Biomedical subjects

P R Buckland

Publications and source records attributed to P R Buckland.

41 records · Page 3Linked to original sources

PubMed1982

Structure-function relations of the thyrotropin receptor.

The thyrotropin (thyroid-stimulating hormone or TSH) receptor is an amphiphilic membrane component with a relative molecular mass of about 200,000 as judged by gel filtration and an isoelectric point close to pH 5. Analyses with chemical, enzymic and affinity probes indicate that the receptor is a glycoprotein containing a disulphide bridge and that the integrity of the disulphide bond is essential for maintaining the structure of the TSH-binding site. Serum from patients with Graves' disease contains antibodies which inhibit the binding of TSH to its receptor and there is considerable evidence that this effect is due to a direct interaction between the antibodies and the receptor. The antibody-receptor interaction is probably responsible for the TSH agonist properties of Graves' serum and, similarly, the TSH antagonist properties of the sera from a small number of patients can be explained on the basis of antibody-receptor binding. Although TSH and IgG from Graves' disease patients appear to bind to the same receptor, the relationship between the sites for the two substances is not clearly understood. However, Fab fragments of Graves' IgG are as effective as intact IgG in competing with TSH for the receptor and gel filtration and immunoprecipitation studies indicate that the binding of hormone and antibody to the receptor is mutually exclusive. Current evidence suggests therefore that the binding sites for TSH and TSH receptor antibodies are very closely related and may well be identical.

Antibody Specificity↗

PubMedDate not supplied

Antipsychotic regulation of dopamine D1, D2 and D3 receptor mRNA.

A range of antipsychotic drugs, both "typical" and "atypical", was administered to rats over a time course and at several different dosages. The mRNA levels of dopamine D1, D2 and D3 receptor were measured in either whole brain or dissected brain regions. D3 receptor mRNA was up-regulated in whole brain by clozapine (10 and 30 but not 3 mg/kg/day), sulpiride (50 and 100 but not 20 mg/kg/day). haloperidol (3 but not 1 or 0.3 mg/kg/day), flupenthixol (3 but not 1 or 0.3 mg/kg/day), pimozide (4.5 but not 1.5 or 0.5 mg/kg/day) and loxapine (1.2 and 4 mg/kg/day but not 0.4 mg/kg/day). Sulpiride (100 mg/kg/day), clozapine (30 mg/kg/ day) and haloperidol (3 mg/kg/day) all up-regulated the D3 receptor mRNA in nucleus accumbens and olfactory tubercles but not striatum. D1 and D2 receptor mRNA was up-regulated in whole brain by haloperidol and loxapine only, and in the case of haloperidol this was localized to striatum and prefrontal cortex. Haloperidol, clozapine and sulpiride all down-regulated D1 mRNA in hippocampus and additionally haloperidol and sulpiride down-regulated it in the cerebellum. This work shows that all the drugs tested up-regulated D3 receptor, but effects on D1 and D2 receptors were less general.

Animals↗

PubMedDate not supplied

Rat liver tryptophan pyrrolase activity and gene expression during alcohol withdrawal.

Rat liver tryptophan (Trp) pyrrolase activity and gene expression were studied in relation to the alcohol-withdrawal syndrome (AWS). Both activity and gene expression were enhanced after withdrawal of ethanol-containing liquid diets and the time-course of these changes mirrored that of development and intensity of the behavioural disturbances of the AWS. By contrast, no correlation was observed between the AWS-induced behaviour and changes in activity of another hepatic glucocorticoid-inducible enzyme, tyrosine aminotransferase, and a negative correlation was noted between behaviour and the gene expression of this latter enzyme and also of that of the hepatic glucocorticoid receptor. We suggest that the metabolic consequences of activation of liver Trp pyrrolase during alcohol withdrawal may play a role in the behavioural features of the AWS.

Animals↗

PubMedDate not supplied

Genetic association studies of alcoholism--problems with the candidate gene approach.

In recent years, progress has been made in the identification of causative factors in most single gene disorders and those with genes of major effect. In comparison, no genes contributing to a complex disorder have been unambiguously identified. A number of reasons for this have been previously presented in theoretical papers. Alcoholism is such a complex illness and genetic studies into its underlying genetic causes have suffered from lack of power due to small subject numbers, poor selection of control subjects, and over-emphasis on markers with low prior probability of involvement.

Alcoholism↗

PubMedDate not supplied

Tryptophan metabolism in male Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats.

Parameters of tryptophan (Trp) and related metabolism were compared in male Sardinian alcohol-preferring (sP) and -non-preferring (sNP) rats. Liver Trp pyrrolase activity was 38-58% higher in sP than in sNP rats, and this was associated with a greater expression of the enzyme mRNA as measured by multiprobe oligonucleotide solution hybridization. Moderately (about 10-19%), but significantly, lower concentrations of free serum, total serum, and brain Trp were also observed in sP compared with sNP rats. Concentrations of whole brain 5-hydroxytryptamine (5-HT) and its major metabolite 5-hydroxyindol-3-yl-acetic acid (5-HIAA) were, however, 14-21% higher in sP rats. Serum corticosterone concentration was 18% higher in sP rats. We conclude that alcohol preference in Sardinian rats is associated with increased liver Trp pyrrolase activity and mRNA expression leading to a decrease in Trp availability to the brain. Although a simple serotonin deficiency could not be demonstrated in the whole brain, the possibility could not be ruled out that a deficiency may be present in discrete areas of the brain of the sP rat.

Alcoholism↗