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Biomedical subjects

R W Horton

Publications and source records attributed to R W Horton.

At least 55 records · Page 3Linked to original sources
PubMed1989

Beta-adrenoceptors in human brain labelled with [3H]dihydroalprenolol and [3H]CGP 12177.

beta-Adrenoceptor binding sites were characterised and quantitated in post-mortem human brain with [3H]dihydroalprenolol ([3H]DHA) and [3H]CGP 12177. In cerebral cortex, isoprenaline and propranolol displaced both radioligands with uniform affinity. Practolol and CGP 20712A (selective beta 1-adrenoceptor antagonists) displaced with high affinity from a greater proportion of sites than ICI 118,551 and IPS 339 (selective beta 2-adrenoceptor antagonists). In cerebellum, propranolol displaced both radioligands with uniform affinity. ICI 118,551 displaced with high affinity from a greater proportion of sites than CGP 20712A. The density of total beta-adrenoceptors (defined with isoprenaline) and of beta 1- and beta 2-adrenoceptors (defined with CGP 20712A and ICI 118,551 respectively) was studied by saturation binding of both radioligands in 13 brain areas. beta-Adrenoceptor density was higher in caudate, putamen and nucleus accumbens (100-120 fmol/mg protein) than cortex (50-70 fmol/mg protein) and densities were lowest in hypothalamus and cerebellum (27-38 fmol/mg protein). The proportion of beta 1-adrenoceptors (as a % of total beta-adrenoceptors) was high in caudate (80%), putamen (80%) and cortex (60-70%) and lower in hippocampus (40%) and cerebellum (30%). Both radioligands labelled a very similar number of beta-adrenoceptors in all brain regions studied.

Adrenergic beta-Antagonists↗
PubMed1989

5-HT2 receptor binding and 5-HT uptake in mouse brain: developmental changes and the relationship to audiogenic seizure susceptibility in DBA/2J mice.

Abnormal function of serotonergic neurones may be involved in the age-related susceptibility of DBA/2J mice to generalised convulsions induced by auditory stimulation. We have measured 5-HT2 receptor binding sites and synaptosomal 5-HT uptake in 5 brain regions of DBA/2J mice at ages before, during and after their maximal susceptibility to audiogenic seizures and in age-matched C57 B1/6 mice, a strain resistant to audiogenic seizures at all ages. The number of 5-HT2 binding sites was 20% higher in the cerebral cortex of DBA/2J than C57 B1/6 mice at the time of maximal susceptibility of DBA/2J mice to audiogenic seizures but did not differ at other ages. The number of 5-HT2 binding sites did not differ between the two strains at the ages studied in forebrain, mid-brain, hippocampus and pons-medulla. A marked reduction in the number of 5-HT2 binding sites was apparent in the mid-brain, hippocampus and pons-medulla of both strains of mice between 13-15 days of age and 21-23 days of age. Synaptosomal 5-HT uptake did not differ significantly between DBA/2J and C57 B1/6 in any of the brain regions at the ages studied. The higher density of cortical 5-HT2 binding sites in DBA/2J mice may contribute to their susceptibility to sound-induced seizures.

Acoustic Stimulation↗
PubMed1989

[3H]5-HT binding in post-mortem human cerebral cortex: methodological considerations.

The effects of different membrane preparations and assay conditions on [3H]5-HT binding to post-mortem human cortical tissue was studied. Optimal binding necessitated thorough removal of endogenous 5-HT and this was achieved either by hypotonic lysis or by preincubation of the membranes at 37 degrees C. Calcium chloride (4 mM) increased specific [3H]5-HT binding. The further addition of ascorbic acid (5.7 mM) or ascorbic acid and clorgyline (10 microM) reduced specific [3H]5-HT binding.

Adult↗
PubMed1989

[3H]5-hydroxytryptamine binding sites in postmortem human brain.

Binding sites for [3H]5-hydroxytryptamine (5-HT) in postmortem human frontal cortex, hippocampus and amygdala were studied by displacement with 5-HT selective drugs. The results demonstrated the selective labelling of 5-HT1-like sites by [3H]5-HT in the cortex, with little or no labelling of 5-HT2 or 5-HT3 sites. Self-displacement of the binding of [3H]5-HT is consistent with the presence of a single population of sites, indicating that 5-HT is non-selective for the 5-HT1 subtypes. Around 40% of the 5-HT1 sites in the frontal cortex and amygdala were of the 5-HT1A subtype, in contrast to 60% in the hippocampus. The drug RU 24969 consistently displaced with, a high affinity, a greater proportion of [3H]5-HT sites than did 8-OH-DPAT in all three regions of the brain. The nature of these additional sites was not established. A small proportion (less than 10%) of [3H]5-HT sites in the frontal cortex appeared to be of the 5-HT1C subtype, as these sites were displaced with high affinity by mianserin.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1989

3H-imipramine binding to freshly prepared platelet membranes in depression.

