Carole Czudek

Deficit and hemispheric asymmetry of GABA uptake sites in the hippocampus in schizophrenia

There is increasing evidence of a deficit or disturbance of neurons in the brains of schizophrenic patients--evidence that particularly implicates the frontal or temporal lobes. As yet there is no direct neurochemical correlate of the transmitter systems involved, although changes in some neurotransmitters in the temporal lobe have been reported. Radiolabeled nipecotic acid, a specific inhibitor of uptake sites to gamma-aminobutyric acid (GABA), has provided a marker of GABAergic neurons. The binding of this ligand to brain tissue taken at autopsy has demonstrated a decreased density of GABA uptake sites in the hippocampus in schizophrenia. This decrease was found to correlate in the left hemisphere with increased concentration of dopamine in the amygdala, providing a link between neuropathology, evidence of laterality, and the dopamine hypothesis of the disease.

Dopamine deficits in the brain : the neurochemical basis of parkinsonian symptoms in AIDS

We sought to determine whether the motor dysfunctions and neuroleptic sensitivity that can occur in patients with AIDS relates to a deficit of striatal dopamine innervation similar to that of Parkinsons disease. For this purpose we measured concentrations of dopamine and its major metabolite homovanillic acid (HVA) in caudate nucleus tissue taken post-mortem from patients with AIDS and from appropriate age-matched control subjects. Dopamine and HVA concentrations were both significantly reduced in the AIDS group, with 20 of 34 patients exhibiting dopamine concentrations below the control range. This finding is consistent with a loss of nigrostriatal dopaminergic neurones, and may underlie the motor dysfunction and neuroleptic sensitivity that can occur in AIDS patients, indicating the potential value of antiparkinsonian therapy in such patients.

Alzheimer-like neurotransmitter deficits in adult Down's syndrome brain tissue.

Brain tissue taken at necropsy from five cases of Downs syndrome and six controls was analysed for changes in neurotransmitter markers. Concentrations of noradrenaline (NA), dopamine (DA) and its major metabolite homovanillic acid (HVA), 5-hydroxytryptamine (5HT) and its metabolite 5-hydroxyindoleacetic acid (5HIAA) were determined by means of HPLC, whilst choline acetyltransferase (ChAT) was measured by a radiochemical technique. Significant reductions in NA, 5HT and ChAT were found in most cortical and subcortical regions of the Downs syndrome tissue investigated. The neuropathological lesions were assessed using a fluorescent stain for neuritic plaques and neurofibrillary tangles. These were present to varying extents in every Downs syndrome case except the youngest but were not found in control tissue of comparable age. The results indicate profound transmitter deficits and neuropathological abnormalities in adult patients with Downs syndrome, which closely resemble those of Alzheimers disease.

Serotonin concentrations and turnover in brains of depressed suicides

5-Hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) concentrations and 5-HT turnover (5-HIAA/5-HT) were determined in 6 brain regions from 19 suicide victims in whom a retrospective diagnosis of depression was established, and 19 age- and sex-matched control subjects. Thirteen of the suicides were free of psychoactive drugs at the time of death; 5 were receiving antidepressant drugs. 5-HT, 5-HIAA and 5-HT turnover did not differ significantly between the total, drug-free and antidepressant-treated suicides and controls in frontal and temporal cortex, caudate and hippocampus. 5-HIAA concentration was significantly higher in amygdala of drug-free suicides than controls, whereas 5-HT and 5-HT turnover did not differ. 5-HT concentration was significantly lower in putamen of the total and antidepressant-treated suicides and a similar reduction was also apparent in the drug-free suicides. 5-HT turnover in putamen was significantly higher in the total and drug-free suicides compared to controls. 5-HT and 5-HIAA concentrations in putamen were significantly lower in drug-free suicides who died by non-violent means than in those who died by violent means. Differences between controls and suicides could not be attributed to age, sex or postmortem delay. These results offer no support for the view that 5-HT turnover is reduced in depressed subjects who commit suicide.

New Approaches to the Drug Treatment of Schizophrenia

Publisher Summary This chapter attempts to cover the major approaches to drug development for the treatment of schizophrenia. In doing so, the chapter describes the pharmacological rationale for these approaches and, where possible, relates this to the understanding of the neuronal basis that is still very limited, of the disease. At present, it is apparent that undesirable motor or other side effects are not required correlates of antipsychotic action and in fact may reduce the acceptability of treatment and hence patient compliance. This provides a rationale for the identification of improved antipsychotic drugs. Two further limitations of current drug treatment of schizophrenia have expanded the search for more specific and more effective antipsychotics. Concurrent with ongoing pharmacological research, recent work is beginning to shed light on the abnormalities that are present in the brain in schizophrenia. The application of quantitative histopathological techniques and the development of methods for brain imaging have provided evidence for a neuropathology of schizophrenia, while postmortem neurochemical studies have also indicated the involvement of neurotransmitter systems in this pathology. Although these findings have already provided pointers toward potential antipsychotic mechanisms, there is still a way to go before psychopharmacological research draws substantially from such pathological studies. It is evident that in many cases the development of antipsychotic drugs still relies on heuristic observation, with the essential mechanisms of action remaining obscure. Nevertheless, the chapter indicates that pharmacological research is coming closer to defining those mechanisms.

