Effects of atomoxetine on attention in Wistar rats treated with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4).

The aim of the present study was to assess the effects of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4), which allows a depletion of noradrenergic terminals in a dose-dependent manner, on attention in rats as measured using the five-choice serial-reaction time task (5CSRTT). In addition, we investigated whether the effects of DSP4 treatment can be reversed by atomoxetine. Atomoxetine is a selective noradrenaline reuptake inhibitor and has been shown to be effective in the treatment of attention deficit hyperactivity disorder. Wistar rats were trained in the 5CSRTT and treated with one of the three doses of DSP4 (10, 20 or 50 mg/kg) or saline. Following DSP4 treatment, rats were injected with three doses of atomoxetine (0.1, 0.5 or 1 mg/kg) or saline and tested in the 5CSRTT. The treatment with DSP4 caused a reduction in activity and a decline of performance in parameters related to attention in the 5CSRTT. Whether or not these impairments are due to attention deficits or changes in explorative behaviour and activity remains to be investigated. The treatment with atomoxetine had no beneficial effect on the rats' performance regardless of the DSP4 treatment. The present findings support the role of noradrenaline in modulating attentional processes and call for future studies regarding the effects of atomoxetine on attention in rats.

Effects of methylphenidate on attention in Wistar rats treated with the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4).

The aim of this study was to assess the effects of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) on attention in rats as measured using the 5-choice-serial-reaction-time task (5CSRTT) and to investigate whether methylphenidate has effects on DSP4-treated rats. Methylphenidate is a noradrenaline and dopamine reuptake inhibitor and commonly used in the pharmacological treatment of individuals with attention deficit/hyperactivity disorder (ADHD). Wistar rats were trained in the 5CSRTT and treated with one of three doses of DSP4 or saline. Following the DSP4 treatment rats were injected with three doses of methylphenidate or saline and again tested in the 5CSRTT. The treatment with DSP4 caused a significant decline of performance in the number of correct responses and a decrease in response accuracy. A reduction in activity could also be observed. Whether or not the cognitive impairments are due to attention deficits or changes in explorative behaviour or activity remains to be investigated. The treatment with methylphenidate had no beneficial effect on the rats' performance regardless of the DSP4 treatment. In the group without DSP4 treatment, methylphenidate led to a reduction in response accuracy and bidirectional effects in regard to parameters related to attention. These findings support the role of noradrenaline in modulating attention and call for further investigations concerning the effects of methylphenidate on attentional processes in rats.

The effects of nutritional polyunsaturated fatty acids on locomotor activity in spontaneously hypertensive rats.

The present study investigated the effects of nutritional omega-3 polyunsaturated fatty acids on locomotor activity in spontaneously hypertensive rats (SHRs), which are used as an animal model of attention-deficit/hyperactivity disorder (ADHD). For 6 weeks, two groups of randomly assigned SHRs received food either enriched with or deficient in omega-3 fatty acids (based on the American Institute of Nutrition-93 G/AIN93G). Using an open field, locomotor activity was subsequently assessed for 6 days. A marked difference in locomotor activity as assessed by the distance travelled in the open field was found between the two groups of rats. In comparison with rats fed with omega-3 fatty acid-enriched food, the animals on the omega-3 fatty acid-deficient diet showed a significantly higher locomotor activity. The present findings demonstrated that nutritional enrichment with omega-3 fatty acids was associated with reduced motor activity in an established animal model of ADHD and support the notion that omega-3 polyunsaturated fatty acids may play a role in the pathophysiology of ADHD.

Spatial memory in spontaneously hypertensive rats (SHR).

The spontaneously hypertensive rat (SHR) is an established animal model of ADHD. It has been suggested that ADHD symptoms arise from deficits in executive functions such as working memory, attentional control and decision making. Both ADHD patients and SHRs show deficits in spatial working memory. However, the data on spatial working memory deficits in SHRs are not consistent. It has been suggested that the reported cognitive deficits of SHRs may be related to the SHRs' locomotor activity. We have used a holeboard (COGITAT) to study both cognition and activity in order to evaluate the influence of the activity on the cognitive performance of SHRs. In comparison to Wistar-Kyoto (WKY) rats, SHRs did not have any impairment in spatial working memory and reference memory. When the rats' locomotor activity was taken into account, the SHRs' working memory and reference memory were significantly better than in WKY rats. The locomotor activity appears to be a confounding factor in spatial memory tasks and should therefore be controlled for in future studies. In the SHR model of ADHD, we were unable to demonstrate an impairment of working memory which has been reported in patients with ADHD.

The effects of the neurotoxin DSP4 on spatial learning and memory in Wistar rats.

