Biomedical subjects

S C Stanford

Publications and source records attributed to S C Stanford.

At least 19 recordsLinked to original sources

PubMed2001

Differences in central noradrenergic and behavioural responses of Maudsley non-reactive and Maudsley reactive inbred rats on exposure to an aversive novel environment.

The present experiments compared the noradrenaline and behavioural responses of inbred Maudsley reactive (MR) and non-reactive (MNRA) rats when they are exposed to the light or dark arena of a light/dark shuttle-box. Behavioural scores confirmed that both strains of rats perceived the light arena to be more aversive than the dark one. Using in vivo microdialysis, exposure to the light, but not the dark, arena was found to increase noradrenaline efflux in both the frontal cortex and the hypothalamus of MNRA and MR rats. However, whereas the increase in the frontal cortex of both strains and the hypothalamus of MR rats was transient, the hypothalamic response in MNRA rats was maintained throughout exposure to the test zone. Strain differences in activity/visit and time/visit were evident but it was not possible to discern whether this could be attributed to the strain difference in the hypothalamic noradrenaline response. Nevertheless, it remains possible that, by comparison with MR rats, the prolonged noradrenaline response in the hypothalamus of MNRA rats could contribute to their well-documented, greater resistance to aversive environmental stimuli.

Animals↗

PubMed2000

A microdialysis study of the noradrenergic response in rat frontal cortex and hypothalamus to a conditioned cue for aversive, naturalistic environmental stimuli.

RATIONALE: Extracellular noradrenaline concentration in the rat forebrain is increased by aversive environmental stimuli. This study investigated whether conditioned cues for such stimuli have the same effect. METHODS: After training rats to associate a tone (conditioned cue) with transfer from a neutral zone to a brightly lit zone of a light/dark shuttle-box (unconditioned stimulus), microdialysis probes were implanted into the frontal cortex and hypothalamus under halothane anaesthesia. Changes in extracellular noradrenaline concentration were then monitored on exposure to the tone alone. Parallel experiments monitored rats' behaviour in the light arena. RESULTS: A single exposure to the light arena increased extracellular noradrenaline in the frontal cortex and the hypothalamus but neither a single, nor repeated, exposure to the tone alone had any effect. After conditioning trials, the tone alone increased extracellular noradrenaline in the frontal cortex but not the hypothalamus, whilst the tone+transfer to the light arena resulted in a prolonged increase in extracellular noradrenaline in both brain regions. The time that rats spent within the light arena was also prolonged. CONCLUSIONS: Noradrenergic neurones in the frontal cortex, but not the hypothalamus, respond to conditioned cues for aversive environmental stimuli. However, prolongation of the noradrenergic response in both brain regions could contribute to the behavioural adaptation to such unconditioned stimuli.

Acoustic Stimulation↗

PubMed2000

CNS drugs III: psychotherapeutics.

This two-day symposium reviewed specific aspects of current drug development for psychiatric disorders. The aim was to identify how existing drugs could he improved and what approaches could he adopted to develop new drugs acting by different mechanisms. The meeting was attended by approximately 50 delegates, mainly from multinational pharmaceutical companies or smaller private biotechnology based companies with a few academic clinicians and preclinical scientists. The topics covered on the first day included the influence of genomics and proteomics on drug discovery with reference to antipsychotics, GABAA receptor subunit specific compounds as a route to improved anxiolytics. AMPA receptor modulators as add-on therapy in schizophrenia and corticotrophin releasing factor receptors as targets in depression. The second day placed a greater emphasis on drugs influencing amine neurotransmission; an aspect already raised on the first day by discussion of 5-HT-moduline. The main areas covered were how serotonergic ligands could he used with greater effect in depression and schizophrenia, the therapeutic value of serotonin noradrenaline uptake inhibitors (SNRIs) and the potential clinical value of new amine re-uptake inhibitors. Finally, the meeting discussed the impact of various technological advances in genetics. neuroimaging and psychometric testing in psychotherapeutic drug discovery.

