Gross regional cerebral hypofunction with normal CT scan in Creutzfeldt-Jakob disease.
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Aged↗
Biomedical subjects
G M Goodwin
Publications and source records attributed to G M Goodwin.
The effects of antidepressant treatments and lithium upon 5-HT1A receptor function.
1) The functional effects of the 5-HT1A receptor selective ligand, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) can be divided into effects mediated by presynaptic (somato-dendritic) autoreceptors and postsynaptic receptors. Hypothermic responses in the mice and rat reflect presynaptic effects. Stereotypic motor responses in the rat reflect postsynaptic function. 2) These functional models of 5-HT1A receptor activity have been used to examine the effects of different antidepressant treatments and lithium during acute (24h) and chronic (14 day) administration. 3) Presynaptic 5-HT1A-mediated hypothermia is attenuated by chronic treatment with amitriptyline, desipramine, zimeldine, high dose mianserin, tranylcypromine, lithium and repeated electroconvulsive shock (ECS). Thus, all these treatments may increase tolerance to increased release of 5-HT. 4) Postsynaptic 5-HT1A-mediated motor effects are attenuated by desipramine, zimeldine and ECS but enhanced by lithium. 5) The 5-HT1A receptor appears to be an important locus for the actions of antidepressant treatments and lithium.
Animals↗
The pattern of function-related regional cerebral blood flow investigated by single photon emission tomography with 99mTc-HMPAO in patients with presenile Alzheimer's disease and Korsakoff's psychosis.
Single photon emission tomography (SPET) with the lipophilic blood flow marker 99mTc-hexamethyl propyleneamine oxime (99mTc-HMPAO) has been used to determine regional uptake of radiolabel into brain regions of patients with presenile Alzheimer's disease and Korsakoff's psychosis, and age-matched controls. Using occipital cortical uptake as reference area, the pattern of relative regional cerebral blood flow (rCBF) was determined in other cortical areas and basal ganglia. In Alzheimer's disease, reduction in rCBF occurred most strikingly in posterior temporal and parietal areas. By contrast, in Korsakoff's psychosis, posterior temporal rCBF was maintained, although there was a trend to reduced tracer uptake in other cortical areas. These impairments of flow were correlated with impairments of neuropsychological function. In Alzheimer's disease, left posterior temporal and left parietal regions in particular showed rCBF to be strongly correlated with most aspects of cognitive function. In Korsakoff's psychosis, however, impaired flow in frontal regions was correlated with impaired performance on tests of memory and orientation. The findings in Alzheimer's disease show quantitative parallels with those from studies using Positron Emission Tomography (PET), and extend our understanding of the relationship between cognition and regional brain function in dementia. The findings in Korsakoff's psychosis offer the first direct evidence linking frontal lobe dysfunction with the cognitive impairment seen in the disorder.
Adult↗
The neuroendocrine responses and psychological effects of infusion of L-tryptophan in anorexia nervosa.
The secretion of prolactin and growth hormone (GH), together with subjective ratings of sedation and hunger, were determined in 13 in-patients with anorexia nervosa and 15 controls during the intravenous infusion of L-tryptophan (100 mg/kg). Prolactin responses were not different between groups but GH responses were markedly blunted in patients. In addition sedation responses in patients were attenuated compared with controls. Hunger ratings were reduced by the infusion in controls but were too variable to be interpreted in the patients. Plasma amino acid levels were also determined before and after infusion of L-tryptophan. Tryptophan levels were comparable in the two groups as were the levels of tyrosine, phenyl alanine, valine, leucine and iso-leucine. The results suggest that some aspects of 5-hydroxytryptamine function may be attenuated in anorexia nervosa. However, they undoubtedly contrast with the finding of enhanced hormonal responses in acute dieting and may be relevant to the interpretation of similar experiments in depressive illness.
Adult↗
Luteinizing hormone responses to luteinizing hormone releasing hormone (LHRH) in acute mania and the effects of lithium on LHRH and thyrotrophin releasing hormone tests in volunteers.
The endocrine responses to Luteinizing Hormone Releasing Hormone (LHRH) of eight drug-free males with mania were determined. Basal levels of Luteinizing Hormone (LH) and the plasma levels following injection of LHRH were elevated in patients compared with controls; Follicle Stimulating Hormone (FSH) and testosterone were not different. Elevated levels of LH have been described previously in recovered manic patients and have been suggested to be state-independent features of mania. In order to clarify the status of this finding, the effects of lithium administration upon hormone responses to LHRH in six male volunteers were also investigated, together with the effects upon Thyrotrophin Releasing Hormone (TRH) stimulation of Thyroid Stimulating Hormone (TSH) and prolactin release. Lithium increased the basal levels of LH and levels after injection of LHRH without effect upon FSH and testosterone. Lithium also increased basal and TRH stimulated release of TSH and basal prolactin levels. Lithium was without effect upon prolactin responses to TRH. The results are discussed in relation to current information on the mechanism of lithium's action. The implications for neuroendocrine work on recovered patients taking lithium are also explored.
