Biomedical subjects
E MacDonald
Publications and source records attributed to E MacDonald.
Plasma catecholamine and serum testosterone responses to four units of resistance exercise in young and adult male athletes.
The plasma noradrenaline (NA) and adrenaline (A) concentration responses of seven young male athletes [15 (SD 1) years] and seven adult male athletes [25 (SD 6) years] were investigated together with the serum testosterone (Tes) concentration responses in four different half-squatting exercises. The loads, number of repetitions, exercise intensity and recovery between the sets were manipulated such that different types of metabolic demand could be expected. However, the amount of work done was kept equal in each kind of exercise. After the most exhausting unit of exercise (E3; two sets of 30 repetitions with 50% of 1 repetition maximum and with 2-min recovery between the sets) the plasma NA concentration was significantly lower in the younger than in the adult subjects [15.7 (SD 7.8) vs 32.7 (SD 13.2) nmol x l(-1), P < 0.05], while the A concentrations were similar. In the other three exercises no differences in the plasma catecholamine concentration responses among the groups were observed. The postexercise Tes concentrations, however, were significantly lower in the younger than in the adult subjects in every exercise unit. No correlations between the plasma catecholamine and serum Tes concentration responses were observed in any of the exercise units in either group. The results of the present study may suggest reduced sympathetic nervous activity in the younger subjects compared to the adults in response to exhausting resistance exercise. The results may also suggest that the catecholamines were less involved in eliciting an increase in Tes secretion in these resistance exercises.
The role of the dorsal raphe-serotonergic system and cholinergic receptors in the modulation of working memory.
The present study investigated the role of the dorsal raphe-serotonergic system and its interaction with muscarinic or nicotinic receptors in the modulation of working memory and motor activity by assessing the effects of serotonin lesion with pCA and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. The pCA lesion did not impair the choice accuracy or motor activity of rats in the DNMTP-task. The lower dose of scopolamine (0.075 mg/kg) impaired percent correct responses already at the shortest delay which is not indicative of a working memory impairment per se. Scopolamine also disrupted motor activity markedly. The effects of scopolamine 0.075 mg/kg on the choice accuracy were aggravated by pCA treatment. Furthermore, the effects of N-methylscopolamine (0.150 mg/kg) were comparable with scopolamine. The higher dose of mecamylamine (3.0 mg/kg) also interfered with motor activity and it decreased the choice accuracy. The performance disruption induced by mecamylamine was not as severe as that seen with scopolamine. Mecamylamine did not reveal any interaction with the serotonergic lesion. Hexamethonium slightly decreased the percent correct responses, while not interfering with motor activity of rats. The present results suggest that: (i) lesion of serotonergic fibers with pCA does not significantly impair the choice accuracy or interfere with motor activity of rats; (ii) the blockade of cholinergic receptors does not impair working memory per se, but disrupts motor activity, and (iii) pCA lesion of serotonergic fibers aggravates the non-mnemonic choice accuracy impairment induced by central muscarinic blockade, while not interacting with the cholinolytics in modulation of motor activity.
Long-term effects of portacaval anastomosis on the 5-hydroxytryptamine, histamine, and catecholamine neurotransmitter systems in rat brain.
Portacaval anastomosis (PCA) in the rat is used as a model for portal systemic encephalopathy. Changes in the serotonergic, histaminergic, and catecholaminergic neurotransmitter systems are often found shortly after PCA. We have examined the long-term effects of PCA on the aminergic systems in brains of male Wistar rats, which 8 months previously had been subjected to PCA. Precursors, amines, and metabolites were assayed by HPLC. Eight months after PCA, the catecholamine levels were unchanged in all brain regions. In contrast, tryptophan was evenly increased throughout the brain. The accumulation of 5-hydroxytryptophan after decarboxylase inhibition (NSD-1015; 100 mg/kg i.p.) and the endogenous levels of 5-hydroxyindoleacetic acid were significantly higher in PCA rats, particularly in the hypothalamus and midbrain, whereas 5-hydroxytryptamine concentrations were unchanged. Histamine levels were elevated throughout the brain with the greatest increase found in the hypothalamus and in the striatum. tele-Methylhistamine levels were significantly elevated in cortex and hypothalamus. We conclude that 8 months after PCA, catecholaminergic systems had reestablished their homeostasis, whereas serotonergic and histaminergic systems still show profound disturbances in their function. With histamine, this is reflected as an increase in the amounts of both transmitter and metabolite; serotonergic neurons respond by increasing only the level of the metabolite.
