under debate. In the current investigation, the authors evidenced a putative role of monoamines and, more specifically, of serotonin in the regulation of cerebral motor activity in healthy subjects. The effects on cerebral motor activity of a single dose of fluoxetine (20 mg), an inhibitor of serotonin reuptake, and fenozolone (20 mg/50 kg), an amphetamine-like drug, were assessed by functional magnetic resonance imaging. Subjects performed sensorimotor tasks with the right hand. Functional magnetic resonance imaging studies were performed in two sessions on two different days. The first session, with two scan experiments separated by 5 hours without any drug administration, served as time-effect control. A second, similar session but with drug administration after the first scan assessed drug effects. A large increase in evoked signal intensity occurred in the ipsilateral cerebellum, and a parallel, large reduction occurred in primary and secondary motor cortices (P < 10(-3)). These results are consistent with the known effects of habituation. Both drugs elicited comparable effects, that is, a more focused activation in the contralateral sensorimotor area, a greater involvement of posterior supplementary motor area, and a widespread decrease of bilateral cerebellar activation (P < 10(-3)). The authors demonstrated for the first time that cerebral motor activity can be modulated by a single dose of fluoxetine or fenozolone in healthy subjects. Drug effects demonstrated a direct or indirect involvement of monoamines and serotonin in the facilitation of cerebral motor activity.

Paradoxical effects of serotonin and opioids in pemoline-induced self-injurious behavior.

Self-injurious behavior (SIB) is a symptom of various psychiatric disorders with differing etiologies. Although no generally effective pharmacological treatment of SIB is available, subsets of individuals exhibiting SIB have been found to respond to opioid antagonists and selective serotonin reuptake inhibitors (SSRIs). The present study evaluated the efficacy of these two treatments in the pemoline-induced model of self-biting behavior (SBB) in rats. Using a factorial design, adult rats receiving daily pemoline at 100 mg/kg or the peanut oil vehicle were pretreated with either distilled water vehicle (1 cc/kg), naltrexone (1 mg/kg), or paroxetine (1 mg/kg). Each day, animals were rated on the severity of SBB and also periodically behavioral changes were evaluated using various other outcome measures. Paroxetine significantly increased the severity of SBB induced by pemoline, while naltrexone only marginally increased the SBB. These results were not expected and suggest that further studies into the role of serotonin agonists and antagonists are needed in evaluating this model.

Dopaminergic and glutamatergic interactions in the expression of self-injurious behavior.

Self-injurious behavior occurring in persons with severe mental retardation is a clinically significant and poorly understood problem. Multiple neurotransmitter systems have been implicated in the pathogenesis of this behavior, particularly dopaminergic, opioidergic, and serotonergic systems. Pemoline, a central stimulant, administered systemically at high doses reliably produces self-biting behavior in the rat. The systemic bolus of pemoline produces sustained neostriatal levels of pemoline for over 24 h in a continuous infusion paradigm. Studies of the effect of cortical lesions on pemoline-mediated behaviors reveal that cortical damage, as is common in profound mental retardation, lowers the threshold for pemoline-induced self-biting behavior. Data from the corticostriatal slice suggests that sustained exposure to pemoline produces a shift in N-methyl-D-aspartate receptor-mediated responses rendering them more susceptible to dopaminergic enhancement. Thus, dopaminergic and glutamatergic interactions appear to play an important role in the development and expression of self-biting in the pemoline model.

Intensive and sustained air operations: potential use of the stimulant, pemoline.