Central Nervous System Agents↗

PubMed1999

Effect of novel environmental stimuli on rat behaviour and central noradrenaline function measured by in vivo microdialysis.

RATIONALE: Although physically aversive stimuli induce functional changes in central noradrenergic neurones, little is known about the noradrenergic response to environmentally aversive stimuli. OBJECTIVES: The first aim was to characterise environmental features that are perceived as stressful by rats. The second was to investigate whether changes in the concentration of extracellular noradrenaline are induced by these environmental features. METHODS: A light/dark shuttle-box was used to test rats' behavioural response to a range of stimuli (novelty, bright light, and the presence of an unfamiliar rat), either before or after microdialysis probe implantation. Changes in the concentration of extracellular noradrenaline in the frontal cortex and hypothalamus in vivo were then evaluated on exposure to these same test conditions. RESULTS: Naive rats spent less time in a brightly-lit test arena than a dark one. However, the behavioural response to the light arena was attenuated by the presence of an unfamiliar rat. Probe implantation intensified the response to the light arena but did not affect behaviour in the dark arena. In the microdialysis studies, there was no change in the concentration of extracellular noradrenaline on transfer of rats to the dark arena but there was an increase in both the frontal cortex (+45%) and hypothalamus (+75%) on exposure to the light arena. A similar increase was induced in both brain regions when the light arena contained an unfamiliar rat. CONCLUSIONS: Implantation of a microdialysis probe modifies the behavioural responses to certain environmental stimuli. Regardless of this, the extent to which rats perceive a novel environment as aversive is not the only determinant of the noradrenergic response to such stimuli. However, differences in stimulus controllability in the microdialysis and the behavioural experiments could influence the apparent intensity of the stress.

Animals↗

PubMed1999

Comparison of changes in the extracellular concentration of noradrenaline in rat frontal cortex induced by sibutramine or d-amphetamine: modulation by alpha2-adrenoceptors.

1. The effects of sibutramine (0.25 - 10 mg kg-1, i.p.) on extracellular noradrenaline concentration in the frontal cortex of halothane-anaesthetized rats were compared with those of d-amphetamine (1 - 3 mg kg-1, i.p.) using in vivo microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of these drugs on extracellular noradrenaline concentration were also investigated by pretreating rats with the selective alpha2-adrenoceptor antagonist, RX821002. 2. Sibutramine induced a gradual and sustained increase in extracellular noradrenaline concentration. The dose-response relationship was described by a bell-shaped curve with a maximum effect at 0.5 mg kg-1. In contrast, d-amphetamine induced a rapid increase in extracellular noradrenaline concentration, the magnitude of which paralleled drug dose. 3. Pretreatment with the alpha2-adrenoceptor antagonist, RX821002 (dose 3 mg kg-1, i.p.) increased by 5 fold the accumulation of extracellular noradrenaline caused by sibutramine (10 mg kg-1) and reduced the latency of sibutramine to reach its maximum effect from 144 - 56 min. 4. RX821002-pretreatment increased by only 2.5 fold the increase in extracellular noradrenaline concentration caused by d-amphetamine alone (10 mg kg-1) and had no effect on the latency to reach maximum. 5. These findings support evidence that sibutramine acts as a noradrenaline uptake inhibitor in vivo and that the effects of this drug are blunted by indirect activation of presynaptic alpha2-adreno-ceptors. In contrast, the rapid increase in extracellular noradrenaline concentration induced by d-amphetamine is consistent with this being mainly due to an increase in Ca2+-independent release of noradrenaline.

Adrenergic alpha-Antagonists↗

PubMed1999

Modulation of sibutramine-induced increases in extracellular noradrenaline concentration in rat frontal cortex and hypothalamus by alpha2-adrenoceptors.

