Self-injurious behavior produced in rats by daily caffeine and continuous amphetamine

Self-biting (SB) is an unusual behavioral effect of high doses of certain amphetamine-like drugs in rats. This bizarre behavior has received little attention, perhaps because the high doses of drug required and the dramatic disturbance of the animals' behavioral repertoire have raised the possibility that SB is a high dose phenomenon. However, we have found that continuous administration of very low amounts of amphetamine reliably produces SB in rats, and that this behavioral change can be very selective. We compared SB produced by continuous amphetamine to SB produced by daily caffeine; the latter has been proposed as an animal model for self-injurious behavior (SIB) in the Lesch-Nyhan syndrome. Subcutaneous silicone pellets containing amphetamine base were implanted for 4.5 days; caffeine was administered daily for 10 days. The amphetamine pellets produced the highest rate of SB (75% vs 40%) with the least toxic effects (no deaths vs three deaths). Neither drug produced stereotypy. The dopamine antagonist haloperidol was only marginally effective in controlling SB produced by daily caffeine but the dopamine antagonist pimozide (which has a longer duration of action) prevented SB by amphetamine pellet rats. Continuous release amphetamine pellets may provide an alternative to the caffeine model of SIB in humans, particularly for the Lesch-Nyhan syndrome.     

Self-injurious behaviour in autistic children: a neuro-developmental theory of social and environmental isolation

Rationale

Self-injurious behaviour is not one of the three core symptoms that define autism. However, children on the autism spectrum appear to be particularly vulnerable. Afflicted children typically slap their faces, punch or bang their heads, and bite or pinch themselves. These behaviours can be extremely destructive, and they interfere with normal social and educational activities. However, the neurobiological mechanisms that confer vulnerability in children with autism have not been adequately described.

Objectives

This review explores behavioural and neurobiological characteristics of children with autism that may be relevant for an increased understanding of their vulnerability for self-injurious behaviour.

Methods

Behavioural characteristics that are co-morbid for self-injurious behaviour in children with autism are examined. In addition, the contributions of social and environmental deprivation in self-injurious institutionalized orphans, isolated rhesus macaques, and additional animal models are reviewed.

Results

There is extensive evidence that social and environmental deprivation promotes self-injurious behaviour in both humans (including children with autism) and animal models. Moreover, there are multiple lines of convergent neuroanatomical, neurophysiological, and neurochemical data that draw parallels between self-injurious children with autism and environmentally deprived humans and animals.

Conclusions

A hypothesis is presented that describes how the core symptoms of autism make these children particularly vulnerable for self-injurious behaviour. Relevant neurodevelopmental pathology is described in cortical, limbic, and basal ganglia brain regions, and additional research is suggested.     

Infravesical outflow obstruction in rats: a comparison of two models

1. A new model of infravesical outflow obstruction was developed in male rats by the repeated s.c. administration of testosterone for 5-15 days (3 mg/kg die). The effects of this treatment which produced a 65% increase of prostate weight (10 days) on bladder voiding was evaluated in urethane anesthetized rats by the transvesical infusion of saline and compared to the cystometric alterations produced by application of a silk ligature at urethral level in female rats (4-8 weeks before) as described by Malmgren et al. (1987a, b). 2. Testosterone-pretreatment for 10 days produced little changes in bladder weight, bladder capacity or amplitude of micturition contraction but determined a marked increase in residual volume, indicating that infravesical outflow obstruction impaired significantly bladder voiding. Furthermore, detrusor instability was observed in the majority of testosterone-treated rats. 3. The participation of an active component to voiding impairment in testosterone-treated rats was suggested by the effect of intravenous prazosin which improved voiding efficiency. 4. In urethra-ligated female rats there was a marked increase in bladder weight which was paralleled by a dramatic alteration in micturition reflex that is marked increase in bladder capacity and residual volume. 5. It is concluded that these two models of infravesical outflow obstruction produce cystometric patterns simulating the urodynamic alterations observed in patients with benign prostatic hyperplasia and are potentially suitable for development of drugs in this field.     

Activity and learning in rats after magnesium pemoline

Summary Manesium pemoline enhances the learning of a conditioned avoidance response in rats. 24 hours later this enhancing effect is no longer significant. With the same doses, magnesium pemoline induces a marked hyperactivity. In an experimental situation of simple visual discrimination magnesium pemoline does not alter the performance of the animals but seems to bring about an abnormal fixation of certain types of behaviour.     

