PubMed Health⌕ Search

Biomedical subjects

R W Horton

Publications and source records attributed to R W Horton.

At least 73 records · Page 4Linked to original sources
PubMed1987

Platelet alpha 2-adrenoceptor binding and function during the menstrual cycle.

Blood platelet receptors are widely used as peripheral models of central nervous system receptors, particularly in attempts to understand the biological basis of a number of neurological and psychiatric disorders. It is important to differentiate factors other than the primary disease process which may influence platelet receptors. One such potential factor is the menstrual cycle. In this study we have determined platelet high-affinity alpha 2-adrenoceptor binding, using the agonist ligand 3H-UK-14,304 and platelet aggregatory responses to adrenaline in 14 healthy young women, sampled on four occasions at weekly intervals. Our results indicate that, within the limits of individual variation, neither the KD or Bmax of high-affinity 3H-UK-14,304 binding or the aggregatory responses to adrenaline differed significantly between various stages of the menstrual cycle.

Adolescent↗
PubMed1987

Synaptosomal high-affinity noradrenaline uptake does not differ between mice susceptible (DBA/2J) and resistant (C57 BL/6) to audiogenic seizures.

Abnormalities in noradrenaline-mediated neurotransmission have been advocated as a basis of the age-related susceptibility of DBA/2J mice to generalised convulsions induced by auditory stimulation. We have measured the kinetics of synaptosomal high-affinity noradrenaline uptake in 5 brain regions of DBA/2J mice at ages before, during and after their maximal susceptibility to audiogenic seizures, and age-matched C57 BL/6 mice, a strain resistant to audiogenic seizures at all ages. No differences were found between the two strains of mice in any of the brain regions studied. Abnormalities of high-affinity noradrenaline uptake do not contribute to audiogenic seizure susceptibility of DBA/2J mice.

Acoustic Stimulation↗
PubMed1987

Alpha 2-adrenoceptors in depression.

Studies of the mode of action of antidepressant treatments and the biological basis of depression have recently concentrated on monoamine neurotransmitter receptors. This paper reviews the studies relating to alpha 2-adrenoceptors. Chronic administration of some but not all antidepressant treatments to animals alters the number and function of brain alpha 2-adrenoceptors. In man, platelet alpha 2-adrenoceptors have been widely studied as a quantifiable peripheral model of central alpha 2-adrenoceptors. The majority of studies have not identified clear differences in platelet alpha 2-adrenoceptors between drug-free depressed patients and control subjects, nor have they identified unequivocal effects of antidepressant treatments. Methodological problems and choice of radioligand may contribute to discrepancies between studies. Central alpha 2-adrenoceptor function in man has been assessed by measuring neuroendocrine and physiological responses to clonidine. Despite considerable variation in procedure, in diagnostic criteria, and in the interval since previous treatment, most studies find the growth hormone response attenuated in depressed patients. This provides the strongest evidence to date of an abnormality of alpha 2-adrenoceptors in depression. However, it seems likely that none of the measures to date adequately mirrors the function of the cortical and limbic receptors implicated in the pathophysiology of depression. It is also likely that no single neurotransmitter abnormality is common to all depressed subjects and that future studies should be aimed at the inter-relationship and dysregulation of several neurotransmitter systems.

Animals↗
PubMed1986

Platelet high affinity adrenoceptor binding sites labelled with the agonist [3H]UK-14,304, in depressed patients and matched controls.

Increased numbers of platelet high affinity alpha 2-adrenoceptors binding sites have been reported in depressed patients using the agonist radioligand [3H]clonidine, whereas no differences from controls have been found using antagonist radioligands. We have measured platelet high affinity alpha 2-adrenoceptors in 13 depressed patients and 14 well-matched controls using a new selective agonist radioligand, [3H]UK-14,304. Unlike previous studies using [3H]clonidine, we find no differences in Bmax or KD of the high affinity alpha 2-adrenoceptor binding sites between the 2 groups.

Adult↗
PubMed1986

Platelet radioligand binding and neuroendocrine challenge tests in depression.

The purpose of this work was to examine the number and function of alpha 2-adrenoceptors and the number of serotonin uptake sites in depressed patients and controls. Platelet alpha 2-adrenoceptors and platelet serotonin uptake sites were labelled with [3H]yohimbine and [3H]imipramine respectively. Central alpha 2-adrenoceptor function was assessed by growth hormone and other responses to challenge with the alpha 2-agonist clonidine. No overall difference in the binding parameters was observed between the control and depressed groups, but the results highlight the importance of drug-free interval, menopausal status and membrane protein concentration within the binding assays in the interpretation of such studies. The growth hormone response to clonidine tended to be blunted in depressed females and was significantly blunted in the subgroup of depressives who failed to suppress plasma cortisol concentrations in response to dexamethasone. Depressed subjects also showed a smaller decrease in diastolic blood pressure and a smaller increase in sedation than control subjects.

