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C A Marsden

Publications and source records attributed to C A Marsden.

At least 163 records · Page 9Linked to original sources
PubMed1987

Repeated atypical neuroleptic administration: effects on central dopamine metabolism monitored by in vivo voltammetry.

Changes in extracellular DOPAC levels were monitored simultaneously in the nucleus accumbens and striatum of halothane/N2O anaesthetised rats using in vivo differential pulse voltammetry with carbon fibre electrodes following repeated administration of the atypical neuroleptics thioridazine and clozapine. Thioridazine (20 mg/kg s.c.) increased the DOPAC peak in the nucleus accumbens and striatum of rats treated with saline for the previous 21 days by 66% +/- 5 S.E.M. and 91% +/- 16 respectively. No such increase was recorded in the nucleus accumbens of rats previously treated with thioridazine (20 mg/kg s.c.) for 21 days. Similarly the increase in the striatum produced by a challenge dose on day 22 was markedly attenuated compared to controls although analysis of absolute DOPAC peak heights revealed extracellular DOPAC to be elevated above basal levels in this region (but not the nucleus accumbens) indicating a possible selective action of this drug to induce absolute tolerance to its acute effects in the nucleus accumbens after repeated administration. Administration of increasing doses of apomorphine (0.05, 0.1, 0.25 mg/kg s.c.) 1 h after a challenge dose of thioridazine (20 mg/kg s.c.) on day 22 to rats treated with the neuroleptic for the previous 21 days produced a progressive decrease in extracellular DOPAC levels both in the nucleus accumbens and striatum. Repeated administration of clozapine (50 mg/kg s.c.) for 21 days failed to induce tolerance to the acute effects of this drug, extracellular DOPAC levels increasing by 60% +/- 8 and 90% +/- 18 in the nucleus accumbens and striatum respectively following challenge with the drug on day 22.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Adrenaline in the CNS: in vivo evidence for a functional pathway innervating the hypothalamus.

This article reviews the evidence, obtained from studies employing the technique of intracerebral dialysis, to monitor changes in extracellular adrenaline in the hypothalamus, that adrenaline is released from nerve endings in the hypothalamus and has a functional role. Studies using [3H] adrenaline to determine the specificity of uptake mechanisms for adrenaline indicate that labelled adrenaline is also taken up by noradrenergic nerve endings. This supports the need to develop techniques to monitor changes in endogenous release of adrenaline. In this study, it has been shown that inhibition of phenylethanolamine-N-methyltransferase selectively decreases tissue levels in the hypothalamus and in vivo release of adrenaline, while monoamine oxidase inhibition and antagonism of alpha 2-adrenoceptors increases the release of both adrenaline and noradrenaline. The "selective" noradrenergic neurotoxin DSP4 caused an initial increase in the release of both catecholamines, followed by a marked decrease in their release. Stimulation of the adrenaline-containing neurones in the rostral ventrolateral medulla (C1 region) increased the release of adrenaline in the posterior hypothalamus, but not that of noradrenaline, while also increasing mean arterial blood pressure. Pharmacological evidence indicates that B2-adrenoceptors in the hypothalamus and the spinal cord are involved in the rise in mean arterial pressure, as the response is reduced by a selective B2-antagonist (ICI 118551). The rise in mean arterial blood pressure during C1 stimulation is enhanced by the alpha 2-antagonist idazoxan, supporting observations that alpha 2-adrenoceptors are involved in the pre-synaptic regulation of release of adrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗
PubMed1987

Behavioural and biochemical evidence for the release of noradrenaline in mouse brain by TRH and some of its biologically stable analogues.