BACKGROUND: Intensive and sustained military operations involve long periods of overnight work and the occasional use of a stimulant to maintain performance may be beneficial. In this context a dose response study was carried out to investigate the effects of pemoline, a dopamimetic agent, on overnight work and to assess potential residual effects on subsequent sleep. METHODS: Six healthy volunteers participated in a placebo-controlled, double-blind, cross-over trial involving a 12-h period of work during which subjective alertness and performance on a range of tasks were assessed at 1.5 h intervals following ingestion at 2000 hours of pemoline (10, 20, 30 and 40 mg) and, on two occasions, placebo. The work period was preceded by a 6-h sleep period with temazepam 20 mg, and followed by a 4-h recovery sleep with no medication. All sleep periods were recorded electroencephalographically. RESULTS: There was no difference between sleep periods preceding the work period. Subjective alertness and performance on all tasks deteriorated significantly during the work period, with the earliest impairments in performance observed at 0200 hours. Pemoline increased subjective alertness and performance on all but two tasks, compared with placebo. The onset of activity was seen 4.5 h after drug ingestion and alerting effects of 30 and 40 mg pemoline persisted beyond the work period, disturbing morning recovery sleep. Doses of 10 and 20 mg pemoline had no effect on recovery sleep. CONCLUSION: The present studies indicate that a 20 mg dose of pemoline may be suitable for maintaining nocturnal performance without having adverse effects on recovery sleep.

Dopaminergic agents and stimulants as antidepressant augmentation strategies.

Dopaminergic agents and stimulants have been used to manage depression when conventional antidepressant treatments fail. We reviewed evidence for the role of dopaminergic dysfunction in depression, the use of dopaminergic agents as antidepressants, and the use of dopaminergic agents and stimulants as antidepressant adjuncts. Dopamine may be part of the pathophysiology of depression for a subset of patients. When used with caution and an appreciation of the potential risk of abuse, dopaminergic agents and stimulants may be useful for patients refractory to antidepressants alone.

Effects of pemoline on spontaneous and event-related electrical activity of the brain.

The effect of pemoline on the electrical activity of the brain (electroencephalogram, EEG) was studied in relation to time since sleep and time of day in 6 healthy subjects carrying out periods of work lasting 18 h. Power of the spontaneous EEG increased with time since sleep and amplitude of the P3 event-related response decreased. The changes may be interpreted as the reduction in alertness with time awake. In contrast, pemoline decreased power of the spontaneous EEG and increased the amplitude the P3 response, effects that are consistent with improved alertness. The changes in brain activity were paralleled by effects on performance, in terms of percentage of correct responses and reaction time. Performance decreased with time awake, and was improved by pemoline compared with placebo. The drug counteracted the adverse effects of time since sleep, with the beneficial effect of the drug persisting over the 18-hour period of work. The findings emphasise that spontaneous and event-related activity of the EEG may be used both to complement measures of performance in the laboratory and to assess behaviour in occupational situations where performance testing is impractical.

Pemoline alters dopamine modulation of synaptic responses of neostriatal neurons in vitro.

Pemoline, a central stimulant, administered systemically at high doses (300 mg/kg) reliably produces self-biting behavior in rats. Pemoline-induced self-biting shares many similarities with self-injury seen in certain human disorders. Recent evidence has shown that alterations in neostriatal neurochemistry accompany the self-biting behavior seen in the rat. The present study used intracellular electrophysiological techniques to reveal changes in neostriatal cellular physiology in slices from rats which had displayed self-injury. Depolarizing postsynaptic potentials (DPSPs) were examined in neostriatal slices from rats that received pemoline and had been engaging in self-injurious behavior and from two control populations: rats that received the same concentration of pemoline and did not engage in self-biting, and rats that received vehicle alone (peanut oil). Data were acquired in standard artificial cerebral spinal fluid. DPSPs were evoked by cortical electrical stimulation in the slice. In neurons from rats that received the vehicle or that had received pemoline but had not engaged in self-injury, dopamine (DA, 20 microM) application produced a significant decrease in the size of the cortically evoked neostriatal DPSP. In contrast, DA application produced an increase in DPSP size in neurons from rats which had received pemoline and had engaged in self-injury. Bath application of a combination of D1 and D2 receptor agonists best replicated the enhancing effect of DA. Furthermore, the enhancement could be blocked by pretreatment with the competitive N-methyl-d-aspartate receptor antagonist, 2-amino-5-phosphonopentanoic acid. The results indicate that alterations in neostriatal DA-glutamate interactions accompany pemoline injections which produce self-injurious behavior.