Adult↗
PubMed1986

Brain adrenoceptor binding sites in mice susceptible (DBA/2J) and resistant (C57 Bl/6) to audiogenic seizures.

We have examined if the age-related susceptibility of DBA/2J mice to audiogenic seizures is the result of an abnormality in the number or sensitivity of brain adrenoceptors. The binding of alpha 1-, alpha 2-, and beta-adrenoceptor ligands to membranes prepared from whole brain or regions of brain of DBA/2J mice was measured at various ages, corresponding to the periods before, during, and after the maximal sensitivity to audiogenic seizures. For comparison, we have studied concurrently age-matched C57 Bl/6 mice, a strain resistant to audiogenic seizures at all ages. There was no difference in the binding of alpha 2- or beta-adrenoceptor ligands to whole brain membranes between the two strains of mice at any age. The maximal number of alpha 1-adrenoceptor binding sites was lower in whole brains of DBA/2J mice than of C57 Bl/6 mice at all ages studied except 13-15 days of age. The differences were small (maximally 17%) but were statistically significant at 21-23 days of age, the time of maximal sensitivity of DBA/2J mice to audiogenic seizures. No difference between the two strains was found in the number or affinity of alpha 1- or alpha 2-adrenoceptor binding sites at any age in any of the brain regions studied. The age-related susceptibility of DBA/2J mice to audiogenic seizures is not the result of an abnormality in number or sensitivity of alpha 2- or beta-adrenoceptor binding sites, but a reduced number of alpha 1-adrenoceptor binding sites may be involved.

Acoustic Stimulation↗
PubMed1986

Development of the gamma-aminobutyric acid neurotransmitter system in the rat cerebral cortex during repeated administration of the GABA-transaminase inhibitor ethanolamine O-sulphate.

Ethanolamine O-sulphate (400 mg/kg, i.p.) was administered to rat pups at 9 days of age and on alternate days up to 17 days of age. At 18 days of age, gamma-aminobutyric acid (GABA) concentration was increased (three- to fourfold), glutamic acid decarboxylase (GAD) activity reduced to 55% of control, and the number of GABAA and GABAB binding sites increased in the cerebral cortex. This is the same pattern of change as seen previously with oral administration of ethanolamine O-sulphate to the adult rat but the changes occur more rapidly in the developing rat. A lower dose of ethanolamine O-sulphate (100 mg/kg, i.p.), administered according to the same schedule, caused a twofold increase in cortical GABA at 18 days of age whereas GAD activity and GABAA binding were not significantly altered.

4-Aminobutyrate Transaminase↗
PubMed1985

Platelet 3H-imipramine binding in pregnancy and the puerperium.

Platelet 3H-imipramine binding was examined in a cross-sectional study of 70 Caucasian women in pregnancy and the early post-partum period, and in 23 nonpregnant women of childbearing age. Mood was also assessed in the pregnancy and post-partum sample. No significant differences in number of binding sites (Bmax) were found, but an increase in the equilibrium dissociation constant (Kd) was demonstrated at 5-7 days post-partum.

Adult↗
PubMed1984

Synaptosomal [3H]GABA uptake and [3H]nipecotic acid binding in audiogenic seizure susceptible (DBA/2) and resistant (C57 B1/6) mice.

The kinetics of [3H]GABA uptake into synaptosomes prepared from the cerebral cortex, cerebellum and pons-medulla of DBA/2 (audiogenic seizure susceptible) and C57 B1/6 (audiogenic seizure resistant) mice were determined at various ages. Vmax of uptake decreased with age in all regions of both strains, Km was unchanged. There were no regional differences in the Vmax between strains at any age but Km was lower in DBA/2 mice at 21-23 days in cerebellum and at 40-43 days in pons-medulla. There were no strain differences in the binding of [3H]nipecotic acid to crude cortical membrane fractions at any age. The age related audiogenic seizure susceptibility of DBA/2 mice is not related to an abnormality of neuronal GABA uptake.

Acoustic Stimulation↗
PubMed1982

Regional heterogeneity of benzodiazepine binding sites in rat brain.