The aim of the present study was to investigate the effect of DSP4-induced noradrenaline depletion on learning and memory in a spatial memory paradigm (holeboard). Since Harro et al. Brain Res 976:209-216 (2003) have demonstrated that short-term effects of DSP4 administration include both noradrenaline depletion and changes in dopamine and its metabolites-with the latter vanishing within 4 weeks after the neurotoxic lesion-the behavioural effects observed immediately after DSP4 administration cannot solely be related to noradrenaline. In the present study, spatial learning, reference memory and working memory were therefore assessed 5-10 weeks after DSP4 administration. Our results suggest that the administration of DSP4 did not lead to changes in spatial learning and memory when behavioural assessment was performed after a minimum of 5 weeks following DSP4. This lack of changes in spatial behaviour suggests that the role of noradrenaline regarding these functions may be limited. Future studies will therefore have to take into account the time-course of neurotransmitter alterations and behavioural changes following DSP4 administration.

Effects of DSP4 and methylphenidate on spatial memory performance in rats.

In this experiment, we have investigated the spatial memory performance of rats following a central noradrenaline depletion induced by three different doses of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and following administration of three different doses of methylphenidate (MPH). The rats were required to find food pellets hidden on a holeboard. The sole administration of DSP4 induced only minor cognitive deficits. However, the treatment with MPH increased the reference memory error, the impulsivity and the motor activity of the DSP4-treated rats. Since the noradrenergic terminals in a DSP4-treated rat are significantly reduced, the administration of MPH has little effect on the noradrenergic system and increases dopaminergic rather than noradrenergic activity, resulting in an imbalance with relatively high dopaminergic and low noradrenergic activities. It is suggested that a reduction of noradrenaline and an increase of dopamine induce ADHD-related deficits and that the depletion of noradrenaline is not sufficient for an appropriate rat model of ADHD.

The COGITAT holeboard system as a valuable tool to assess learning, memory and activity in mice.

The comprehensive and stress-free assessment of various aspects of learning and memory is a prerequisite to evaluate mouse models for neuropsychiatric disorders such as Alzheimer's disease or attention deficit/hyperactivity disorder (ADHD). COGITAT is an automated holeboard system allowing simultaneous assessment of spatial working and reference-memory performance which we have adapted in this study to enable its usage with mice. The holeboard apparatus consists of an open-field chamber with a 25-hole floor insert, each hole being monitored by infrared light beams, located on three different levels, allowing the distinction between visits of holes, i.e. the animal reaches the bottom of the hole, or inspections, which means only superficial exploration of the hole. Across trials, animals learn a pattern of five baited holes. Here, we show that C57BL/6 mice readily acquire this task within 5 days when submitted to six trials per day. A number of individual parameters - overall exploratory activity, number of visits into or inspections of holes, number of baited, unbaited, or previously baited holes visited or inspected, reinspections of or revisits into any holes, number of pellets eaten, time to find pellets, and reference and working memory errors-are obtained simultaneously and results are immediately available after the end of each experiment. The muscarinic antagonist scopolamine impaired task performance, while the cognitive enhancer metrifonate (an acetylcholinesterase inhibitor) reduced error rates. Overall, our data indicate that this spatial learning task will be useful to characterize spatial memory in various genetic or pharmacological mouse models.

Differential effects of methylphenidate on problem solving in adults with ADHD.

OBJECTIVE: Two studies were performed to assess both divergent and convergent thinking in adults with ADHD. METHOD: The first study compared the problem-solving abilities of healthy participants (N = 144) and unmedicated adults with ADHD (N = 144). In the second study, problem-solving abilities of adults with diagnosed ADHD (N = 22) were examined twice, that is, on and off methylphenidate (MPH), and compared with the performance of a healthy control group (N = 22). Convergent thinking was measured using a Tower of London task, whereas divergent thinking was assessed using verbal fluency tasks. RESULTS: Adults with ADHD off MPH displayed marked deficits of both divergent and convergent thinking. MPH treatment resulted in a marked improvement of convergent thinking, while no effect of medication was found regarding divergent thinking. CONCLUSION: Pharmacological treatment of adults with ADHD revealed a differential effect of MPH on problem solving abilities.

Detrimental effects of gum chewing on vigilance in children with attention deficit hyperactivity disorder.

Impairments of attention are cardinal features of attention deficit hyperactivity disorder (ADHD) and can seriously affect the daily life of children with ADHD. Despite effective treatment strategies, there is a need of further treatment options that can be added to available and well established treatments. Further treatment options are needed since available treatments are often time consuming, expensive and limited regarding their external validity. Recent research demonstrated that gum chewing has beneficial effects on cognition including certain aspects of attention. Therefore, gum chewing may benefit children with ADHD in situations requiring particular cognitive efforts. In a crossover study, attentional functioning of 32 children with ADHD and 32 children without the condition was examined. All participants were assessed with chewing gum and without chewing gum. A computerized test was used for the assessment of vigilance and sustained attention. The findings of the present study suggest that gum chewing during task execution has detrimental effects on vigilance of both healthy children and children with ADHD. Sustained attention was not affected by gum chewing. Chewing gum, therefore, appears not to improve attentional performance in children with ADHD.