1. The effects of sibutramine (0.25 - 10 mg kg-1 i.p.) on extracellular noradrenaline concentration in the frontal cortex and hypothalamus of freely-moving rats were investigated using microdialysis. The role of presynaptic alpha2-adrenoceptors in modulating the effects of sibutramine in these brain areas was also determined. 2. Sibutramine induced an increase in extracellular noradrenaline concentration, the magnitude of which paralleled dose, in both brain areas. In the cortex, this increase was gradual and sustained, whereas in the hypothalamus it was more rapid and of shorter duration. 3. In both the cortex and hypothalamus, pretreatment of rats with the alpha2-adrenoceptor antagonist RX821002 (3 mg kg-1 i.p.) potentiated increases in the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i. p.), by 7 and 10 fold respectively. RX821002 also reduced the latency of sibutramine to reach its maximum effect in the cortex, but not in the hypothalamus. 4. Infusion of RX821002 (1 microM) via the probe increased the accumulation of extracellular noradrenaline induced by sibutramine (10 mg kg-1 i.p.) in both brain areas. In the hypothalamus, the effects of RX821002 on the accumulation of noradrenaline induced by sibutramine were 2 fold greater than those in the cortex. 5. These findings support evidence that sibutramine inhibits the reuptake of noradrenaline in vivo, but that the accumulation of extracellular noradrenaline is limited by noradrenergic activation of presynaptic alpha2-adrenoceptors. Furthermore, the data suggest that terminal alpha2-adrenoceptors in the hypothalamus exert a greater inhibitory effect over the control of extracellular noradrenaline accumulation than do those in the cortex.

Adrenergic alpha-Antagonists↗

PubMed1999

Plasma catecholamines, pharmacotherapy and mood of subjects with cardiovascular disorder.

This study investigated whether drug therapy explains why the concentration of arterial plasma catecholamines in patients who have received an orthotopic heart transplant (OHT) or coronary bypass and graft (CABG) is greater than in those with heart failure (HF). The results suggest that the differences in plasma catecholamine concentrations in these groups of patients could not be attributed to administration of any of the drugs studied here. An additional finding is that the use of aspirin is associated with a higher concentration of plasma noradrenaline, but not adrenaline. Patients who were taking aspirin also had a more positive mood, as rated by the Profile of Mood States; this was mainly because they had a lower fatigue score than did patients who were not taking this drug. In contrast, several agents (warfarin, Ca2+-channel blockers and 'mixed cardiac' drugs), which had no effects on catecholamine overspill, were linked with negative mood; this was expressed consistently as a higher tension score. These findings suggest that drugs which are administered for their effects in the periphery could also influence patients' psychological status. With the possible exception of aspirin, this does not involve changes in spillover of catecholamines in the periphery.

Adult↗

PubMed1999

Postoperative delirium indicating an adverse drug interaction involving the selective serotonin reuptake inhibitor, paroxetine?

We report a postoperative delirium expressed by a 49-year-old female patient during recovery from anaesthesia. Prominent features of the delirium, which lasted for nearly 2 days, included agitation, confusion, uncontrolled limb movements, abnormal ocular function, hypertension, pyrexia, brisk reflexes, ankle clonus and raised creatine kinase. The delirium did not respond to naloxone, diazepam or flumazenil. The patient had not been prescribed neuroleptics but, before surgery, she had been taking the selective serotonin reuptake inhibitor, paroxetine, to relieve her depression. During surgery, she was given morphine, which increases release of the neurotransmitter, serotonin, and ondansetron, which blunts neuronal release of dopamine. Although there is no clear explanation for the delirium, it had many features in common with problems associated with paroxetine withdrawal, the serotonin syndrome and the malignant neuroleptic syndrome. We offer several alternative explanations for this event, all of which rest on disruption of serotonergic and/or dopaminergic transmission and which could also involve inhibition by paroxetine of the P450 enzyme, CYP2D6, which metabolizes ondansetron.