Displacement of [3H]propyl-beta-carboline-3-carboxylate ([3H]PrCC) and [3H]flunitrazepam ([3H]FNM) was studied in rat hippocampus and cerebellum. Diazepam displaced both ligands with equal potency in both regions. Ethyl-beta-carboline-3-carboxylate (beta CCE) and CL 218,872 displaced [3H]PrCC more potently than [3H]FNM and were more potent in the cerebellum than the hippocampus. Beta CCE and CL 218,872 interact more potently with BZ1 than BZ2 sites, while diazepam is equipotent. GABA and chloride ions enhance the potency of diazepam and CL 218,872 but not beta CCE.

Animals↗
PubMed1982

gamma-Aminobutyric acid and benzodiazepine binding sites in audiogenic seizure-susceptible mice.

The properties of gamma-aminobutyric acid recognition sites, benzodiazepine binding sites and the effect of exogeneous gamma-aminobutyric acid on benzodiazepine binding were determined in crude membrane fractions prepared from the brains of DBA/2 mice at ages before (8-9 and 17-18 days), during (22-23 and 28-29 days) and after (40-43 days) the age of high susceptibility to audiogenic seizures. These have been compared with data from age-matched mice of a strain (TO) with lower audiogenic seizure susceptibility. The number of high-affinity [3H]gamma-aminobutyric acid binding sites was lower at all ages in DBA/2 mice compared with TO mice, but the affinity was higher in DBA/2 mice. The number of low-affinity [3H]gamma-aminobutyric acid binding sites was lower at 8-9 days and 40-43 days in DBA/2 mice, but was not significantly different from TO mice at other ages. For [3H]flunitrazepam binding, the only difference found was a slight reduction in the number of binding sites at 28-29 days of age in DBA/2 mice. gamma-Aminobutyric acid stimulation of [3H]flunitrazepam binding was not significantly different up to 22-23 days of age, but was higher in DBA/2 mice at 28-29 days and lower at 40-43 days. Impairment of gamma-aminobutyric acid function is a possible permissive factor in the age-dependent audiogenic seizure susceptibility in DBA/2 mice.

Acoustic Stimulation↗
PubMed1982

Cerebral glutamic acid decarboxylase activity and gamma-aminobutyric acid concentrations in mice susceptible or resistant to audiogenic seizures.

DBA/2 mice between 21 and 28 days of age are highly susceptible to sound-induced seizures. Drug studies suggest a possible deficit of gamma-aminobutyric acid (GABA)-mediated neurotransmission may be involved. We have measured the whole brain GABA concentration and glutamic acid decarboxylase activity in DBA/2 mice at various ages before, during, and after the period of maximal susceptibility to audiogenic seizures. Corresponding determinations were carried out on age-matched TO mice, a strain much less susceptible to audiogenic seizures than DBA/2 mice at all ages. No significant differences in GABA concentration or glutamic acid decarboxylase activity were found between strains at any age. The susceptibility of DBA/2 mice to audiogenic seizures does not result from a gross inability to synthesise or store GABA.

Acoustic Stimulation↗
PubMed1980

Regional cerebral blood flow in the rat during prolonged seizure activity.

In order to evaluate the possible contribution of regional insufficiency in blood flow to the development of epileptic brain damage, we have measured changes in total and regional cerebral blood flow (tCBF and rCBF) during the course of prolonged sustained seizures. We have used both a particle distribution method (radioactively labelled microspheres) and a diffusible tracer method (iodo [14C]antipyrine). Seizures were induced with bicuculline (1.2 mg/kg, i.v.) in rats with neuromuscular paralysis, mechanically ventilated with 70% N2O/30% O2, rCBF was determined in 13 brain regions after 10, 30, 60 and 120 min of seizure activity. Microsphere and iodo[14C]antipyrine methods gave identical control values for tCBF (0.88 +/- 0.02 vs 0.86 +/- 0.07 ml/g brain/min) and closely similar rCBF values. The increases in tCBF after 10 and 30 min seizure activity were less as measured with microspheres than with iodo [14C]antipyrine (2.42 +/- 0.29 vs. 4.99 +/- 0.94 and 1.79 +/- 0.18 vs 3.05 +/- 0.30 mg/g brain/min, respectively). With microspheres, rCBF values showed considerable interhemisphere variability, but did not do so with iodo [14C]antipyrine. The regional pattern of flow changed during seizures. Changes in neocortical rCBF tended to match changes in tCBF. Consistent decreases in rCBF relative to tCBF were seen in the pons-medulla and cerebellum at all seizures times. Relative increases in rCBF were seen at all seizure times in the thalamus, and at 10 and 30 min in colliculi and midbrain. In the hippocampus, rCBF was unchanged (relative to tCBF) at 10 and 30 min, but was increased at 60 and 120 min of seizure activity. Thus, regions developing epileptic brain damage in this model of status epilepticus (hippocampus, thalamus, neocortex) show increases in rCBF greater than those in regions not showing brain damage (cerebellum, brain stem).