3H-Imipramine binding was measured in freshly prepared platelet membranes from 47 drug-free major depressives and 46 healthy controls. Where possible, platelet binding in depressed subjects was repeated following treatment. A significant negative correlation was found between Bmax and assay protein concentration and Bmax values were corrected for this effect. Adjusted Bmax was significantly lower (by 14%) in female depressed patients than in female control subjects, and the difference was of similar magnitude premenopausally and postmenopausally. No such difference was found in males. Kd did not differ significantly between depressed and control subjects. Multiple regression analysis confirmed significant effects on Bmax of presence of depressive illness, age (positive correlation), and season (higher in summer). Within the depressed sample, Bmax was significantly lower in those subjects with obsessional features. Endogenicity (Research Diagnostic Criteria or Newcastle), dexamethasone suppression test result, drug-free interval, family history of depression, depressive psychosis, suicidal ideation, and past history of suicide attempts were not significantly related to Bmax. Paired comparisons revealed no significant effect on Bmax of 6 weeks' treatment with imipramine, maprotiline, or BRL 14342 or of a course of electroconvulsive therapy.

Adult↗
PubMed1988

Brain GABAA/benzodiazepine binding sites and glutamic acid decarboxylase activity in depressed suicide victims.

We have investigated the involvement of gamma-aminobutyric acid (GABA) in depression by quantitating benzodiazepine (BZ) binding sites, the ability of GABA to stimulate BZ binding and glutamic acid decarboxylase activity in frontal and temporal cortex obtained at postmortem examination from 21 suicide victims and 21 age- and sex-matched controls. We limited our study to suicide victims with clear evidence of depression, in the absence of symptoms of other psychiatric disorders. Thirteen of the depressed suicide victims had not been prescribed psychoactive drugs recently and none were found in their blood at postmortem; of the remaining 8 suicides, 6 were receiving antidepressant drugs, alone or in combination with other drugs. The number of BZ binding sites was significantly greater (by 18%) in the frontal cortex of the total group of depressed suicides compared to controls, but did not differ in the temporal cortex. The increase in the number of BZ binding sites in the frontal cortex was of similar magnitude when drug-free (16%), drug-treated (21%) and antidepressant-treated suicides (16%) were compared to matched controls, although the increase was only statistically significant for the drug-treated suicides. The Kd of BZ binding and the ability of GABA to stimulate BZ binding did not differ significantly between controls and the total, drug-free, drug-treated or antidepressant-treated suicides in either cortical area. Glutamic acid decarboxylase activity did not differ significantly between control and suicide groups, but was markedly reduced in subjects dying by carbon monoxide poisoning. The present study provides evidence for a greater number of BZ binding sites in the frontal cortex of depressed suicide victims, which could not clearly be attributed to drug treatment.

Adult↗
PubMed1988

Brain 5-HT2 receptor binding sites in depressed suicide victims.

5-HT2 receptor binding sites were measured (by saturation binding of [3H]ketanserin) in brain tissue obtained at postmortem from 19 suicide victims with definite evidence of depression and 19 sex and age-matched control subjects. Five of the suicide victims were receiving antidepressant drugs prior to death; 13 suicide victims had not been prescribed antidepressant or other psychoactive drugs recently and none were found in their blood at postmortem. The number of serotonin-2 (5-HT2) binding sites in frontal, temporal and occipital cortex and amygdala did not differ significantly between the depressed suicide victims and controls, either in the total suicide group or in the antidepressant drug-free suicides. The number of 5-HT2 binding sites in the hippocampus did not differ from controls in the total suicide group but was significantly lower (by 23%) in the antidepressant-free suicide group. The affinity of [3H]ketanserin binding did not differ from controls in the antidepressant-free suicides but was lower (increased Kd) in those subjects receiving antidepressant drugs. No correlation was found between the time of death and storage of tissue or the duration of tissue storage prior to assay and the number or affinity of 5-HT2 binding sites. A significant negative correlation was found between age of the subject and the number of 5-HT2 binding sites in the frontal and occipital cortex. The present study of suicide victims with definite evidence of depression do not confirm previous studies of increased numbers of 5-HT2 binding sites in suicide victims and suggest that these previous findings may be related to factors other than depression.