Genetics of early-onset obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is characterized by recurrent, intrusive and disturbing thoughts as well as by repetitive stereotypic behaviors. Epidemiological data are similar in children and adults, i.e., between 1 and 3% of the general population suffer from OCD. Children with OCD are often seriously impaired in their development. OCD, especially of early onset, has been shown to be familial. Several candidate genes of predominantly neurotransmitter systems have been analyzed and a total of three genome-wide linkage scans have been performed until now. Analyses of candidate genes in linkage regions have not provided evidence for their involvement in OCD, with the exception of the glutamate transporter gene SLC1A1 on 9p24. Genome-wide association analyses are in progress and the results will promote further independent replication studies. The consideration of subtypes regarding age of onset, symptom dimensions and/or comorbid disorders is needed.

Animal models of attention deficit/hyperactivity disorder (ADHD): a critical review.

Attention deficit/hyperactivity disorder (ADHD) involves clinically heterogeneous problems including attention deficits, behavioural hyperactivity and impulsivity. Several animal models of ADHD have been proposed, ranging from models with neurotoxic lesions to genetically manipulated animals. An ADHD model is supposed to show phenomenological similarities with the disorder, i.e. it should mimic the three core symptoms (face validity). A model should also conform to an established or hypothesized pathophysiological basis of the disorder (construct validity). Finally, an animal model should be able to predict previously unknown aspects of the neurobiology of ADHD or to provide potential new treatments (predictive validity). The currently proposed models are heterogeneous with regard to their pathophysiological alterations and their ability to mimic behavioural symptoms and to predict response to medication. This might reflect the heterogeneous nature of ADHD. Since the knowledge about the biology of ADHD from human studies is limited, one cannot at present decide which model best represents ADHD or certain ADHD subtypes. Animal models with good face and predictive validity may be useful for investigations of the underlying biological substrates of ADHD. At present, the models in use should be described as animal models of ADHD-like symptoms rather than models of ADHD.

Alterations of nocturnal activity in rats following subchronic oral administration of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) is neurotoxic when administered to the brain and alters motor behaviour following intraperitoneal administration. We have assessed the long-term effects of oral TaClo administration on nocturnal motor behaviour in rats. Two groups of rats received TaClo orally at a dose of either 0.2 or 0.4 mg/kg twice daily for 7 weeks. The control group was given saline. No change in locomotor activity was observed 4-9 days after the end of the 7-week administration of TaClo. In addition, the spontaneous motor activity was altered dose-dependently 9 months after oral TaClo administration, with an increase in the low-dose TaClo group and a decrease in the high-dose group. Oral administration of TaClo in rats may be useful in investigating the hypothesis that in Parkinson's disease, an unknown pathogenic factor crossing the intestinal mucosa barrier can induce neurodegenerative processes eventually affecting the entire brain.

Vigilance and sustained attention in children and adults with ADHD.

OBJECTIVE: The present article tests the hypothesis of a sustained attention deficit in children and adults suffering from ADHD. METHOD: Vigilance and sustained attention of 52 children with ADHD and 38 adults with ADHD were assessed using a computerized vigilance task. Furthermore, the attentional performance of healthy children (N = 52) and healthy adults (N = 38) was examined. RESULTS: Children and adults with ADHD performed significantly less well in the vigilance task than healthy participants (main effect for group). Furthermore, children and adults showed a significant decrease of performance over time (time-on-task effects). However, there was no greater decrement of performance with the passage of time in patient groups than in control groups (group-by-time interaction). CONCLUSION: The present results do not support the hypothesis of a sustained attention deficit in children and adults with ADHD.

Detection of malingered attention deficit hyperactivity disorder.

The aim of the present study was to determine whether malingering of adult attention deficit hyperactivity disorder (ADHD) can be detected using a self-report rating scale. A sample of 78 university students was allocated to three different conditions. The conditions were (a) a control group, (b) a naïve simulation group and (c) a coached simulation group. Furthermore, 12 adult students with a diagnosed ADHD participated in the present study. Participants were administered the Brown Attention Deficit Disorder Scale for Adults. While the control group and the patient group were asked to complete the scale with accuracy, the simulation groups were requested to feign an ADHD. Statistical analysis revealed that both simulation groups were able to successfully feign an ADHD. The results indicate that self-report rating measures are not sensitive enough to allow the detection of feigned ADHD.

The effect of caffeine on handwriting movements in skilled writers.

In laboratory tasks, caffeine has been shown to improve psychomotor performance. The aim of the present experiment was to assess the effects of caffeine on a skilled everyday life task in habitual caffeine consumers. The assessment of handwriting movements of 20 adults was performed following the administration of 0mg/kg (placebo), 1.5mg/kg, 3.0mg/kg or 4.5mg/kg of caffeine. A digitising tablet was used for the assessment of fine motor movements. Participants were asked to perform a simple writing task. Kinematic analysis of handwriting movements showed that, in comparison to placebo administration, high doses of caffeine (i.e., 4.5mg/kg) can produce improvements in handwriting as indicated by more fluent handwriting movements as well as an increase in maximum velocity and maximum positive and negative accelerations. The results suggest that higher doses of caffeine can enhance psychomotor performance.