Repeated pemoline produces self-injurious behavior in adult and weanling rats

Self-injurious behavior (SIB) is a serious problem among the mentally handicapped and is often accompanied by other repetitive or stereotyped behaviors. Acute administration of high doses of amphetamine or pemoline to rats produces transient SIB which is accompanied by severe deterioration of the behavioral repertoire. Repeated subcutaneous (SC) administration of pemoline to rats produces a high incidence of SIB without the dramatic behavioral changes produced by high doses of oral pemoline. Repeated pemoline increased locomotions and rears and produced intermittent stereotyped sniffing and licking/biting. However, the animals were still able to eat, drink, sleep and groom. Hotplate tests provided no evidence for analgesia. Because SIB is often associated with human developmental disorders, the effects of repeated SC administration of pemoline to weanling rats was also investigated. SC injections every 12 hours produced a high rate of SIB in weanling rats.     

Pharmacologic control of pemoline induced self-injurious behavior in rats

Administration of oral Pemoline produces long lasting amphetamine-type stereotyped behavior and persistent self-biting behavior in rats. The effects of haloperidol, pimozide, diazepam, and serotonin depletion by pretreatment with p-chlorophenylalanine (PCPA) or chronic pretreatment with p-chloroamphetamine (PCA) on abnormal behavior produced by pemoline were studied. Diazepam consistently increased the duration of stereotyped behavior. It also reduced licking/biting and self-biting but the latter effects were not consistent. Pretreatment with PCA had negligible effects on stereotyped behavior. Pretreatment with PCPA dramatically increased locomotion and rearing without affecting the other components of stereotypy--stereotyped head movements, licking/biting, and self-biting. Haloperidol (0.2 and 0.3 mg/kg) produced a dose related normalization of pemoline induced behaviors, including elimination of self-biting. Pimozide (0.5, 0.8 and 1.3 mg/kg) had little or no effect on behaviors such as locomotions, rears, licking/biting, or stereotyped head movements but eliminated self-biting at 1.3 mg/kg. These data suggest that pemoline, like amphetamine, produces stereotyped behavior through central dopaminergic mechanisms. Dopaminergic mechanisms also appear to be involved in pemoline induced self-biting. pemoline is apparently pharmacologically and behaviorally very similar to amphetamine. Pemoline may provide a useful animal model for syndromes characterized by self-injurious behavior and other repetitive behaviors.     

Hippocampal injections of magnesium pemoline and the extinction of a bar press response in rats

Stainless steel cannulae were implanted in the medial hippocampus of 24 rats. The subjects were then trained to press a bar for milk reinforcement. After a fixed amount of training the animals were divided into four groups. A control group received injections of Holman's ringer (via the cannulae) while each of three experimental groups received a different dose of magnesium pemoline. The animals then performed an additional number of bar presses. Twenty-four hours later the time and number of bar presses to an extinction criterion were measured. The low and medium drug-dose group exhibited increased resistance to extinction. The results were discussed with regard to the effect magnesium pemoline has on performance variables and RNA synthesis.This work was supported by Australian Research Grants Committee and Sigma Xi funds to Dr. J. C. Saunders. The authors gratefully acknowledge the assistance of Mr. G. R. Bock and Mrs. J. Sack and thank Abbott Laboratories for supplying the drug.     

不同方法构建大鼠实验性牙周炎模型的研究

目的建立实验性牙周炎动物模型,为研究不同时期、不同程度牙周炎发生、发展及治疗提供依据。方法采用200～250gWistar大鼠,丝线或正畸结扎丝结扎大鼠上颌第一磨牙,分别于2、4、6周取材观察其病理学变化。结果与对照组相比正畸结扎丝组大鼠在临床及病理组织学方面均出现不同程度牙龈出血、牙周袋形成、牙槽骨吸收的牙周炎表现;丝线结扎组观察期内丝线大部分脱落,未诱导出牙周炎表现。结论正畸结扎丝法成功建立大鼠牙周炎动物模型,能模拟临床牙周炎的自然发生过程,可以研究牙周病不同程度的病理变化。     

Gestational caffeine modifies offspring behaviour in mice

Dams from two strains of mice, BALB/c and C57BR were treated during gestation with caffeine, at doses of about 60, 80 and 100 mg/kg/day, in their drinking water. The resulting offspring were behaviourally tested over a 6-month period commencing at age 9 months. When compared with controls, mice from dams that had received caffeine demonstrated longer latencies in a passive avoidance test, and differences were also noted for female C57BR offspring in activity and habituation measures. Having controlled as far as possible for post-natal maternal and environmental effects, the most likely conclusion is that caffeine has a direct pharmacological action on the foetus, and should therefore be classed as a behavioural teratogen in mice.     