Adolescent↗
PubMed1988

Opposing effects of activation of central GABAA and GABAB receptors on brown fat thermogenesis in the rat.

Baclofen (a GABAB agonist) stimulates body temperature, metabolic rate and brown adipose tissue (BAT) in the rat through a central action, but no effects of gamma-aminobutyric acid (GABA) itself on these parameters were observed. In the present study, it was found that the central effects of (+/-)baclofen (0.5-2.0 micrograms injection i.c.v.) on the temperature (1.2 degrees C increase) and metabolic rate (44-76% increase) of brown adipose tissue were inhibited by previous treatment with the GABAA agonist, muscimol (0.05 micrograms). Injection of GABA alone (12 micrograms) did not significantly affect these parameters, but in the presence of the GABAA antagonist bicuculline (2.5 micrograms), GABA significantly increased the temperature (0.3 degrees C) and oxygen consumption (22%) of brown fat. (-)Baclofen was found to be approximately 50-times more effective in stimulating the temperature of brown adipose tissue than (+/-)baclofen. The results indicate that activation of central GABAB receptors stimulates the activity and hence metabolic rate of brown adipose tissue. However, activation of the GABAA receptors opposes the effects of GABAB stimulation on the thermogenesis of brown fat.

Adipose Tissue, Brown↗
PubMed1988

Paradoxical enhancement of seizures in the gerbil after chronic treatment with sodium valproate.

Handling-induced seizures in male and female gerbils, at 1 year of age, were significantly increased following continuous administration of sodium valproate throughout postnatal life (600 mg/l in drinking fluid of gerbil dams and of the offspring after weaning; 82-111 mg/kg daily). The weight of the brain and gain in body weight of the valproate-treated gerbils were not significantly changed. Three components of the GABAA receptor complex were examined in cerebral cortical tissue from control gerbils and gerbils chronically treated with valproate. No significant differences were found in saturation binding of [35S]-t-butyl-bicyclophosphorothionate or [3H]flunitrazepam, or in the ability of GABA to stimulate the binding of [3H]flunitrazepam. Further studies of this enhancement of susceptibility to seizures are required since it may be of potential clinical relevance.

Animals↗
PubMed1988

Brain GABAB binding sites in depressed suicide victims.

Binding sites for gamma-aminobutyric acid, type B (GABAB), were measured in post-mortem brain samples (frontal cortex, temporal cortex, and hippocampus) from a group of suicide victims and a group of sex- and age-matched controls. Retrospective psychiatric diagnosis was performed, and only suicide victims with clear evidence of depression in the absence of symptoms of other psychiatric or neurological disorders were studied. There were no significant differences between depressed suicides and controls in the number or affinity of GABAB binding sites in the frontal or temporal cortex and no difference in GABAB binding (measured at two concentrations) in the hippocampus. Thirteen of the depressed suicides had not been prescribed antidepressant drugs recently, and none were found in their blood at postmortem. The number of GABAB binding sites in the frontal and temporal cortex and GABAB binding in the hippocampus did not differ significantly between these drug-free suicides and matched controls. The Kd was higher, however, in the temporal cortex of the drug-free suicides than in the controls. A significant negative correlation was found between age and the number of GABAB binding sites in the temporal cortex (on the basis of pooled data from suicides and controls). These results indicate that GABAB binding sites are unaltered in the brains of depressed suicide victims.

Adolescent↗
PubMed1988

Effects of chronic oral administration of the antidepressants, desmethylimipramine and zimelidine on rat cortical GABAB binding sites: a comparison with 5-HT2 binding site changes.

1. The effects of chronic oral administration of desmethylimipramine (DMI) or zimelidine (1.25 and 5 mg kg-1 twice daily for 21 days) were studied on rat whole cortical gamma-aminobutyric acidB (GABAB) binding sites. No changes in receptor affinity or number were found with either drug. 2. A subsequent study of GABAB binding sites using higher doses of these drugs (5 and 10 mg kg-1) and rat frontal cortex was also without effect, when investigated 24 h after termination of drug administration or 72 h after DMI administration (5 mg kg-1). 3. The number of frontal cortical 5-hydroxytryptamine2 (5-HT2) binding sites was significantly and dose-dependently decreased after both drugs, whereas the number of hippocampal 5-HT2 binding sites was not significantly altered after either drug. 4. As the number of frontal cortical GABAB binding sites was unaltered whereas the number of 5-HT2 binding sites was significantly decreased under identical study conditions, it may be concluded that the effects of antidepressant administration upon GABAB binding sites is a less consistent observation than their effects on 5-HT2 binding sites.