5-HT1A receptor agonist (8-OH-DPAT) and 5-HT2 receptor agonist (DOI) disrupt the non-cognitive performance of rats in a working memory task.
The present study investigated the role of 5 -HT1A and 5 -HT2 receptors in the execution of a working memory task (delayed non-matching to position, DNMTP) by assessing the influence of 8-OH-DPAT (5-HT1A receptor agonist) and DOI (5-HT2 receptor agonist) on the performance of rats lesioned with 5,7-dihydroxytryptamine (5,7-DHT) and their controls. Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid levels were reduced in examined brain areas (especially in the hippocampus where there was a 90 percent reduction). Noradrenaline concentrations were also decreased (mostly on the same side of the injection) by about 20 percent. 5,7-DHT lesioned rats did not significantly differ from their controls in performance in the DNMTP task. At the 30 microg/kg dose, 8-OH-DPAT did not affect the DNMTP-performance of rats, but at the higher dose (100 microg/kg) it reduced the probability of responding to the sample lever. DOI (100 and 300 microg/kg) also interfered with the non-cognitive performance of rats. Since neither of these agonists affected significantly the choice accuracy, they do not appear to influence the working memory per se. The 5,7-DHT lesioned rats did not differ from their controls in response to these agonists. These results suggest that the combination of 5-HT1A receptor stimulation by 8-OH-DPAT and 5-HT2 receptor stimulation by DOI can interfere with the non-cognitive performance of rats in the DNMTP task. The results further indicate that the effect of 8-OH-DPAT may be mediated through post-synaptic rather than pre-synaptic 5-HT1A receptors.
An evaluation of practice nurses working with general practitioners to treat people with depression.
BACKGROUND: The diagnosis and treatment of depression constitutes a significant component of a general practitioner's workload. A pilot study has suggested that the practice nurse may have an important contribution to make in the care of patients with depression. AIM: To evaluate an extended role for practice nurses in improving the outcome of depression through two specially-designed interviews running in parallel. METHOD: Two naturalistic, random allocation studies took place concurrently over four months. Study 1 evaluated the effectiveness of standardized psychiatric assessment by a practice nurse and feedback of information to the general practitioner (GP). Study 2 evaluated the above assessment and feedback combined with nurse-assisted follow-up care. Twenty general practices participating in the Medical Research Council General Practice Research Framework took part in the study. Subjects included general practice attenders identified as depressed by their GP. The main outcome measures were a change in Beck Depression Inventory (BDI) scores and in the proportion of patients fulfilling DSM-III criteria for major depression. RESULTS: A total of 577 patients were recruited; 516 [89% (95% CI = 86-92%)] were rated as depressed on the BDI and 474 [82% (95% CI = 79-85%)] met criteria for DSM-III major depression. Altogether, 524 (91%) patients completed follow-up at four months. All groups of patients showed improvement, but no difference in the rate of improvement was shown for the nurse intervention groups. BDI mean scores fell from 18.54 (95% CI = 17.53-20.06) to 11.53 (95% CI = 10.02-13.04) in Study 1, and from 21.01 (95% = CI 20.26-21.86) to 10.62 (95% CI = 9.73-11.51) in Study 2. The proportion of patients fulfilling criteria for DSM-III major depression in Study 1 fell from 80% (95% CI = 73-87%) to 30% (95% CI = 22-38%), and in Study 2 from 80% (95% CI = 76-84%) to 27% (95% CI = 23-31%). Prescription rates of antidepressant medication were higher than expected, ranging between 63% and 76% in the two studies. CONCLUSION: There was an increase in the rate of antidepressant prescription, but no additional benefit could be adduced for patients who received a nurse intervention.