Small doses of clonidine probably induce hypoactivity (a distinct form of sedation) by stimulating presynaptic alpha 2-adrenoceptors. This was attenuated by injection of 0.1-10 mg/kg of thyrotropin releasing hormone (TRH) or its biologically stable analogues, CG3509, CG3703 and RX77368, when these were given 10 min before clonidine. This effect was dose-dependent in all cases, but the analogues were more potent than TRH. The TRH metabolites, TRH acid and histidyl-proline diketopiperazine (10 mg/kg) were without effect. This response was still attenuated by the analogues, but not TRH, when these were given 1 hr before clonidine. The results, therefore, suggested that it was the basic tripeptide structure which was active and TRH was less potent than its analogues because of rapid metabolism. Attenuation of hypoactivity by TRH and analogues was not due to increased dopaminergic function because apomorphine (5 mg/kg) was ineffective. Thyrotropin releasing hormone (20 mg/kg), CG3509 (10 mg/kg) and CG3703 (1 mg/kg) also induced locomotor activity and produced various other behavioural changes. This was inhibited by prazosin (3 mg/kg) and haloperidol (0.5 mg/kg) but not by yohimbine (1 mg/kg). Apomorphine (5 mg/kg)-induced activity was inhibited by haloperidol and yohimbine but not by prazosin. This indicated that the activity produced by the TRH compounds, but not apomorphine, was partly mediated by alpha 1-adrenoceptors. Both CG3509 (10(-5) and 10(-4) M) and RX77368 (10(-4) M) evoked the release of endogenous noradrenaline from slices of hypothalamus in vitro. The TRH analogues, however, had no affinity for alpha 1- or alpha 2-adrenoceptors in ligand-receptor binding experiments. Viewed overall, the data showed that TRH and its analogues induced the release of noradrenaline in the brain. In addition, a comparison of the behavioural effects of TRH compounds with dopamine and alpha 1-adrenoceptor agonists suggested that in mice these behavioural responses resulted from stimulation of both noradrenergic and dopaminergic function.

Adrenergic alpha-Antagonists↗
PubMed1987

Involvement of catecholaminergic neurones and alpha-adrenoceptors in the wet-dog shake and forepaw licking behaviour produced by the intrathecal injection of an analogue of thyrotrophin-releasing hormone (CG 3509).

Intrathecal injection of the analogue of TRH, CG 3509, into conscious rats produced dose-related wet-dog shakes and forepaw licking, which showed a bell-shaped relationship of intensity to dose. Pretreatment with alpha-MPT intraperitoneally, markedly reduced levels of noradrenaline and dopamine in the spinal cord and brainstem and attenuated both CG 3509-induced responses, while intrathecal treatment with DSP4 selectively reduced noradrenaline in the spinal cord without affecting either behaviour. Since denervation supersensitivity may develop following treatment with DSP4, these results are not inconsistent with a proposal that bulbospinal noradrenergic neurones modulate the behaviour induced by CG 3509. Wet-dog shakes and forepaw licking induced by CG 3509 were reduced by pretreatment with phenoxybenzamine or prazosin, suggesting that a tonic noradrenergic pathway may facilitate both behavioural responses through alpha 1-adrenoceptors. Methoxamine, combined with CG 3509 partially attenuated the wet dog shake behaviour, but methoxamine produced marked hindlimb jerking which might physiologically antagonise wet-dog shakes. Concomitant administration of clonidine and CG 3509 potently reduced wet-dog shakes in a dose-related manner but did not significantly affect forepaw licking, while idazoxan did not significantly affect either response. The latter findings imply that alpha 2-adrenoceptors play different roles in modulating the two behavioural responses and the possible synaptic location of the receptors is discussed. Taken together these results suggest that CG 3509 may release noradrenaline from bulbospinal neurones regulating motor function.

Adrenergic alpha-Agonists↗
PubMed1987

Measurement of catecholamines, indoleamines, thyrotrophin releasing hormone and substance P in rat and human spinal cord using a common extraction method.