Adult↗
Comments on the Northwick Park 'Functional' Psychosis Study.
"Functional psychosis is conventionally subdivided into schizophrenia and manic depressive psychosis. Response to treatment is assumed to be a validating criterion for these diagnoses. The efficacy of pimozide (a dopamine antagonist neuroleptic), lithium, and a combination of the two was compared with that of placebo in a 4-week trial in 120 functionally psychotic patients, each of whom was assessed for psychotic symptoms, manic symptoms, and depressive symptoms. The sample was subdivided into patients with predominantly elevated mood, predominantly depressed mood, and no consistent mood change. Pimozide reduced psychotic symptoms in all groups of patients. The only significant effect of lithium was to reduce elevated mood. Thus dopamine blockade seems relevant to the resolution of psychotic symptoms in all types of 'functional' psychosis, but the mode of action of lithium in psychotic patients concerns only mood. Application of standardised classifications of functional psychosis to these data did not change this conclusion."
Bipolar Disorder↗
Cerebral vascular transit time in Alzheimer's disease and Korsakoff's psychosis and its relation to cognitive function.
The cerebral vascular transit time of 17 patients with pre-senile dementia of the Alzheimer type (ATD), nine abstinent patients with alcoholic Korsakoff's psychosis (KOR), and ten age-matched controls was determined by the bolus intravenous injection of pertechnetate. A gamma camera was used to estimate the median transit time (MTT) of the radioactive bolus in a planar (non-tomographic) projection normal to the vertex. The spread of the bolus arriving at the aortic arch was measured independently by a single external detector over the chest, and correction made for the transit time of this input function in calculating the net MTT for the head. Both ATD and KOR groups showed lengthened net MTTs, compatible with reduced cerebral blood flow, and which were correlated with reduced cognitive function. It is concluded that the method employed gives a simple, inexpensive estimate of function-related blood flow to the brain in pre-senile dementia.
Aged↗
Adenoidal hypertrophy in HIV-infected patients.
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Adenoids↗
Differential patterns of local cerebral glucose utilization in response to 5-hydroxytryptamine agonists.
Local cerebral glucose utilization was measured in parallel groups of conscious rats following intravenous injection of either 1 mg/kg 8-hydroxy-2-(di-N-propylamino)tetralin (a 5-hydroxytryptamine 1A binding site agonist), 3 mg/kg 5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole, succinate (a 5-hydroxytryptamine1B agonist), or saline alone, using the 2-deoxyglucose quantitative autoradiographic techniques (n = 5 in each of the three groups). Following both drugs, local rates of glucose use in the majority of the 72 brain areas analysed remained unaltered, but in some other regions either increases or decreases were observed. In keeping with the observed behavioural response to 8-hydroxy-2-(di-N-propylamino)tetralin there were marked increases in cerebellum (+56%) and motor cortex where a columnar arrangement of increased metabolism (+34%) contrasted with adjacent columns of decrease (-26%). Hippocampal areas showed moderate decreases in glucose use (-13 to -21%). All areas which increased following 8-hydroxy-2-(di-N-propylamino)tetralin also increased following 5-methoxy 3-(1,2,3,6-tetrahydro-4-pyridinyl)1H indole, succinate, but in the latter case all elements of the basal ganglia were also increased, including globus pallidus (+105%) and the striatum where the changes (+54%) were limited to a discrete dorsal region of the nucleus. In the hippocampus only dorsal dentate gyrus was decreased (-24%) whilst a moderate increase (+16%) was observed in dorsal subiculum. The complexity of these results contrasts with previous 2-deoxyglucose investigations where less specific 5-hydroxytryptamine receptor ligands were used, and suggests that certain aspects of brain function may be selectively targeted by systemic pharmacological manipulation of endogenous serotonergic systems.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Repeated electroconvulsive shock prevents increased neocortical beta 1-adrenoceptor binding after DSP-4 treatment in rats.