Alpha2-adrenergic control of dopamine overflow and metabolism in mouse striatum.
The effects of the alpha2-adrenoceptor drugs, medetomidine and atipamezole, on dopamine overflow evoked by low (6 Hz-10 s) and high (50 Hz-4 s) frequency electrical stimulation of the median forebrain bundle were studied in striatum of BALB/C mice anaesthetized with chloral hydrate with fast in vivo voltammetry techniques. The effects of these drugs on the basal concentrations of dopamine metabolites were also investigated by means of differential pulse voltammetry. Medetomidine dose dependently decreased dopamine overflow in nucleus accumbens in the dose range 5-100 microg/kg, s.c. This effect was seen only at low frequency stimulation and reached 85% at a dose of 100 microg/kg. Medetomidine also decreased the basal concentration of striatal homovanillic acid. This effect did not exceed 35%. Atipamezole antagonized the inhibitory effects of medetomidine on the dopamine overflow. but showed no effect itself. We suggest that alpha2-adrenoceptors in dopaminergic terminal fields in the mouse striatum are involved in the regulation of dopamine release at physiological stimulation frequencies.
Evaluation of the effects of a specific alpha 2-adrenoceptor antagonist, atipamezole, on alpha 1- and alpha 2-adrenoceptor subtype binding, brain neurochemistry and behaviour in comparison with yohimbine.
In the present study we evaluated the alpha 1- and alpha 2-adrenoceptor subtype binding, central alpha 2-adrenoceptor antagonist potency, as well as effects on brain neurochemistry and behavioural pharmacology of two alpha 2-adrenoceptor antagonists, atipamezole and yohimbine. Atipamezole had higher selectivity for alpha 2- vs. alpha 1-adrenoceptors than yohimbine regardless of the subtypes studied. Both compounds had comparable affinity for the alpha 2A-, alpha 2C- and alpha 2B-adrenoceptors, but yohimbine had significantly lower affinity for the alpha 2D-subtype. This may account for the fact that significantly higher doses of yohimbine than atipamezole were needed for reversal of alpha 2-agonist (medetomidine)-induced effects in rats (mydriasis) and mice (sedation and hypothermia). The effect on central monoaminergic activity was estimated by measuring the concentrations of transmitters and their main metabolites in whole brain homogenate. At equally effective alpha 2-antagonising doses in the rat mydriasis model, both drugs stimulated central noradrenaline turnover (as reflected by increase in metabolite levels) to the same extent. Atipamezole increased dopaminergic activity only slightly, whereas yohimbine elevated central dopamine but decreased central 5-hydroxytryptamine turnover rates. In behavioural tests, atipamezole (0.1-10 mg/kg) did not affect motor activity but stimulated food rewarded operant (FR-10) responding (0.03-3 mg/kg) whereas yohimbine both stimulated (1 mg/kg) and decreased (> or = 3 mg/kg) behaviour in a narrow dose range in these tests. In the staircase test, both antagonists increased neophobia, but in the two compartment test only yohimbine (> or = 3 mg/kg) decreased exploratory behaviour. The dissimilar effects of the antagonists on neurochemistry and behaviour are thought to be caused by non alpha 2-adrenoceptor properties of yohimbine. In conclusion, the alpha 2-antagonist atipamezole blocked all alpha 2-adrenoceptor subtypes at low doses, stimulated central noradrenergic activity and had only slight effects on behaviour under familiar conditions, but increased neophobia. The low affinity for the alpha 2D-adrenoceptor combined with its unspecific effects complicates the use of yohimbine as pharmacological tool to study alpha 2-adrenoceptor physiology and pharmacology.
Additive deficits in the choice accuracy of rats in the delayed non-matching to position task after cholinolytics and serotonergic lesions are non-mnemonic in nature.
