Biomedical subjects
F Owen
Publications and source records attributed to F Owen.
Dopamine receptor changes in schizophrenia in relation to the disease process and movement disorder.
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Behavioural and biochemical effects of chronic amphetamine treatment in the vervet monkey.
Five vervet monkeys were administered increasing doses (4--12 mg/kg/day) of d-amphetamine over a period of 35 days. Three phases od behavioural change were discerned: phase 1 during which animals exhibited repetitive stereotyped action sequences with rapid head movements, occasional abnormal grooming, picking at the cage, hand-staring and snatching; phase 2 in which behaviour became progressively more restricted and animals became markedly unresponsive to auditory, visual and tactile stimuli; phase 3 was characterised by the abrupt development of gross over-responsiveness to environmental stimuli, ataxia and tremor. At post-mortem, by comparison with controls, amphetamine-treated monkeys showed marked depletions of the monoamines dopamine (DA), noradrenaline (NA) and serotonin (5-HT) in corpus striatum and cerebral cortex and reductions in the activities of tyrosine hydroxylase and dopa decarboxylase in striatum. Turnover of these monoamines, assessed by high-performance liquid chromatography determinations of their respective metabolites, was also reduced. These findings are interpreted as evidence of monoamine neurone destruction, most severely in the case of DA neurones. Though there was a non-significant reduction in 3H-spiperone binding (reaching almost 50% in nucleus accumbens), numbers of receptors for the monoamines nA and 5-HT were not significantly changed, and the activities of the enzymes choline acetyltransferase and glutamine decarboxylase were similar in experimental and control animals. The contrast of these findings with those seen in post-mortem brains in schizophrenia is discussed.
Abnormal involuntary movements in schizophrenia: are they related to the disease process or its treatment? Are they associated with changes in dopamine receptors?
Abnormal involuntary movements indistinguishable from those now described as tardive dyskinesia were reported in schizophrenic patients by Kraepelin long before the introduction of neuroleptic drugs. Two large surveys of mental hospital patients including patients who had never received neuroleptics also revealed involuntary movements; indeed, the incidence was not substantially different from that in drug-treated patients. This fact casts doubt on the widely held assumption that these movements are persistent and irreversible effects of neuroleptic drugs. In an animal model of dyskinesia, abnormal movements were seen after administration of a phenothiazine and a thioxanthene but not after haloperidol. The syndrome appeared to be unrelated to dopamine receptor blockade or to changes in dopamine receptors. In postmortem striatal tissue from patients with schizophrenia, ligand binding to D-1 and D-2 dopamine receptors was not increased in patients who had been found to have abnormal involuntary movements in comparison with those who did not have such movements; as previously reported, binding to D-2 receptors was increased in patients with schizophrenia in comparison with controls. It is concluded that dyskinetic changes occur as a consequence of the process of schizophrenia and perhaps other diseases. Whether or not persistent and irreversible changes can be caused either in animals or humans by neuroleptic administration has yet to be clearly established. Whether they occur as a manifestation of the disease process or a consequence of drug administration, such dyskinesias are unassociated with changes in D-1 or D-2 receptors.
Studies on possible mechanisms of action of electroconvulsive therapy; effects of repeated electrically induced seizures on rat brain receptors for monoamines and other neurotransmitters.
There is evidence that repeated electroconvulsive shocks (ECS) in rats potentiate dopamine (DA)-, serotonin (5HT)- and alpha-noradrenergic (alpha-NA)-mediated drug-induced behaviour and reduce opiate-induced behaviours. These studies suggest changes at the level of the receptor or beyond. However, high affinity in vitro 3H-ligand binding studies in brain membranes from ECS-treated control rats failed to demonstrate generalized ECS-induced changes in 5HT, DA, alpha-NA or opiate receptor binding. Binding of the beta-receptor ligand dihydroalprenolol (3H-DHA) was significantly reduced in ECS-treated rat brain membranes. This may be secondary to effects on NA neurones since ECS-induced reduction of 3H-DHA binding did not occur in animals with 6-hydroxydopamine-induced depletion of cortical noradrenaline. In conjunction with other studies, the results suggest that electroconvulsive therapy may have a noradrenergic mechanism of action.
Effect of chronic amphetamine administration on central dopaminergic mechanisms in the vervet.
A biochemical study of central dopaminergic mechanisms was carried out in brain tissue from vervet monkeys who had been subjected to chronic amphetamine administration. The brain concentrations of dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) were markedly reduced. Significant reductions were also observed in the activities of dopa-decarboxylase (DDC) and tyrosine hydroxylase (TH). A kinetic study of TH revealed a 60% reduction in maximum reaction velocity, consistent with destruction of DA neurones. However, homovanillic acid (HVA) concentrations were only moderately reduced, suggesting a nearly normal production of DA. Hence despite the large depletions in DA concentrations, high affinity binding of 3H-spiperone binding to striatal DA receptors was no different from controls. The results are discussed in relation to the amphetamine psychosis in humans.
The relationships between clinical response, psychophysiological variables and plasma levels of amitriptyline and diazepam in neurotic outpatients.