Repeated electroconvulsive shock (ECS) was administered to rats previously injected with DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride), a noradrenergic neurotoxin. The normal increase in neocortical beta 1-adrenoceptor binding caused by noradrenaline depletion was effectively prevented by ECS. This finding suggests that the plasticity of the beta 1-adrenoceptor may be partially independent of endogenous noradrenaline concentration. Additionally, functional noradrenergic neurons are not necessarily a critical requirement for the antidepressant effect of electroconvulsive treatment in humans.
Animals↗
The effects of dieting and weight loss on neuroendocrine responses to tryptophan, clonidine, and apomorphine in volunteers. Important implications for neuroendocrine investigations in depression.
The increases in the growth hormone (GH) level following intravenous infusion of the 5-hydroxytryptamine precursor tryptophan, the alpha 2-adrenoceptor agonist clonidine hydrochloride, and subcutaneous injection of the dopamine agonist apomorphine hydrochloride were determined in volunteers before and in the third week of a weight-reducing diet (1200 kcal/d). The increases in the prolactin level following intravenous infusion of tryptophan and in response to protirelin were also determined. In male subjects, the GH responses to tryptophan and apomorphine were markedly increased by dieting; while also significantly increased, the GH responses to clonidine were much less affected. Female subjects showed similar trends in the GH responses to tryptophan and clonidine. In male subjects, prolactin responses to tryptophan and protirelin were not increased by dieting. In females, the prolactin response to protirelin was similarly not increased, but the prolactin response to tryptophan was markedly enhanced. These results are relevant to the use of neuroendocrine tests in depression. In addition, they suggest different effects of weight loss on neurotransmitter function in men and women.
Adult↗
Attenuation by electroconvulsive shock and antidepressant drugs of the 5-HT1A receptor-mediated hypothermia and serotonin syndrome produced by 8-OH-DPAT in the rat.
The hypothermia and motor behavioural syndrome produced in rats by injection of the 5-HT1A ligand 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) has been studied following administration of electroconvulsive shock under halothane anaesthesia (ECS) and during the administration of antidepressant drugs. Repeated ECS attenuated the hypothermic response to 8-OH-DPAT (0.1 mg/kg SC) immediately after the last of five shocks given spread out over 10 days with a maximal effect 21 days after the final shock. A single ECS was without effect. The serotonin syndrome produced by 8-OH-DPAT (0.75 mg/kg SC) was also attenuated, although simple motility was increased. Zimeldine (20 mg/kg) and desipramine (20 mg/kg), when given once daily for 14 days also attenuated the hypothermia and the serotonin syndrome provoked by 8-OH-DPAT. The hypothermic response was somewhat reduced 24 h after a single injection of zimeldine but not 45 min after zimeldine (5 mg/kg IP). At a high dose (20 mg/kg) tranylcypromine clearly attenuated both responses 24 h after a single injection. Tranylcypromine (6 mg/kg IP) showed a smaller effect after a single injection but attenuated the behavioural syndrome on repeated administration. Repeated injection of flurazepam (10 mg/kg IP) was without effect on either the behavioural or hypothermic response to 8-OH-DPAT. These findings are consistent with the view that responses mediated via the 5-HT1A receptor may be involved in the mechanism of action of antidepressant treatments.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
The pharmacology of the behavioural and hypothermic responses of rats to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT).
The hypothermic and motor behavioural responses to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) have been investigated in the rat. The dose-effect relationship showed that hypothermia appeared at a lower dose than a definite motor syndrome. The hypothermic response to 8-OH-DPAT was attenuated following depletion of 5-hydroxytryptamine (5-HT) by repeated intraperitoneal (IP) administration of parachlorophenylalanine (200 mg/kg) or by injection of 5,7-dihydroxytryptamine (5,7-DHT, 100 micrograms) into the region of the third ventricle; the motor behavioural response produced simultaneously was not. Indeed, after 5,7-DHT, it was increased. Quipazine (1 mg/kg, IP) antagonised the hypothermic response and facilitated the motor behaviour. Clenbuterol (2.5 mg/kg, IP) increased both hypothermic and motor responses. (+/-)-propranolol was without effect on the simple hypermotility produced by 8-OH-DPAT, although it is known to antagonise the hypothermic and stereotyped motor responses. It is concluded that 8-OH-DPAT probably produces its hypothermic effects by actions at 5-HT receptors located presynaptically on 5-HT neurones, while the stereotyped components of the serotonin syndrome appear to be mediated by post-synaptic receptors.
8-Hydroxy-2-(di-n-propylamino)tetralin↗
Captopril as an antidepressant: lack of effect in animal models of serotonergic function.
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8-Hydroxy-2-(di-n-propylamino)tetralin↗
Dieting changes serotonergic function in women, not men: implications for the aetiology of anorexia nervosa?
