The relation between motor activity and [3H]uridine uptake in the mouse brain.

Using microautoradiography ex vivo we tested the effect of forced running on a roller drum for 3 h on the nuclear incorporation of [5-(3)H uridine] in mouse brain. Specific neuron types with increased nuclear labelling included primary motor cortex layer 5 nerve cells with nuclei greater than 12 microm (+38%) and large neuron nuclei in putamen (+58%). Mice running for 45 min do not show any change in the labelling of nerve cell nuclei compared with mice moving freely in the cage. The [(3)H]uridine uptake in other cell types, e.g. other neurons in cortical layer 5, neurons in sensory cortex and in the other cell layers in motor cortex, were not different from control mice. We conclude that RNA synthesis is normally low in adult mouse brain, but that physical exercise stimulates RNA synthesis in specific populations of large neurons in the motor system.

New diagnostic vistas.

There are many difficulties in establishing criteria for better drug compliance and improved quality assurance in the treatment of schizophrenic patients. The most serious problem (especially with first episodes) is that of diagnosis. Since no biological markers for schizophrenia have been found the clinician is referred to "symptom collecting"--including collecting social data. In spite of many attempts there is still no general agreement of the concept of schizophrenia. This deplorable fact is reflected in the everchanging subdivisions of the schizophrenias over the decades: from a division of acute and chronic dementia praecox via a classification of simple, hebephrenic, catatonic, paranoid forms, on to new classifications based on positive/negative manifestations, divisions of type I/type II forms etc. The many different rating scales are reflections of the same problem, as are the different diagnostic systems (e.g. DSM-III and ICD-10). The recent attempts to make a synthesis of these systems seem promising but raise new problems related to etiological and pathogenetic views of psychiatric disorders.

Neuronal uridine metabolism.

Uridine and other nucleic acids form part of RNA, DNA, coenzymes, second messengers, etc. Uridine uptake in nerve cells is an expression of neuronal RNA synthesis. More knowledge of uridine functions in neurones may give a better understanding of mechanisms underlying dementia, and they could be useful in treating brain tumors. Pakkenberg and co-workers have studied the uridine uptake in the brains of mice and monkeys under various conditions (after hypoxia, after carbon-dioxide treatment, after MPTP treatment, after electrostimulation, etc.) and the results are correlated with other biological brain parameters.

The effect of MPTP on uridine uptake in murine nerve cells.

Sixty, 3-month-old, male Theiler mice were injected with 1 mg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) each i.p. Six groups of 5 animals each were then injected with 0.25 mCi [5-H3]uridine i.v. at intervals of 6h, 1,2,5,7 and 9 weeks after MPTP injection and each group was killed 1 h after uridine injection. Microautoradiograms were performed and the grain number determined in nerve cell nuclei in the striatum, substantia nigra and cerebral cortex. An initial increase in uridine uptake was found in substantia nigra, followed by a decrease during the following 9 weeks. A decrease in uptake occurred in the striatum from weeks 5-9, but without any initial increase. An increase in uptake was observed in the cortex 2 weeks after MPTP injection. Thus, in mice, a single injection of MPTP has a significantly prolonged effect upon the basic metabolic process (RNA synthesis) in substantia nigra and striatum. Selegiline, which causes a significant decrease in uridine uptake, also protects nerve cells from the effect of MPTP. The amount of dopamine in striatum and substantia nigra following MPTP did not change significantly during the 9 weeks. However, the amount of dihydroxyphenylalanine (DOPA) increased in both these areas during this period.

Clinical features and long-term treatment with pimozide in 65 patients with Gilles de la Tourette's syndrome.

During the last seven years 65 patients with Gilles de la Tourette's syndrome have been treated. Pimozide was used as the preferred drug because of our experience of treating other hyperkinesias which indicated fewer side-effects than with haloperidol. Of the 65 patients with Gilles de la Tourette's syndrome, 59 were treated with pimozide alone or in combination with tetrabenazine or clonidine. The dose ranges of pimozide were 0.5-9 mg per day. Eighty-one percent experienced a good clinical response without side-effects. The side-effects seen in our patients were sedation, gain in weight, depression, pseudoparkinsonism and akathisia; acute dystonic reactions, blurred vision, slurred speech and xerostomia did not occur. No cases of tardive dyskinesia were seen.

Enkephalin analogue in schizophrenia. Double blind cross-over trial.

In a double blind, cross-over study 10 chronic schizophrenic patients with productive symptoms in spite of neuroleptic treatment received the methionine-enkephalin analogue FK 33-824 2 mg i.m. daily for 7 consecutive days. Ratings performed by the Brief Psychiatric Rating Scale did not show any significant differences between FK 33-824 and the active placebo pentobarbital. The clinical condition of one patient worsened during and after the administration of FK 33-824. It is suggested that this might be due to a dopamine stimulating effect. The discrepancy between the findings of the present and a previous open study is discussed. The present study does not support the hypothesis of dysfunction of the endorphin system in schizophrenia.

Neuropharmacology of tics.