Analgesics, Opioid↗

PubMed1998

A partial noradrenergic lesion induced by DSP-4 increases extracellular noradrenaline concentration in rat frontal cortex: a microdialysis study in vivo.

The effect of systemic administration of the selective neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) on noradrenaline efflux in the frontal cortex was studied in freely-moving rats using microdialysis in vivo. Five days after treatment with DSP-4 (40 mg/kg i.p.), the noradrenaline content of the frontal cortex was reduced by 75%. Yet, noradrenaline efflux in the frontal cortex was nearly two-fold greater in DSP-4 treated rats than in saline-injected controls. Local infusion of the noradrenaline-selective uptake blocker, desipramine (5 microM), via the microdialysis probe, increased noradrenaline efflux in rats from both groups. Perfusion of Ringer's solution, containing 80 mM K+, also increased noradrenaline efflux in both groups, but the increase after DSP-4 pretreatment was greater than in the controls. In contrast, removal of Ca2+ from the infusion medium reduced noradrenaline efflux in both treatment groups. These results indicate that, at this dose, DSP-4 increases the extracellular concentration of noradrenaline in rat frontal cortex despite causing a partial lesion of noradrenergic neurones. This is due to an increase in the release of noradrenaline, although reduced clearance is also likely. These data challenge the assumption that depletion of noradrenaline content after treatment with DSP-4 invariably translates into diminished noradrenergic transmission.

Animals↗

PubMed1998

Psychological adjustment after cardiac transplantation.

Psychosocial function improves after cardiac transplantation but the extent of improvement is not established. Neither are the factors established that account for variability in function between patients following successful transplantation. We therefore compared illness-related dysfunction in patients following orthotopic cardiac transplantation (OCT) with that in angina-free patients following coronary artery bypass graft (CABG) and stable patients in heart failure awaiting transplantation (HF). We also measured two factors that might contribute to variation in function: emotional distress and concern with physical symptoms. Psychosocial function was as good in OCT as in CABG patients and, in both, was better than in HF patients. Differences in emotional distress and in physical symptoms showed a similar pattern and contributed to, but did not completely account for, differences in function. Concern with physical symptoms contributed to variability in functional impairment in HF but not CABG patients; transplantation strengthened this relationship. The results show that successful cardiac transplantation enhances psychosocial function to a level comparable with that after CABG, and suggest targets for psychological or educational intervention to improve quality of life after transplantation in patients whose recovery is inhibited by concern about physical symptoms.

Adaptation, Psychological↗

PubMed1998

The anxiogenic agents, yohimbine and FG 7142, disrupt the noradrenergic response to novelty.

Whether or not abnormal noradrenergic transmission can be a causal factor in anxiety is controversial. The present experiments examined this question by comparing the effects of two anxiogenic agents on noradrenaline efflux in the frontal cortex of freely moving rats. A single anxiogenic dose of either yohimbine (2.5 or 5 mg/kg) or FG 7142 (10 or 20 mg/kg) was administered to rats by i.p. injection. Yohimbine increased spontaneous efflux of noradrenaline, but FG 7142 had no effect. However, subsequent exposure of rats to a novel environment increased noradrenaline efflux in vehicle-, but not drug-treated rats. Calculation of the net change in noradrenaline efflux caused by transfer to the novel environment showed that this was reduced by yohimbine, whereas FG 7142 increased it. These two compounds also had different effects on locomotor activity in the novel environment. The results suggest that anxiety is unlikely to be invariably associated with increased noradrenergic transmission, in the frontal cortex at least. However, it remains possible that any disruption of the noradrenergic response to stress could be an underlying feature of anxiety.

Adrenergic alpha-Agonists↗

PubMed1998

Evidence from microdialysis and synaptosomal studies of rat cortex for noradrenaline uptake sites with different sensitivities to SSRIs.

