[Neurobiology of attention deficit hyperactivity disorder]. / Neurobiologische Grundlagen der Aufmerksamkeitsdefizit-/Hyperaktivitätsstörung.

The origin of ADHD is multifactorial and both the aetiology and pathophysiology of ADHD are as yet incompletely understood. The monoamine deficit hypothesis of ADHD postulates a dysbalance in the interaction of the neurotransmitters dopamine, noradrenaline and serotonin. Pathophysiological mechanisms involved in ADHD include alterations in fronto-striatal circuits. The currently proposed animal models of ADHD are heterogeneous with regard to their pathophysiological alterations and their ability to mimic behavioural symptoms and to predict response to medication. Some evidence points to a genetic basis for ADHD which is likely to involve many genes of small individual effects. In summary, specific neurobiological substrates of ADHD are unknown and multiple genetic and environmental factors appear to act together to create a spectrum of neurobiological liability.

Effects of the noradrenergic neurotoxin DSP4 on spatial memory in the rat.

Patients with attention-deficit/hyperactivity disorder (ADHD) show various cognitive impairments such as deficits in attention or working memory. Most symptoms of ADHD are thought to be associated with a dysbalance between the neurotransmitters noradrenaline and dopamine in the brain. In order to investigate the role of noradrenaline in this context we have produced a central depletion of noradrenaline in rats by administering different doses (10, 20 or 50 mg/kg body weight) of the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) and assessing the behavioral consequences with a modified hole board task. The administration of DSP4 affected the working memory error, while reference memory and motor functions were not affected. The use of different doses of DSP4 to influence prefrontal functions and to understand the dysbalance of dopamine and noradrenaline in ADHD appears to be a promising approach.

The long-term effects of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) on cognitive performance in rats.

The neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) has been reported, both in vitro and in vivo models, to produce neurodegeneration and parkinsonian symptoms after prolonged exposure in rats. The aim of the present study was to investigate the effects of TaClo on the cognitive performance of rats. We used the COGITAT hole board system where rats can find hidden pellets by exploring the board. TaClo-treated rats found as many pellets as control rats treated with saline. Furthermore, their search was as efficient as that of control animals since there were no differences between the groups regarding explorative activity, visits to non-baited holes and time needed to find the pellets. These results suggest that there is no deficit in spatial memory following the chronic administration of TaClo to rats.

Attentional functioning in children with ADHD - predominantly hyperactive-impulsive type and children with ADHD - combined type.

Although particular importance has been attributed to attention deficits in attention deficit hyperactivity disorder (ADHD), there is no consensus as to the exact nature of inattention in ADHD or which components of attention are affected. The present study was based on a neuropsychological model of attention and assessed various components of attention in 23 children with ADHD/predominantly hyperactive-impulsive type (ADHD-H), 32 children with ADHD/combined type (ADHD-C) and healthy children (N(1) = 23 and N(2) = 32). A computerized test battery consisting of reaction time tasks of low complexity was used for the assessment of attention (alertness task, vigilance task, divided attention task, visual scanning task, incompatibility task, test of crossmodal integration, flexibility task). In comparison to healthy participants, patient groups were impaired in measures of vigilance, divided attention, selective attention and flexibility but not in measures of alertness. Analysis of the test performance of patient groups revealed no differences between children with ADHD-H and children with ADHD-C. The results of the present study suggest that both children with ADHD-H and children with ADHD-C are seriously impaired in attentional functioning. Children with ADHD-H and children with ADHD-C produced comparable results in measures of attention.

Cerebral oligemia and iron influence in cerebral structures--element of morbus parkinson models?

The consequences of short phases of restricted cerebral blood flow and iron enrichment of striatal tissues resulted in an animal model that could correspond to the basic features of a model for Parkinson's disease. An automatic and computerized hole-board offers simultaneous data on learning and cognitive memory capabilities, learning of distinct patterns of distributed food pellets found and eaten in a given time, switches between different locations of food in the holes and in different layout patterns. Wistar rats after 60 min of bilateral clamping of the carotid arteries (BCCA) under pentobarbital anesthesia received 1.5 microg FeCl3 injected one week after BCCA unilaterally into the ventrolateral striatum. The experiments showed that reduced cerebral blood flow and increased iron within the striatal tissue had the effect of retarding reactions. Rats after BCCA and iron need 180 s to find pellets deep inside holes that are distributed in a distinct pattern. During only 60 or 30s BCCA plus iron rats are no longer able to find the same number of pellets as over 180s. Rats after BCCA plus NaCl do not show such reduced success. These results point to the idea that cerebral oligemia and increased iron in the striatum stimulate the pathological symptoms of Parkinson's disease which need also more time to have reaction and success (see Fig. 5). The data covering abbreviated time-spans show how heavily the BCCA + Fe animals are dependent on longer times.