An extraction method is described that allows the measurement of 5-hydroxyindoleacetic acid, dopamine, noradrenaline, substance P and thyrotrophin releasing hormone in the same sample of rat or human spinal cord. The substances were extracted using a mixture of 45% ethanol/0.1 M acetic acid and 0.02% sodium metabisulphite. The amines were then measured using high performance liquid chromatography with electrochemical detection and the peptides by radioimmunoassay. The common extraction method makes maximum use of limited postmortem material, reduces assay time and allows study of the interrelationships between the amines and peptides in rat or human spinal cord.

Animals↗
PubMed1987

Electrical stimulation of the C1 region of the rostral ventrolateral medulla of the rat increases mean arterial pressure and adrenaline release in the posterior hypothalamus.

By using intracerebral dialysis in combination with high performance liquid chromatography and electrochemical detection, extracellular posterior hypothalamic adrenaline, noradrenaline, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid were measured in the anaesthetized rat and changes in their levels monitored following administration of tranylcypromine and electrical stimulation of the rostral ventrolateral medulla. Tranylcypromine (10 mg/kg i.p.) administration decreased basal extracellular 3,4-dihydroxyphenylacetic acid and 5-hydroxyindole acetic acid levels with a simultaneous increase in adrenaline and noradrenaline levels. Electrical stimulation of the C1 area of the rostral ventrolateral medulla increased (+56.6%) extracellular adrenaline levels in the posterior hypothalamus with a simultaneous increase in mean arterial pressure (+48 mm Hg) compared to prestimulation control values. No change was seen in posterior hypothalamic extracellular levels of noradrenaline, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindole acetic acid during the stimulation period. Electrical stimulation of areas close to but outside the C1 region had no effect on either mean arterial pressure or posterior hypothalamic extracellular levels of the amines or the metabolites. The increase in adrenaline levels in the hypothalamus during stimulation of the C1 region supports the evidence for an adrenergic pathway from the rostral ventrolateral medulla to the hypothalamus and suggests that the increase in mean arterial pressure during electrical stimulation to the C1 region may relate to a specific increase in adrenaline levels.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1987

Lack of selectivity between the uptake of [3H]adrenaline and [3H]noradrenaline into rat hypothalamic slices.

The uptake of [3H]adrenaline and [3H]noradrenaline into rat hypothalamic slices was compared for determination of whether adrenaline uptake was independent of uptake into noradrenergic neurones. Kinetic analysis revealed a similar high-affinity uptake process for both adrenaline and noradrenaline, with Km and Vmax values within similar ranges. These uptakes were inhibited by desipramine and maprotiline in a dose-dependent manner, but the selective dopamine and 5-hydroxytryptamine uptake inhibitors benztropine and fluoxetine, respectively, were without effect. Competition for uptake sites by unlabelled adrenaline with [3H]adrenaline and [3H]-noradrenaline and by unlabelled noradrenaline with [3H]-adrenaline and [3H]noradrenaline was very similar. Lesioning of the major adrenaline-containing cell group (C1 cell group) decreased the hypothalamic adrenaline concentration but had no effect on hypothalamic [3H]adrenaline or [3H]noradrenaline uptake. The results suggest that exogenous adrenaline is largely taken up by high-affinity sites on noradrenergic nerve terminals.

Animals↗
PubMed1987

Regional distribution of substance P- and thyrotrophin-releasing hormone-like immunoreactivity and indoleamines in the rabbit spinal cord.

The distribution of thyrotrophin-releasing hormone (TRH), substance P, and the indoleamines [5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA)] has been examined in selected regions of the thoracic and lumbar spinal cord of the rabbit using sensitive radioimmunoassays for the first two and HPLC with electrochemical detection for the indoleamines. The levels of TRH- and substance P-like immunoreactivity (TRH-I and SP-I, respectively) were greatest in the ventral and dorsal grey matter, respectively. The level of TRH-I in most thoracic regions was greater than that in equivalent lumbar regions, but the only segmental difference in SP-I was in the ventral grey matter, where the lumbar segment contained more immunoreactivity. 5-HT and 5-HIAA were more evenly distributed than either peptide and showed no segmental variation in levels in equivalent regions, but the ventral grey matter contained significantly higher levels of 5-HT and had a greater 5-HT/5-HIAA ratio than all other regions. The absolute levels and the overall distribution of SP-I, TRH-I, and indoleamines in the thoracolumbar cord of the rabbit was very similar to that previously reported in both rats and humans, and the possible functional role of the peptides and indoleamines in spinal neurones is discussed.