The effects of caffeine in the social interaction test and on exploration in rats: comparison with ethanol and clorazepate

The effects of caffeine (20mg/kg) in the holeboard and social interaction tests were compared with those of ethanol (0.4g and dipotassium clorazepate (3mg/kg), following acute administration in one group of rats or after five daily injections in another group. The rats were put in pairs into an unfamiliar arena with high levels of illumination (n = 80), or tested individually in the holeboard (n = 80). Acute caffeine produced no effect on the time spent in social interaction, although it enhanced the number of social contacts, and both genital and total sniffing. Following five injections, caffeine also increased the time spent in social interaction. Acute clorazepate enhanced this time but this effect showed partial tolerance after five injections. Clorazepate also enhanced the number and duration of social contacts, increasing social grooming and genital sniffing, regardless of the duration of the treatment. Ethanol increased the time spent in social interaction following five injections, and increased social grooming. In the holeboard, stimulant effects were observed for caffeine and clorazepate, showing partial tolerance and without any effect on head dipping. In the social interaction test, only a stimulant effect for caffeine was obtained. The results of this study suggest that, under some circumstances, caffeine may enhance social interaction, in a manner similar to standard anxiolytics. Such an effect is potentiated by repeated administration.     

Behavioral interaction between cocaine and caffeine: a drug discrimination analysis in rats

The effects of caffeine upon the discriminative and rate-altering effects of cocaine were examined in rats. Using a food-reinforced two-lever operant procedure, 12 Sprague-Dawley male rats were trained to discriminate between 10 mg/kg cocaine and saline. Stimulus generalization tests with both cocaine and amphetamine resulted in a dose-related increase in cocaine-appropriate responding. A variable response rate topography was produced by cocaine. Caffeine also engendered a dose-related increase in cocaine-appropriate responding and resulted in a potency ratio of 15:1 when compared to cocaine. In contrast, increasing doses of caffeine produced a biphasic response rate function (first increases and then decreases). Response choice data suggested a potency relationship of amphetamine greater than cocaine greater than caffeine. Caffeine potentiated the discriminative stimulus properties of cocaine. Isobolographic analysis characterized this interaction as simple additivity. However, caffeine's effects upon the rate-altering effects of cocaine resulted in a biphasic interaction pattern. With low doses of cocaine in combination with various doses of caffeine, the interaction for rate reduction is best categorized as "supra-additive," in contrast, increasing either the cocaine dose or caffeine dose could change the interaction to simple additivity and/or infra-additivity.     

Self-injurious behavior in rats produced by intranigral microinjection of GABA agonists

Bilateral injection of the GABA agonist muscimol (10–300 ng) into the caudal substantia nigra (pars reticulata) of rats produced dose-dependent stereotyped gnawing and self-biting. Limiting the opportunity to graw on inanimate objects shifted the dose-response curve for muscimol-induced self-injurious behavior (SIB) to the left and increased the maximum incidence of SIB. Microinjection of muscimol (30 ng) into the rostral and caudal regions of the substantia nigra were equally effective in producing SIB, though the incidence of SIB decreased sharply when muscimol was injected 1 mm rostral or caudal to the substantia nigra. Bilateral intranigral injection of THIP (100–1000 ng) and (±)baclofen (100–1000 ng) induced a low incidence of SIB. However, neither IP administration of picrotoxin (5 mg/kg) or simultaneous microinjection of (+)bicuculline methiodide (BMI; 300 or 1000 ng) along with muscimol (30 ng) blocked muscimol-induced SIB. In fact, (+)BMI increased the occurrence of self-biting and reduced the latency to onset of SIB. The involvement of GABAergic mechanisms in muscimol-induced SIB is discussed.     

Self-injurious behaviour, traumatic life events and alexithymia among treatment-seeking opiate addicts: prevalence, pattern and correlates

Objective

Aim of this study was to determine the prevalence and pattern of self-injurious behaviour (SIB) and identify the predictors of SIB among treatment-seeking opiate addicts.

Methods

Participants were 80 consecutively consenting opiate addicts admitted into community and inpatient treatment programmes of a large South London National Health Service (NHS) Mental Health Trust. Substance dependence was diagnosed with ICD-10. The following instruments were administered: self-injurious behaviour questionnaire, traumatic life events questionnaire, Toronto alexithymia scale and substance abuse assessment questionnaire.

Results

Lifetime SIB prevalence rate was 49% (95% CI = 37–60). There was no difference in lifetime SIB rates of male (50%) and female (46%) patients. The predominate function of SIB among opiate addicts was affect-regulation followed by self-punishment. Using a logistic regression, sexual harassment and difficulty identifying feelings were the only independent significant predictors of SIB, with the influence of age of first traumatic event and gender partialled out.