Animals↗
PubMed1979

Convulsant and anticonvulsant actions in DBA/2 mice of compounds blocking the reuptake of GABA.

Compounds blocking the uptake of GABA into neurons or glia have been injected intracerebroventricularly (icv) or intraperitoneally (ip) in DBA/2 mice, age 21-28 days. Protection against audiogenic seizures was seen 30 min after the icv injection of (+)-2,4-diaminobutyric acid (0.5-2.0 mumoles), (+/-)-nipecotic acid (1.6-3.2 mumoles), (+)-ethyl nipecotate (0.4-0.8 mumoles), (-)-piperazic acid (4 mumoles) and putrescine (2 mumoles) or the ip injection of (+)-2,4-diaminobutyric acid (4-8 mmoles/kg and (+)-ethyl nipecotate (0.24-0.32 mmoles/kg). Of these ethyl nipecotate and nipecotic acid were the most effective anticonvulsants icv, but nipecotic acid was ineffective ip. Limb myoclonus and other epileptic manifestations (rearing, wild running, tonic clonic seizures) occurred in the absence of auditory stimulation after (+)-2,4-diaminobutyric acid (0.5-2.0 mumoles), (+/-)-cis-3-aminocyclohexane carboxylic acid (3.2-6.4 mumoles) and putrescine (2 mumoles). beta-Alanine (2-4 mumoles, icv) depressed respiration but did not protect against audiogenic seizures or induce myoclonus.

Alanine↗
PubMed1979

Anticonvulsant activity in photosensitive baboons, Papio papio, of two new 1,5 benzodiazepines.

Two new 1,5 benzodiazepines have been evaluated acutely as anticonvulsants in baboons, Papio papio, with photosensitive epilepsy. BAU 426 (8-Chlor-6-[2-chlorphenyl]-4H-s-triazolo-[4,3-a] [1,5-benzodiazepin-5-[6-H]on) and BAU 500 (analogue of BAU 426 with [2-trifluor methylphenyl] substituted for [2-chlorphenyl]), 0.1--5.0 mg/kg, were administered i.v. to baboons with and without priming with D,L allylglycine. BAU 426 or BAU 500, 0.1--0.2 mg/kg, produced partial or transient protection against photically induced myoclonus or epileptic responses. Complete protection, in the absence of signs of sedation or acute neurological toxicity, was seen 1--4 h after 0.5--2 mg/kg. EEG changes typical of benzodiazepines were seen for 1--3 h and clinical signs of sedation with some muscular hypotonia were evident for 1 h after either drug, 5 mg/kg. Clinical trials are required to determine if these compounds are superior to 1,4 benzodiazepines as anticonvulsants.

Animals↗
PubMed1979

Dopamine-dependent hyperactivity in the rat following manipulation of GABA mechanisms in the region of the nucleus accumbens.

The effect of manipulation of GABA mechanisms in the region of the nucleus accumbens on dopamine-dependent locomotor hyperactivity in the rat has been studied. Two models of hyperactivity were used: (1) the injection of dopamine into the region of the nucleus accumbens in nialamide-pretreated animals and (2) the systemic administration of d-amphetamine. Both GABA and the GABA agonist 3-aminopropane sulphonic acid (3-APS) depressed hyperactivity in a dose-related manner. High concentrations of GABA (greater than 100 micrograms) were required to produce a significant effect and the response was short-lived possibly reflecting the efficient GABA inactivating mechanisms. 3-APS proved to be approximately 10 times more potent as compared to GABA in the dopamine-accumbens hyperactivity model. Conversely GABA receptor antagonism with low doses of either picrotoxin or bicuculline enhanced the mild locomotor response induced by a low dose of dopamine injected into the nucleus accumbens. However such results were difficult to evaluate fairly as higher doses of the GABA antagonists resulted in varying degrees of generalized seizures. Blockade of GABA uptake systems with cis-1, 3-aminocyclohexane carboxylic acid (ACHC), nipecotic acid or beta-alanine within the region of the nucleus accumbens produced dose-related depression of dopamine-dependent hyperactivity in both models. GABA uptake blockade (nipecotic acid) significantly enhanced the GABA-mediated depression of hyperactivity induced by bilateral injection of dopamine into the nucleus accumbens. The results demonstrate an inhibitory action of GABA and drugs facilitating GABA-ergic transmission on dopamine-dependent hyperactivity in the rat. Although open to criticisms of not being able to distinguish between true GABA effects and the results of non-specific neuronal depression the hyperactivity model underlines the potency of the GABA uptake blocking compounds and their possible potential for future clinical use.

Amino Acids↗