1. Microdialysis of the frontal cortex of freely-moving rats and uptake of [3H]noradrenaline into cortical synaptosomes were used to evaluate changes in efflux of noradrenaline in vivo and uptake of [3H]noradrenaline in vitro, respectively, induced by the selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the tricyclic antidepressant, desipramine. 2. Noradrenaline efflux was increased during local infusion into the cortex of each of these drugs. All three agents also inhibited synaptosomal uptake of [3H]noradrenaline; this inhibition was unaffected by a substantial (50%) lesion of central 5-hydroxytrytaminergic neurones induced by intracerebroventricular infusion of 5,7-DHT (150 microg). 3. A noradrenergic lesion (70%), induced by pretreatment with the selective neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 40 mg kg(-1) i.p.), 5 days earlier, abolished the increase in noradrenaline efflux caused by local infusion of fluoxetine. In contrast, the desipramine-induced increase in efflux was greater than in non-lesioned rats whereas the effect of citalopram on noradrenaline efflux was unaffected by DSP-4 pretreatment. 4. The combined results of all these experiments suggest that there could be more than one, functionally distinct, noradrenaline uptake site in rat frontal cortex which can be distinguished by their different sensitivities to desipramine and the SSRIs, fluoxetine and citalopram.

5,7-Dihydroxytryptamine↗

PubMed1997

Psychological stress does not affect plasma catecholamines in subjects with cardiovascular disorder.

Whereas the effects of cardiac transplantation on the catecholamine response to physical exercise have been studied previously, the impact on psychological stress is unknown. Here, the arterial catecholamine response to the Stroop test of patients with an orthotopic heart transplant (OHT) was compared with that in subjects who had received a coronary artery bypass graft (CABG) or who were in heart failure and destined for a heart transplant (HF). Subjects were tested whilst sitting and their usual drug therapy was maintained. The Stroop test increased subjects' subjective tension but did not affect arterial concentrations of adrenaline or noradrenaline in any group of subjects. Also, the concentration of both catecholamines was significantly higher in OHT and CABG subjects than in the HF group, but their relative concentration was unaffected by cardiovascular status or stress. It is concluded that the absolute concentrations of arterial catecholamines, but not their relative concentrations, depend on clinical status. Moreover, under these test conditions, subjects with a history of cardiovascular disorder do not show the normal catecholamine response to psychological stress.

Adolescent↗

PubMed1996

Increased noradrenaline efflux induced by local infusion of fluoxetine in the rat frontal cortex.

In microdialysis experiments in vivo, local infusion of either the selective serotonin reuptake inhibitor, fluoxetine, or the selective noradrenaline uptake inhibitor, desipramine, increased noradrenaline efflux in rat frontal cortex. Synaptosomal uptake of [3H]noradrenaline was used to test whether inhibition of uptake could contribute to this effect of fluoxetine. Low concentrations of fluoxetine were less effective than desipramine at inhibiting [3H]noradrenaline uptake; both compounds were more potent than the selective serotonin reuptake inhibitor, citalopram. To investigate whether this inhibition of uptake involved an action on noradrenergic neurones, experiments compared the effects of a noradrenergic lesion, induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), on the inhibition of uptake by fluoxetine, desipramine and citalopram. The lesion reduced [3H]noradrenaline uptake in the presence of fluoxetine and citalopram but increased it in the presence of desipramine. The results suggest both that inhibition of noradrenaline uptake could contribute to the actions of fluoxetine and that a non-noradrenergic mechanisms is a target for this action.

Adrenergic Uptake Inhibitors↗

PubMed1996

Increased levels of extracellular noradrenaline in the frontal cortex of rats exposed to naturalistic environmental stimuli: modulation by acute systemic administration of diazepam or buspirone.