Animals↗
PubMed1988

The interaction of substituted benzamides with brain benzodiazepine binding sites in vitro.

1. The interaction of substituted benzamides with brain benzodiazepine (BDZ) binding sites was examined by their ability to displace [3H]-flunitrazepam ([3H]-FNM) from specific binding sites in bovine cortical membranes in vitro. 2. Clebopride, Delagrange 2674, Delagrange 2335 and BRL 20627 displayed concentration-dependent displacement of [3H]-FNM with IC50 values of 73 nM, 132 nM, 7.7 microM and 5.9 microM, respectively. Other substituted benzamides including metoclopramide, sulpiride, tiapride, sultopride and cisapride were inactive at 10(-5) M. 3. Inhibition by clebopride and Delagrange 2674 of [3H]-FNM binding was apparently competitive and readily reversible. 4. In the presence of gamma-aminobutyric acid (GABA), the ability of diazepam and Delagrange 2674 to displace [3H]-Ro 15-1788 binding was increased 3.6 and 1.6 fold respectively, compared to the absence of GABA, while ethyl beta-carboline-3-carboxylate (beta CCE) and clebopride were less potent in the presence of GABA. 5. Diazepam was 30 fold less potent at displacing [3H]-Ro 15-1788 in membranes that had been photoaffinity labelled with FNM than in control membranes, whereas the potency of beta CCE did not differ. Clebopride and Delagrange 2674 showed a less than two fold loss of potency in photoaffinity labelled membranes. 6. The pattern of binding of clebopride and Delagrange 2674 in these in vitro tests is similar to that found previously with partial agonists or antagonists at BDZ binding sites. 7. Clebopride and Delagrange 2674 inhibited [3H]-FNM binding with similar potency in rat cerebellar and hippocampal membranes, suggesting they have no selectivity for BDZ1 and BDZ2 binding sites. 8. Clebopride and Delagrange 2674 are structurally dissimilar to other BDZ ligands and represent another chemical structure to probe brain BDZ binding sites.

Affinity Labels↗
PubMed1987

Are increases in GABAB receptors consistent findings following chronic antidepressant administration?

Desmethylimipramine and zimelidine (10 mg/kg) were administered to rats once daily for 21 days. Chronic desmethylimipramine significantly reduced the number of 5HT2 binding sites in the frontal cortex but not hippocampus while chronic zimelidine did not affect 5HT2 binding in either brain region. The number and affinity of GABAB binding sites in the frontal cortex were unaltered by either drug.

Animals↗
PubMed1987

Alterations in cerebral glutamic acid decarboxylase and 3H-flunitrazepam binding during continuous treatment of rats for up to 1 year with haloperidol, sulpiride or clozapine.

Rats were treated continuously for 12 months with therapeutically equivalent doses of haloperidol (1.4-1.6 mg/kg/day), sulpiride (102-109 mg/kg/day) or clozapine (24-27 mg/kg/day) and examined for alterations in brain glutamic acid decarboxylase (GAD) and 3H-flunitrazepam binding. Administration of haloperidol, but not sulpiride or clozapine, for 6 or 12 months increased striatal GAD activity. None of the drug treatments altered nigral GAD activity when examined after 1, 3, 6, 9 or 12 months administration. The number of specific 3H-flunitrazepam binding sites (Bmax) in striatal membrane preparations were not altered by 12 months administration of haloperidol, sulpiride or clozapine. Surprisingly, Bmax for 3H-flunitrazepam binding to cerebellar membrane preparations was decreased by 12 months administration of all drug treatments. The dissociation constant (Kd) for 3H-flunitrazepam binding in striatal and cerebellar preparations was not altered. The ability of GABA (0.25-100 microM) alone, and in conjunction with sodium chloride (200 mM), to stimulate specific 3H-flunitrazepam binding in striatal and cerebellar preparations was unaltered by haloperidol, sulpiride or clozapine administration for 12 months. The selective effect of haloperidol, but not sulpiride or clozapine, treatment on striatal GAD activity parallels the ability of haloperidol, but not sulpiride or clozapine, to induce striatal dopamine receptor supersensitivity in the same animals. The actions of haloperidol may reflect its greater ability to induce tardive dyskinesia compared to sulpiride or clozapine.

Animals↗