In a 4 week study of the response of neurotic outpatients to treatment with amitriptyline, diazepam, amitriptyline and diazepam, or placebo clinical and psychophysiological variables and plasma levels of the drug were assessed. Clinical improvements were substantial in all treatment groups but clear relationships between clinical change, psychophysiological change and plasma levels of the drugs were not established. There was no relationship between plasma levels of the drugs and cigarette smoking. It is concluded that neither plasma levels of amitriptyline and diazepam nor change in skin conductance responsivity offer a useful guide to clinical response to drug treatment.
3H-Flupenthixol binding in post-mortem brains of schizophrenics: evidence for a selective increase in dopamine D2 receptors.
The binding of 3H-cis flupenthixol (3H-FPT) to dopamine receptors in membrane preparations from control subjects and schizophrenics was studied. Using a fixed concentration of 3H-FPT, no differences were observed between controls and all schizophrenics, although 3H-FPT binding was increased in schizophrenics who apparently were drug-free at the time of death. Scatchard analysis of 3H-FPT binding revealed that in drug-treated schizophrenics both the number of binding sites (BM) and the dissociation constant (KD) were increased, whilst in drug-free schizophrenics only the BM was increased. Using domperidone to differentiate 3H-FPT binding to D1 and D2 dopamine sites, it was found that only D2 sites were increased in drug-free schizophrenics. The results are discussed with reference to previous studies on dopamine receptors in schizophrenia, and the effects of neuroleptic treatment. It is suggested that a selective increase in D2 receptors may be associated with the disease process in schizophrenia.
Neurotransmitter receptors in brain in schizophrenia.
The binding of the dopamine agonist ADTN and of ligands for the serotonin, muscarinic cholinergic, GABA, and benzodiazepine receptors was studied in 18 schizophrenic and 19 control brains. By contrast with the previously reported increase in binding of the dopamine antagonist spiperone, ADTN binding was not increased, and there was no consistent change in binding of ligands for receptors of substances other than dopamine. The findings suggest that the increase in dopamine receptors (assessed by spiperone binding) in schizophrenia is related to the disease process rather than to previous neuroleptic medication, and may be limited to the type of dopamine receptors that bind butyrophenones.
Platelet monoamine oxidase activity in acute schizophrenia: relationship to symptomatology and neuroleptic medication.
Platelet MAO activity was assessed in 35 schizophrenics during a trial of the isomers of flupenthixol. Enzyme activity was unrelated to severity of symptoms, the presence of delusions, hallucinations or thought disorder or to negative symptoms. In a few patients MAO activity fluctuated widely with time, but in the group of patients on medication there was a slow decrease in enzyme activity which was significant after 28 days of treatment. Enzyme activity after 14 days' drug treatment was still correlated with activity before treatment, but after 28 days this significant correlation disappeared. Slow effects of neuroleptic drugs on platelet MAO activity may explain previous findings of reduced activity of the enzyme in schizophrenia.
Angiotensin-converting enzyme in substantia nigra of schizophrenics.
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Characteristics of 3H-cis-flupenthixol binding to calf brain membranes.
The binding of 3H-cis flupenthixol (3H-FPT) to calf brain membranes was investigated in vitro. Highest levels of 3H-FPT binding were observed in striatum and nucleus accumbens, whilst no significant binding was observed in pituitary. The potencies of neuroleptics, dopaminergic ergot alkaloids and dopamine (DA) agonists in inhibiting 3H-FPT binding to calf striatal membranes were compared with their potencies in inhibiting 3H-spiperone (3H-SPIP) binding and DA-stimulated adenylate cyclase (AC). A high correlation was observed between drug potencies in inhibiting 3H-FPT binding and DA stimulated AC. However, potencies of the drugs inhibiting 3H-SPIP binding were only weakly correlated with their potencies in inhibiting either 3H-FPT binding or DA stimulated AC. A detailed analysis of the inhibition of 3H-FPT binding by butyrophenones revealed two classes of 3H-FPT binding sites. It is suggested that 3H-FPT binds predominantly to a class of dopaminergic sites associated with DA-stimulated AC.
Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months haloperidol administration.
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Raised monoamine oxidase in acute psychosis?
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Time course of the antipsychotic effect in schizophrenia and some changes in postmortem brain and their relation to neuroleptic medication.
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Functional distinction between DA-stimulated adenylate cyclase and 3H-spiperone binding sites in rat striatum.
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Change in the charactertistics of 3H-spiperone binding to rat striatal membranes after acute chlorpromazine administration: effects of buffer washing of membranes.
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A radioreceptor assay for diazepam and its metabolites in serum.
A radioreceptor method is described for the estimation of serum concentrations of diazepam and its metabolites. The technique is simple, rapid and suitable for batch analysis. Ad advantage of the technique is that it gives a measure of the total pharmacological activity of the serum samples towards the benzodiazepine receptor and is thus directly applicable to benzodiazepines other than diazepam. The results obtained by the radioreceptor assay and by a GLC technique are correlated.