In vivo microdialysis was used to investigate the effects of an IP injection of diazepam or buspirone (each at 3 mg/kg) on spontaneous efflux of noradrenaline in rat frontal cortex, and on changes in efflux induced by naturalistic stress. After drug administration, rats either remained in their home cages or were transferred individually to a novel cage, 1 h later. The novel cage was brightly lit (1500 lux) and contained another, unfamiliar rat. After transfer to the novel cage, noradrenaline efflux was lower in diazepam-injected rats than in their vehicle-injected counterparts. However, in both cases, stress caused a significant increase in efflux and the net increase was not affected by diazepam. Similarly, buspirone, which increased spontaneous efflux of noradrenaline, did not affect the net increase in efflux during stress. Neither compound modified locomotor activity in the novel cage. This suggests that any changes in noradrenaline efflux are unrelated to drug effects on non-specific arousal. It is concluded that generically unrelated anxiolytic agents can have different effects on spontaneous efflux of noradrenaline but do not modify the noradrenergic response to naturalistic stimuli.

Animals↗

PubMed1996

Stress: a major variable in the psychopharmacologic response.

The role of central monoaminergic neurones in stress is undisputed, albeit undefined. This is partly because little is known about the influence of the type or intensity of stress, or subjects' stress history, on monoaminergic transmission. That the presynaptic response is stimulus specific is underlined by a study using in vivo microdialysis in freely moving rats. This indicated that graded changes in noradrenaline efflux in the frontal cortex are produced by progressively increasing the number of novel features in the rats' environment. The influence of receptor status on behavioural responses to stress also depends on the stress imposed. This was suggested by studies showing that rats' behavioural response to stress correlated with the density of cortical beta-adrenoceptors. But the precise relationship again depended on features of the stress, possibly its intensity. Finally, it seems that even a single stress challenge (a 6-min swim) causes a long-latency increase in the density of 5-HT2A receptors in mouse cortex. This upregulation was prevented by a history of intraperitoneal injections of saline but not by injections of the monoamine reuptake blocker sibutramine hydrochloride. Collectively, these experiments emphasize the importance of stress as an experimental variable when studying the actions of psychotropic drugs.

Animals↗

PubMed1996

Prozac: panacea or puzzle?

Selective 5-HT (serotonin) reuptake inhibitors (SSRIs) lack many of the adverse side-effects of older antidepressants. One of these compounds, fluoxetine (Prozac), has acquired manifest public awareness that is not evident with other SSRIs. Here, Clare Stanford compares the basic pharmacology of SSRIs to determine whether fluoxetine has any atypical features, and thus provide scientific justification for the attention focused on this compound. Ironically, fluoxetine might be distinctive in that it is the least selective SSRI and has marked effects on catecholamine function in the brain.

Animals↗

PubMed1995

Long-lasting effects of an acute stress on the neurochemistry and function of 5-hydroxytryptaminergic neurones in the mouse brain.

The present experiments investigated the effects of a novel stress challenge (6-min swim test) on behaviour (immobility) and the neurochemistry of cortical 5-hydroxytryptaminergic neurones in CD1 mice. The influence of previous experience of stress (once-daily saline injection) or administration of the noradrenaline and 5-hydroxytryptamine (5-HT) uptake blocker, sibutramine hydrochloride, on any changes was also evaluated. 5-HT2A receptor binding was unchanged 24 h after the last injection of either saline or sibutramine alone but immobility in the swim test was reduced to the same extent by these pretreatments. Seven days, but not 3 h, after the swim test, the density of 5-HT2A receptors and the frequency of 5-HT2A receptor-mediated head-twitches were increased significantly. These increases were prevented by saline injection, but sibutramine prevented the increase in head-twitches only. Sibutramine, but not saline, reduced 5-HT synthesis and 5-HT2A receptor-mediated head-twitches 3 h after the swim and increased synthesis at 7 days. The results indicate that a brief stress can have long-term effects on central 5-hydroxytryptaminergic neurones. Previous experience of stress or sibutramine has marked, but dissimilar, effects on these changes. These findings might be relevant to long-lasting CNS disorders provoked, or aggravated, by stress.

5-Hydroxytryptophan↗