Consequences of a single short lasting cerebral oligemia and the influence of iron injected into the substantia nigra or in the ventrolateral striatum of the rat. Trigger of Parkinson's disease pathogenesis?

One BCCA-phase (bilateral clamping of carotid arteria) leads to an extensive release of striatal dopamine with a subsequent formation of free radicals (Heim et al., 200b). Early investigations did not show histological damage to cerebral structures after 24 and 60 min duration of a BCCA phase (Melzacka et al., 1994). The study here turned out that oligemic damage and an increase in iron (FeCl3) concentration in the ventral striatum was responsible for most of the defective performance of the animals investigated. Striatal damaged animals were unable to correct their deficient performance to the same extent as was possible for animals which had been damaged through BCCA and FeCl3 in the substantia nigra. Furthermore it turn out that with the use of a comprehensive behaviour profile which was able to gather 22 parameters simultaneously, 15 of these parameters did not correspond in the performance of the controls already after BCCA alone. Since during the ageing process, pathological effects may occur in vulnerable structures not only from disturbances to cerebral blood-perfusion but also from enrichment of iron in vulnerable structures (Connor, 1992) the question arose whether this situation did not reveal pathological mechanisms that might triggered the early symptoms of Parkinson's disease.

Removal of short-term isolation stress differentially influences prepulse inhibition in APO-SUS and APO-UNSUS rats.

Epidemiological studies have reported that the risk of developing schizophrenia increases with the number of genes one shares with patients suffering from schizophrenia [Gottesman Schizophrenia Genesis, New York: Freeman; 1991]. In addition, stressful life events are known to increase the risk of developing schizophrenia [Schizophr Res 30 (1998) 251] resulting in the stress hypothesis of schizophrenia. Remarkably, stress increases the release of dopamine and noradrenaline in the nucleus accumbens [Brain Res 554 (1991) 217], which links the stress hypothesis with the known dopamine hypothesis of schizophrenia. Additionally an increased dopamine transmission in the nucleus accumbens (Nacc) is known to disturb prepulse inhibition (ppi) [Pharmacol Biochem Behav 49 (1994) 155], a phenomenon observed in, among others, schizophrenics [Arch Gen Psychiatry 47 (1990) 181]. Some years ago we have genetically selected two rat-lines which are marked by a high (APO-SUS) and by a low (APO-UNSUS) apomorphine susceptibility. Similar to schizophrenics the APO-SUS rat-line shows a reduced ppi [J Neurosci 15 (1995) 7604]. However, these data were obtained after a period of mild stress, namely a 24-h period of social isolation. Mild stress changes the line specific differences of APO-SUS and APO-UNSUS rats. The stress pushes the APO-SUS rat in the direction of an APO-UNSUS and vice versa, especially as far as it concerns the dopamine and noradrenaline activity in the nucleus accumbens [Cools AR, van-den Bos R, Ellenbroek BA, Gaiting function of noradrenaline in the ventral striatum: its role in behavioural responses to environmental and pharmacological challenges. In: Willner P, Scheel-Kruger J, editors. The mesolimbic dopamine system: from motivation to action. New York: Wiley; 1991 [Chapter 6]; Cools AR, Rots NY, De-Kloet ER, Apomorphine-susceptible and apomorphine-unsusceptible Wistar rats: a new tool in the search for the function of striatum in switching behavioural strategies. In: Pea G (Ed.), The basal ganglia IV, New York: Plenum Press; 1994; Brain Res Bull 24 (1990) 49; Behav Neurosci 108 (1994) 1107]. Therefore, in the present paper we investigated the ppi response in non-stressed, i.e. non-isolated APO-SUS and APO-UNSUS rats. In agreement with this hypothesis, we found that removal of the stress led to an increase of ppi in the APO-SUS, but a decrease in the APO-UNSUS. These data clearly shows that the ppi is stress-dependent in APO-SUS and APO-UNSUS rats. It is suggested that the differential stress-induced change in the dopaminergic and the noradrenergic system influences the reaction of APO-SUS and APO-UNSUS rats on ppi.

Long-term behavioural effects of TaClo (1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline) after subchronic treatment in rats.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), which shows a great structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), when administered to rats lead to enhanced spontaneous locomotion when they were tested 4-9 days after subchronic injection at a daily dose of 0.2 mg/kg over a seven week period. However, 9 weeks after the end of the course of injections animals walked more slowly during 12 hours of nocturnal activity, and apomorphine-induced locomotion was decreased 12 weeks later. These results suggest that the drug may exert a progressive neurotoxic effect.