The role of serotonin (5-HT) and its interaction with the muscarinic or nicotinic receptor-mediated mechanisms in the modulation of working memory and motor activity was investigated by assessing the effects of 5-HT lesion and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. A global serotonergic lesion was induced by the intracerebroventricular administration of 5,7-dihydroxytryptamine (5,7-DHT). Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in frontal and parieto-occipital cortices and in hippocampi of 5,7-DHT lesioned rats. 5-HIAA levels were also reduced in striatum. 5,7-DHT lesion slightly impaired choice accuracy of rats in the DNMTP task and also transiently reduced motor activity in rats. Even the lower dose of scopolamine (0.075 mg/kg), a muscarinic receptor antagonist, impaired the choice accuracy already at the shortest delay (i.e. not indicative of a working memory impairment per se), and caused a marked disruption of motor activity (lengthened response latencies, increased probability of omissions and decreased trials completed). Furthermore, the quaternary analogue, N-methylscopolamine (0.150 mg/kg), affected the motor activity of rats to the same extent as scopolamine. Mecamylamine (1.0; 3.0 mg/kg) also interfered with motor activity and it slightly decreased the choice accuracy, which was not dependent on the delay. Although mecamylamine disrupted the performance of rats in the DNMTP task, the disruption was not as severe as that seen with scopolamine. Moreover, both scopolamine and mecamylamine augmented the slight impairment on the choice accuracy of 5,7-DHT lesioned rats, but this was non-mnemonic in character. We conclude that there is no evidence for any major interaction between the serotonergic system and muscarinic or nicotinic cholinergic mechanisms in working memory per se, but muscarinic and nicotinic receptor antagonists may act additively with the 5,7-DHT lesion to disrupt the choice accuracy of rats.
Gene targeting--homing in on alpha 2-adrenoceptor-subtype function.
The alpha-adrenoceptor was subdivided into three subtypes: alpha 2A-, alpha 2B- and alpha 2C-adrenoceptors almost ten years ago. Since then, the search has been on to discover and develop subtype-selective agonists and antagonists, but as yet no major breakthrough has been made. In the past year, several strains of genetically engineered mice have become available, either overexpressing, totally lacking or expressing heavily modified alpha 2-adrenoceptor subtypes. Ewen MacDonald, Brian Kobilka and Mika Scheinin describe how these mice may be utilized to elucidate the physiological functions of the receptor subtypes and the properties of future subtype-selective drugs.
Differential effects of three 5-HT receptor antagonists on the performance of rats in attentional and working memory tasks.
The effects of three different serotonin (5-HT) receptor antagonists (ketanserin, methysegide, methiothepin) in the modulation of attention, working memory and behavioural activity were investigated in this study by assessing the performance of rats in two separate cognitive models; the 5-choice serial reaction time (5-CSRT) task, which measures attention, and the delayed non-matching to position (DNMTP) task, which measures working memory. Methysergide and methiothepin bind at the 5-HT1 and 5-HT2 as well as the 5-HT5-7 receptors, with varying degrees of selectivity, and ketanserin binds at the 5-HT2A receptors rather selectively. None of these agents bind to any significant extent to 5-HT3 or 5-HT4 receptors. In the 5-CSRT task, neither methiothepin (0.15 mg/kg) nor ketanserin (1.0 and 3.0 mg/kg) impaired the choice accuracy of rats, although they induced sedation. The low doses of methysergide (1.5 and 3.0 mg/kg) slightly increased the behavioural activity of rats, whereas the high dose of methysergide (15.0 mg/kg) reduced behavioural activity and slightly reduced choice accuracy of the rats in the attentional task (monitoring of visual stimuli) under the baseline conditions or curtailed stimulus duration. This effect was not augmented at the reduced stimulus intensity. These findings suggest that the high dose of methysergide did not interfere with the visual discrimination of rats. Furthermore, methysergide did not reduce motivation for this task, since it did not increase food collection latencies. In the DNMTP task, methiothepin (0.15 mg/kg) induced a delay non-dependent deficit in choice accuracy. This could be due to an impaired alternation ability or akinesia, which increases an actual delay between sample and choice. Methiothepin (0.15 mg/kg) also interfered with behavioural activity of rats. Interestingly, ketanserin (1.0 mg/kg and 3.0 mg/kg) and methysergide (3.0-15.0 mg/kg) neither impaired the choice accuracy nor reduced the behavioural activity of rats in the DNMTP task. These results suggest that the blockade of 5-HT2A receptors does not interfere with attention and working memory per se. However, all three serotonin receptor antagonists interfered with behavioural activity of rats in the 5-CSRT task more severely than in the DNMTP task. The possible role of serotonin and non-serotonin receptors underlying the influence of these antagonists on behavioural activity will be discussed.