Electrochemical detection of human brain transmitter amino acids by high-performance liquid chromatography of stable o-phthalaldehyde-sulphite derivatives.

A simple, sensitive, reliable and reproducible isocratic HPLC technique for the measurement of OPA/sulphite derivatives of human brain amino acid neurotransmitters is described. This employs a sample preparation that is also compatible with the concurrent determination of monoamines and their metabolites on a separate HPLC system. The method has been applied to the determination of GABA and glutamate in brain tissue taken post-mortem from patients with Huntingtons disease and control subjects.

[3H] GBR 12935 binding to the dopamine uptake site in post-mortem brain tissue in schizophrenia

Specific [3H] GBR 12935 binding was performed on striatal tissue (caudate nucleus) obtained post-mortem from brains of schizophrenic patients and matched controls. Scatchard analysis of left and right hemisphere caudate tissue was performed on each individual subject. Kd and Bmax values were obtained by linear regression analysis of Scatchard plots. The results indicated no change in either the density or the affinity of the dopamine uptake site between schizophrenics and controls. Comparison of left and right hemisphere data also failed to demonstrate any asymmetry in the populations of dopamine uptake sites in both groups studied. The results do not support the hypothesis of a functional alteration of presynaptic dopamine systems in the caudate nucleus in schizophrenia.

[3H]Nipecotic Acid Binding to γ-Aminobutyric Acid Uptake Sites in Postmortem Human Brain

Abstract: Binding of [3H]nipecotic acid, a proposed marker for GABAergic neurons, was investigated in postmortem human brain by use of a centrifugation assay. Binding was displaceable, apparently saturable, and to a single site, with typical KD and Bmax values of 1.85 μM and 124.2 pmol/mg of protein in the hippocampus. Regional distribution studies indicated a heterogeneous population of [3H]nipecotic acid binding sites with highest concentrations in the lateral globus pallidus. Putamen tissue from four cases of Huntingtons disease showed a marked reduction in [3H]nipecotic acid binding. Binding correlated with both age and postmortem delay in the hippocampus. There was an effect of agonal state in which prolonged illness before death apparently caused a reduction in binding. Our results indicate that [3H]nipecotic acid may be used successfully as a marker for neuronal GABAergic uptake sites in human brain, but that the effects of variables such as age, postmortem delay, and agonal state must always be taken into account.

Maintenance of cortical somatostatin and monoamine levels in the rat does not require intact cholinergic innervation

Levels of somatostatin, noradrenaline, dopamine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were unchanged in rat neocortex 3 or 6 months after ibotenic acid lesion of the ipsilateral nucleus basalis that reduced cortical choline acetyltransferase levels by over 60%. These results render unlikely the possibility that non-cholinergic neurotransmitter deficits in Alzheimers disease cortex are the consequence of cholinergic degeneration.

Common profile of D1 receptor antagonists and atypical antipstchotic drugs revealed by analysis of dopamine turnover

1. Selective antagonists of dopamine D1 and D2 receptors enhanced 3-methoxytyramine (3-MT) accumulation in the striata and accumbens of tranylcypromine pretreated rats. Selective D1 and D2 agonists produced opposite effects. The smaller changes produced by the D1 agonists and antagonists were probably mediated by neuronal feedback, whereas the larger effects produced by the D2 ligands predominantly reflected pharmacological actions at prejunctional dopaminergic autoreceptors. 2. Atypical antipsychotics evoked small increases in 3-MT similar to the effects of the selective D1 inhibitors, whereas the mixed D1/D2 antagonists mimicked the selective D2 inhibitors by inducing much larger elevations in 3-MT. 3. gamma-Butyrolactone, an inhibitor of dopaminergic neuronal firing, dose-dependently decreased 3-MT accumulation in both the striata and accumbens. 4. gamma-Butyrolactone pretreatment abolished the small increases in 3-MT induced by the selective D1 antagonists and the atypical antipsychotics and also the large increases produced by the mixed D1/D2 antagonists. By contrast, gamma-butyrolactone only partially reversed the marked elevation of 3-MT evoked by the selective D2 antagonists. 5. The above data suggest that in vivo the atypical antipsychotics behave predominantly as selective D1 antagonists.