Conclusion

Given these findings, there is strong evidence to suggest that treatment of opiate addiction should involve routine screening for adult sexual trauma, deficits in emotional regulation and SIB. Where these problems are identified, appropriate psychological intervention should be integral to routine care for affected patients.     

Ethological comparison of the effects of a bovine alpha s1-casein tryptic hydrolysate and diazepam on the behaviour of rats in two models of anxiety

A bovine alpha s1-casein tryptic hydrolysate was previously demonstrated to display an anxiolytic-like activity in the conditioned defensive burying and in the elevated plus-maze models when i.p. injected. The present study assessed the anxiolytic-like effects of this tryptic hydrolysate after an oral administration in rats faced to the same behavioural situations using diazepam as a reference. In a first experiment, the behavioural effects of the hydrolysate in the conditioned defensive burying test were investigated at doses ranging 5-50 mg/kg. The results showed that the minimal dose required to elicit an anxiolytic-like activity is 15 mg/kg. In a second experiment, the alpha s1-casein tryptic hydrolysate (15 mg/kg, p.o.) was demonstrated to display an anxiolytic-like activity similar to diazepam (3 mg/kg, p.o.) in the conditioned defensive burying test and the elevated plus-maze. However, the ethological analysis of behaviour indicated that this hydrolysate has a different activity compared to diazepam. While diazepam induced a disinhibition state in rats, possibly related to the risk-taking behaviour observed after a benzodiazepine ingestion in humans, the tryptic hydrolysate did not display such a side effect. These results suggest that the mechanism of action of the bovine alpha s1-casein tryptic hydrolysate may differ from that of diazepam.     

Relationship between rotational behaviour induced by apomorphine and caffeine in rats with unilateral lesion of the nigrostriatal pathway

The contralateral rotational behaviour produced by apomorphine and caffeine has been studied in 100 rats with unilateral lesion of the nigrostriatal pathway induced with 6-OHDA. Rats with a two-peak rotational pattern induced by apomorphine, showed a greater number of contralateral turns, induced by apomorphine and caffeine, than rats which did not show this rotational pattern. A correlation was observed between the number of rotations induced by apomorphine and those induced by caffeine. A relationship between the two-peak rotational pattern induced by apomorphine and the initial-peak pattern induced by caffeine was also observed.     

Dose-dependent kinetics of caffeine in rats

Caffeine was administered orally to male rats at 3 different doses (1, 10, 100 mg/kg). Plasma and brain concentrations were measured and kinetic parameters calculated. Ratios between doses were much lower than between areas under the curve in plasma as well as in brain. Brain:plasma ratios changed with the dose. Dose-dependent kinetics of caffeine in elimination and absorption is apparent.     

Lipopolysaccharide-induced sickness behaviour evaluated in different models of anxiety and innate fear in rats

The fact that there is a complex and bidirectional communication between the immune and nervous systems has been well demonstrated. Lipopolysaccharide (LPS), a component of gram-negative bacteria, is widely used to systematically stimulate the immune system and generate profound physiological and behavioural changes, also known as 'sickness behaviour' (e.g. anhedonia, lethargy, loss of appetite, anxiety, sleepiness). Different ethological tools have been used to analyse the behavioural modifications induced by LPS; however, many researchers analysed only individual tests, a single LPS dose or a unique ethological parameter, thus leading to disagreements regarding the data. In the present study, we investigated the effects of different doses of LPS (10, 50, 200 and 500 μg/kg, i.p.) in young male Wistar rats (weighing 180-200 g; 8-9 weeks old) on the ethological and spatiotemporal parameters of the elevated plus maze, light-dark box, elevated T maze, open-field tests and emission of ultrasound vocalizations. There was a dose-dependent increase in anxiety-like behaviours caused by LPS, forming an inverted U curve peaked at LPS 200 μg/kg dose. However, these anxiety-like behaviours were detected only by complementary ethological analysis (stretching, grooming, immobility responses and alarm calls), and these reactions seem to be a very sensitive tool in assessing the first signs of sickness behaviour. In summary, the present work clearly showed that there are resting and alertness reactions induced by opposite neuroimmune mechanisms (neuroimmune bias) that could lead to anxiety behaviours, suggesting that misunderstanding data could occur when only few ethological variables or single doses of LPS are analysed. Finally, it is hypothesized that this bias is an evolutionary tool that increases animals' security while the body recovers from a systemic infection.     

A comparison of the effects of caffeine following abstinence and normal caffeine use

Rationale  

Caffeine typically produces positive effects on mood and performance. However, tolerance may develop following habitual use, and abrupt cessation can result in withdrawal symptoms, such as fatigue. This study investigated whether caffeine has a greater stimulant effect in a withdrawn state compared to a normal caffeinated state, among moderate daily caffeine consumers.