Animals↗
PubMed1987

The behavioural response to the 5-hydroxytryptamine1B (5HT1B) receptor agonist--RU-24969 may exhibit a circadian variation in the mouse.

The effects of the 5-hydroxytryptamine1B receptor agonist RU-24969 on locomotor activity were examined at different times during the light-dark cycle in the mouse. A dose-dependent hyperlocomotion was observed following RU-24969 administration which was partially antagonised by the non-selective 5-hydroxytryptamine receptor antagonist metergoline. The dose ratios for RU-24969 at two different times tested (8 hr after lights-on, L8; 5 hr after lights-off, D5) were significantly different in the presence of metergoline (2 and 5 mg/kg i.p.). The data suggest that the receptor(s) involved in the behavioural response to RU-24969 in the mouse exhibit a circadian variation.

Animals↗
PubMed1987

Thyrotrophin releasing hormone--5-hydroxytryptamine interactions in the brain studied using chronic immunization and chemical lesioning techniques.

This study investigates the effects of chemically lesioning 5-hydroxytryptamine (5HT) neurones and chronic passive immunization of central thyrotrophin releasing hormone (TRH) on 5HT and TRH mediated behavioural responses. 5HT lesions produced by 5,7-dihydroxytryptamine (5,7-DHT) enhanced the behavioural response produced by the 5HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MEODMT) while decreasing the locomotor hyperactivity observed following administration of the TRH analogue CG 3509 but having no effect on the reversal of pentobarbitone sleep-time produced by CG 3509. Chronic intracerebroventricular infusion of the purified TRH antibody markedly increased the length of pentobarbitone-induced sleep-time while enhancing the effects of CG 3509 both on locomotor activity and pentobarbitone-induced sleep. TRH antibody infusion also increased the response produced by 5-MEODMT. The results indicate that chronic passive immunization of central TRH induces changes in TRH receptor responsiveness and that there is a functional interaction between TRH and 5HT neuronal systems.

Animals↗
PubMed1986

Influence of anaesthetics on rat striatal dopamine metabolism in vivo.

The effects of 4 anaesthetics, halothane, alpha-chloralose, chloral hydrate and pentobarbitone, on rat striatal extracellular dihydroxyphenylacetic acid (DOPAC) levels were determined using in vivo voltammetry. Stable baseline levels of DOPAC were maintained under halothane/N2O and alpha-chloralose while the extracellular levels of DOPAC gradually declined under chloral hydrate or pentobarbitone anaesthesia. Administration of haloperidol (0.3 mg/kg i.p.) significantly increased DOPAC using halothane/N2O, alpha-chloralose or chloral hydrate but not under pentobarbitone anaesthesia. The greatest increase in DOPAC was seen in rats anaesthetized with alpha-chloralose greater than halothane/N2O greater than chloral hydrate greater than pentobarbitone. Apomorphine (0.5 mg/kg s.c.) given 2 h after haloperidol partially reversed the increase in DOPAC produced by haloperidol. The results suggest care needs to be exercised in the choice of anaesthetic used for voltammetric studies with pentobarbitone being the least recommended.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1986

Chronic immunization of endogenous thyrotrophin-releasing hormone (TRH) in brain alters the behavioural response to pentobarbital and a TRH analogue.

Rats were infused with purified thyrotrophin-releasing hormone (TRH) anti-serum i.c.v. for two weeks and the reversal of pentobarbital-induced anaesthesia, hypothermia and respiratory depression by central administration of a TRH analogue (CG 3509) was measured. After antibody infusion the anaesthesia time was more than doubled but the responses to CG 3509 were increased, suggesting a role for endogenous TRH in arousal mechanisms which is sensitized following chronic immunological blockade.