Semen analysis performed by different laboratory teams: an intervariation study.
Some recent studies have indicated that sperm concentration has decreased during the last 50 years. However, comparisons between laboratories have revealed that geographical differences seem to exist and that any decrease may not be global. One point of criticism concerning comparison of results from different laboratories has been that some of the discrepancies detected could reflect the lack of standardized methods used in the different laboratories. Four teams, each consisting of one physician and one technician from groups which have recently published data on semen quality, met in order to evaluate the variability between their laboratories on semen analysis. Twenty-six fresh semen samples from unselected men were analysed. The groups analysed the samples according to the normal practice in their laboratories, using their own equipment. The variation between laboratories was estimated through a random effects model. For sperm concentration and semen volume assessment a remarkable consistency between laboratories was detected, in contrast to the very considerable inter-individual variation. For sperm motility and morphology assessments interlaboratory consistency was much poorer. In conclusion, evaluation of sperm motility and morphology characteristics requires further standardization in order to achieve comparable data from different laboratories. However, semen volume and sperm concentration are characteristics which can be compared reliably between laboratories, when similar methodologies are used.
Evidence of deteriorating semen quality in the United Kingdom: birth cohort study in 577 men in Scotland over 11 years.
OBJECTIVE: To determine whether the quality of semen has changed in a group of over 500 Scottish men born between 1951 and 1973. DESIGN: Retrospective review of data on semen quality collected in a single laboratory over 11 years and according to World Health Organisation guidelines. SETTING: Programme of gamete biology research funded by Medical Research Council. SUBJECTS: 577 volunteer semen donors. Of these, 171 were born before 1959, 120 were born in 1960-4, 171 in 1965-9, and 115 in 1970-4. MAIN OUTCOME MEASURES: Conventional criteria of semen quality including semen volume (ml), sperm concentration (10(6)/ml), overall motility (% motile), total number of sperm in the ejaculate (10(6)), and total number of motile sperm in the ejaculate (10(6)). RESULTS: When the four birth cohort groups were compared a later year of birth was associated with a lower sperm concentration, a lower total number of sperm in the ejaculate, and a lower number of motile sperm in the ejaculate. The median sperm concentration fell from 98x10(6)/ml among donors born before 1959 to 78x10(6)/ml among donors born after 1970 (P=0.002). The total number of sperm in the ejaculate fell from 301x10(6) to 214x10(6) (P=0.0005), and the total number of motile sperm in the ejaculate fell from 169.7x10(6) to 129.0x10(6) (P=0.0065). CONCLUSION: This study provides direct evidence that semen quality is deteriorating, with a later year of birth being significantly associated with a reduced number of sperm in adult life.
Effects of catecholamines on isolated human colonic smooth muscle.