In pharmacological treatment of Gilles de la Tourette's syndrome neuroleptic (antipsychotic) drugs have been the most effective. This has led to the hypothesis of a relative dopaminergic overactivity in the brain. Animal studies with neuroleptic drugs different in their affinity to different dopamine areas as well as studies with drugs different in their selectivity to different receptors have, however, not shown direct correlations to the clinical response in the treatment of hyperkinetic syndromes. There is a trend that drugs with high affinity to striatal D2-receptors might be the most potent. Other attempts to change brain dopamine in different ways using cholinergic, GABAergic, and peptidergic drugs have given rather poor clinical results. The apparent importance of brain dopamine in a whole range of neuropsychiatric diseases may be due to the central role of basal dopaminergic areas as a relay station for a lot of neuronal pathways.

Effect of electrical convulsions on uridine labeling and activity pattern in nerve cells in mice.

Male white mice were exposed to electroshock and then injected intravenously with 5-[3H]uridine immediately after the shock. After 5, 30, or 60 min or 6, 12, or 24 h, the mice were killed, microautoradiographs were prepared, and grains were counted in the cortex, hippocampus, and basal ganglia. The results of the grain counts were compared with grain counts in the cortex, hippocampus, and basal ganglia of mice exposed to anoxia for 25 s and then treated in the same manner as the first groups. After electroshock the grain count decreased to 25% of that in control animals in the hippocampus and to 50% in the cortex but was normal in the basal ganglia. The counts returned to normal values within 6 h in the hippocampus, and within 1 h in the cortex. After anoxia, the grain counts were normal in the cortex and hippocampus but increased in the basal ganglia. The distribution of cells with a high or low grain count in vertical and horizontal columns of the cortex in control and convulsion animals was analyzed. There were random variations from column to column in both control and convulsion animals. In some anatomic layers there were significantly different grain counts, indicating differences in functional activity.

Tolerability and therapeutic effect of clozapine. A retrospective investigation of 216 patients treated with clozapine for up to 12 years.

Two hundred and sixteen psychiatric patients (183 men and 33 women) hospitalized in Sct. Hans Hospital were treated with clozapine between 1971-1983. All had been treated previously with one or more neuroleptic(s) and had either failed to respond adequately, or their response was limited by side effects. Eighty-five patients were treated exclusively with clozapine, while the remaining 131 received additional medication, mainly other neuroleptic drugs. The mean clozapine dosage was 317 mg/day (range 50-1200), and the mean duration of treatment was 23/4 years (range 1/12-12). The tolerability to clozapine was determined by an evaluation of haematological changes, pronounced side effects and mortality. One patient treated with clozapine (8 months) and nitrofurantoin (8 days) developed a reversible granulocytopenia. One patient (treated with a combination of drugs) had clinically insignificant depression of the leucocytes and three of segmented granulocytes. Seven had a reduction in thrombocytes. Two patients developed cardiac insufficiency, and four epileptic seizures. None of the patients treated exclusively with clozapine developed neurological side effects. A global estimation of therapeutic effect revealed that clozapine alone or in combination with other neuroleptic drugs was significantly better than previous antipsychotic therapy, although 47-63% of the patients showed no change. It is concluded that clozapine is a potent antipsychotic drug offering particular advantages in the treatment of schizophrenic patients with a pronounced symptomatology and tendency towards developing extrapyramidal side effects. Caution is advised in patients with cardiac insufficiency and epilepsy. There appears to be a slight risk of granulocytopenia, and therefore the present monitoring of WBC should continue in order to prevent this reaction and to obtain more complete information regarding risk of granulocytopenia.

The effect of dopamine antagonists in spontaneous and tardive dyskinesia.

Dopamine antagonists are effective in suppressing hyperkinetic symptoms in patients with tardive dyskinesia, spontaneous oral dyskinesia, Huntington's chorea, and Gilles de la Tourette's syndrome. These neuroleptics have no curative effect upon the conditions and may even aggravate symptoms in the long term. In many cases a single neuroleptic drug may lose its effect. A more lasting effect may be obtained by combining drugs with pre- and postsynaptic antidopamine effects.

Mitotic activity in the mouse brain after cortical and striatal lesions.

Following a stab wound in the brain, mice were injected with 3H-thymidine intravenously 15 min before sacrifice. In a first series, the cells in the synthesis phase (S-cells) in the stab canal, in the adjacent areas and in the rest of the section were counted. The animals were sacrificed from 15 min to 3 days after the stab wound. An increased number of S-cells in all 3 regions was found after 2 days. 24 hr later the number of S-cells was back to normal. In another series, a guide cannula was fixed to the skull resulting in a small superficial lesion of the cortex. 2 days later a stab wound in the hemisphere was made through the guide cannula using the above-mentioned technique. The animals were injected with 3H-thymidine as above and sacrificed from 30 min to 6 days after the stab wound. In this series an increased number of S-cells was found in the whole brain 1/2 hr after the last lesion and an increased number of S-cells was found throughout the whole investigation period. The reason for this general induction is not known. In animals without a stab wound, no induction was found outside the cortical lesion.