The increase in plasma prolactin which follows intravenous administration of L-tryptophan (LTP) was used to assess changes in brain 5-hydroxytryptamine (5-HT) function in normal male and female subjects, following a three week period of dieting. In women, but not men, there was a marked increase in the prolactin response to LTP, suggesting that dieting had caused alterations in brain 5-HT-mediated responses. In contrast, dieting did not alter the prolactin response to thyrotropin releasing hormone in either men or women, indicating that the changes in response to LTP could not be attributed to an increase in pituitary reserve of prolactin. These findings suggest that dieting alters brain 5-HT function in women but not in men. Biological factors as well as greater psychosocial pressures to diet may contribute to the high prevalence of eating disorders amongst women.
Adult↗
A review of the biochemical and neuropharmacological actions of lithium.
The pharmacological actions central to the therapeutic effects of lithium have not yet been established, despite almost 40 years of clinical use and scientific investigation. We review the biochemical and neuropharmacological data relating to this problem and attempt to identify profitable areas for further research.
Adenylyl Cyclases↗
Hypothermia induced by baclofen, a possible index of GABAB receptor function in mice, is enhanced by antidepressant drugs and ECS.
1 Intraperitoneal injection to mice of the gamma-aminobutyric acidB (GABAB) receptor agonist (+/-)-baclofen induces a dose-dependent decrease in rectal temperature. 2 Injection of (-)-baclofen intracerebroventricularly at doses that had no effect when given peripherally induced a marked hypothermia. (+)-Baclofen was without effect. 3 The decrease in rectal temperature induced by (-)-baclofen when injected intraperitoneally was highly correlated with an increase in sedation. 4 Repeated administration of amitriptyline (10 mg kg-1 daily for 14 days) resulted in mice displaying an enhanced temperature and sedation response to injection of (+/-)-baclofen (5 mg kg-1) 24 h after the last dose of antidepressant. 5 An enhanced hypothermic response was also seen following repeated administration of zimeldine, mianserin or desipramine (all 10 mg kg-1 daily for 14 days) or repeated electroconvulsive shock (ECS; 5 ECS over 10 days) 24 h after the last treatment. 6 A single administration of any of the antidepressant drugs or ECS or repeated administration of the anxiolytic drug flurazepam (20 mg kg-1 daily for 14 days) did not alter the baclofen-induced hypothermic response. 7 Administration of (+/-)-baclofen (5 mg kg-1) daily for 5 or 14 days attenuated the baclofen-induced hypothermic response. However, one pretreatment dose did not alter the response. 8 It has previously been reported that repeated baclofen administration decreases GABAB receptor number in the brain while repeated administration of antidepressant drugs and ECS increases the density of this receptor. The current data therefore suggest that baclofen-induced hypothermia may provide a simple index of GABAB receptor function in the brain and strengthens the evidence that GABAB receptor function is enhanced by antidepressant drugs and ECS.
5,7-Dihydroxytryptamine↗
The effects of electroconvulsive therapy and antidepressant drugs on monoamine receptors in rodent brain--similarities and differences.
Repeated administration to rodents of electroconvulsive shock (ECS) produces changes in brain monoamine biochemistry and function, several of which are also seen after repeated administration of antidepressant drugs. Both repeated ECS and antidepressant drug administration decrease cortical beta-adrenoceptor density and attenuate the alpha 2-adrenoceptor-mediated sedation response to clonidine injection. Neither procedure alters phenylephrine-induced locomotor activity in mice, a measure of alpha 1-adrenoceptor function. Most antidepressant drugs decrease type 2 5-hydroxytryptamine (5-HT2) receptor density in frontal cortex and 5-HT2 receptor-mediated head-twitch behaviour in mice. In contrast, repeated ECS increases both 5-HT2 receptor density and the head-twitch response, making it difficult to propose any simple hypothesis linking changes in this receptor with antidepressant activity. The putative agonist for the 5-HT1A receptor 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) produces a hypothermic response in mice, apparently by acting as an agonist at presynaptic 5-HT1 receptors. Repeated administration of antidepressant drugs and lithium markedly attenuates this hypothermic response. Repeated ECS also attenuates this response, the attenuation lasting for at least 20 days after the last ECS. Repeated ECS, but not antidepressant drug administration, markedly enhances dopamine-mediated behaviour. While the similarities in action between ECS and antidepressant drugs may help explain the therapeutic action of electroconvulsive treatment, the differences may provide clues to the efficacy of this treatment in drug-resistant depressive illness.
Animals↗