1. The effects of catecholamines and some adrenoceptor agonists and antagonists on isolated preparations of human colonic smooth muscle obtained from surgical resections were examined. 2. Strips of circular smooth muscle displayed rhythmic myogenic spontaneous contractions which were inhibited by catecholamines with an order of potency of isoprenaline (1.0) > noradrenaline (0.32) > adrenaline (0.2). Phentolamine (0.7 microM) significantly shifted the noradrenaline concentration-response curve (CRC) to the right but had no significant effect on isoprenaline or adrenaline. Propranolol (1 microM) significantly shifted the isoprenaline to the right but had no significant effect on noradrenaline or adrenaline. 3. Salbutamol (30 microM) had no inhibitory effect on the spontaneous activity and ICI 118,551 (1 microM) had no effect on inhibitory responses to isoprenaline. Betaxolol (1 microM) significantly shifted the CRC to isoprenaline to the right. BRL 37344 had no effect on spontaneous activity. 4. Responsiveness of circular strips to catecholamines was not affected by age of the patient and no consistent differences between males and females were shown. 5. Strips of taenia coli exhibited little or no spontaneous phasic activity. Noradrenaline and isoprenaline relaxed KCl-induced tone. The effects of noradrenaline and isoprenaline were antagonized by propranolol but not by phentolamine. BRL 37344 had no effect on KCl-induced tone. 6. In conclusion, catecholamines relaxed spontaneous activity of human colon circular smooth muscle through an action on both alpha- and beta-adrenoceptors. The alpha-adrenoceptors were of the alpha 1-subtype. The beta-adrenoceptor-mediated relaxation appeared to be primarily beta 1. In taenia coli, catecholamines relaxed KCl-induced tone via beta-adrenoceptors only.
Reengineering the HIM profession.
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Effects of a selective alpha 2-adrenoceptor antagonist, atipamezole, on hypothalamic histamine and noradrenaline release in vivo.
In vivo microdialysis was used to study the effects of a potent and selective alpha 2-adrenoceptor antagonist, atipamezole, on histamine and noradrenaline release from the medial hypothalamus in anesthetized rats. Local perfusion with atipamezole via the microdialysis probe increased histamine release significantly and dose-dependently. However, the effect of systemic administration of atipamezole (1 mg/kg) was opposite: it significantly decreased histamine release. Local and systemic administration of atipamezole produced an approx. 2-fold increase in noradrenaline release. To study the modulatory effect of noradrenergic neurons on histamine release, noradrenaline synthesis was inhibited with alpha-methyl-p-tyrosine. In the microdialysis experiment, rats that received alpha-methyl-p-tyrosine exhibited no decrease, but rather a slight increase in histamine release in response to systemic atipamezole administration. These results show clearly that atipamezole enhances noradrenaline release in vivo from rat hypothalamus and its effects on histamine release are dependent on the route of drug administration.
Long-term effects of portocaval anastomosis in rats on brain levels of histamine and methylhistamine.
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The effects of d-cycloserine, a partial agonist at the glycine binding site, on spatial learning and working memory in scopolamine-treated rats.
The present study investigated the effect of d-cycloserine, a partial agonist at the glycine binding site on NMDA receptor complex, on the performance of scopolamine-treated adult rats in a water maze task assessing spatial learning and in a delayed non-matching to position task assessing working memory in a spatial context. In the spatial learning task, scopolamine (0.4 mg/kg, i.p.) impaired acquisition (increased escape latency and distance) and increased swimming speed of rats. D-cycloserine (1.0 mg/kg, i.p.) reversed the deficits in acquisition performance but not the increases in behavioral activity. In the working memory task, scopolamine (0.2 mg/kg, i.p.) produced deficits on nonmnemonic rather than on mnemonic performance factors; scopolamine delay-independently decreased the percent correct responses and reduced behavioral activity of rats. D-cycloserine (1.0, 3.0 and 10 mg/kg, i.p.) did not reverse these performance deficits. When administered alone, the moderate to higher doses of d-cycloserine had no effects on working memory but the lower dose produced slight deficits in mnemonic performance factors; the 1.0 mg/kg dose delay-dependently decreased the percent correct responses without affecting behavioral activity of rats. In the water maze task, d-cycloserine had no effects on acquisition performance or behavioral activity of rats. These results suggest that acute, systemic administration of d-cycloserine does not improve spatial learning or working memory. However, at appropriate doses this agent may be efficacious in disease states of central cholinergic hypofunction since 1.0 mg/kg d-cycloserine was able to reverse the scopolamine-induced deficits in acquisition.