Anesthesia, General↗
PubMed1986

In vivo voltammetry in the suprachiasmatic nucleus of the rat: effects of RU24969, methiothepin and ketanserin.

Differential pulse voltammetry was performed in the suprachiasmatic nucleus (SCN) of anaesthetised rats. Peripheral administration of RU24969 (10 mg/kg) a 5HT1 receptor agonist, decreased the size of the 5HIAA oxidation peak whereas it was increased by the non-selective 5HT receptor antagonist methiothepin (10 mg/kg). The effects of RU24969 were attenuated by methiothepin while the 5HT2 receptor antagonist ketanserin (5 mg/kg i.p.) did not affect the response to RU24969. The results suggest that in vivo 5HT release and metabolism in the SCN is probably under the influence of the 5HT1 receptor.

Animals↗
PubMed1986

Regional distribution of immunoreactive-thyrotrophin-releasing hormone and substance P, and indoleamines in human spinal cord.

The regional distributions of thyrotrophin-releasing hormone (TRH) and substance P in postmortem human spinal cord were determined by radioimmunoassay in fresh tissue taken from 22 patients who died without known neurological disease. Dorsal, ventral, and intermediolateral spinal cord regions were obtained from different segmental levels (lumbar L1, 2, 3, and 4; thoracic groups T1-3, T4-6, T7-9, and T10-12) together with selective regions of grey matter of lumbar spinal cord. The effects on peptide levels of the age of the patient, the postmortem time interval, and freezing the tissue samples prior to assay were assessed. Levels of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in regional lumbar and thoracic tissue using HPLC with electrochemical detection. Substance P was found in the highest concentration in the dorsal spinal cord, with no significant segmental differences. In contrast, TRH was present in higher levels in the ventral rather than the dorsal spinal cord, with segmental differences. There was a significant difference in the 5-HT/5-HIAA ratio between dorsal and ventral spinal cord, with the highest ratio in the ventral spinal cord. There were no significant differences in substance P, TRH, or 5-HT levels in spinal cords between 5 and 20 h postmortem or from patients aged between 65 and 90 years. Freezing the tissue (-80 degrees C for 24 h) prior to assay significantly reduced TRH and substance P levels compared to samples assayed immediately without prior freezing.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrochemistry↗
PubMed1986

Changes in the behavioural response to a TRH analogue following chronic amitriptyline treatment and repeated electroconvulsive shock in the rat.

The arousal elicited in rats by injection into the nucleus accumbens of the thyrotrophin-releasing hormone analogue CG 3509 (orotyl-histidyl-prolineamide) was used to assess the responsiveness to thyrotrophin-releasing hormone following repeated treatment with amitriptyline or electroconvulsive shock. Fourteen day administration of amitriptyline (15 mg kg-1 i.p. twice daily) reduced the behavioural response to bilateral intra-accumbens injection of CG 3509 (2 X 2.5 micrograms). CG 3509-induced hyperactivity, recovery from pentobarbitone-induced anaesthesia and the reversal of both pentobarbitone-induced hypothermia and decreased respiration, were all significantly reduced compared to either the response of the animals prior to amitriptyline administration or that observed in rats following chronic saline administration. Repeated administration of electroconvulsive shock (5 shocks over 10 days) significantly increased CG 3509-induced hyperactivity and the degree of reversal of pentobarbitone-induced hypothermia and respiratory depression following CG 3509 administration. The results demonstrate that chronic antidepressant treatments alter the central functional responsiveness to thyrotrophin-releasing hormone. These changes are discussed with respect to the effects of antidepressant treatments on 5-hydroxytryptamine receptors and possible thyrotrophin-releasing hormone--aminergic interactions.

Amitriptyline↗
PubMed1986

Involvement of 5-HT1A- and alpha 2-receptors in the decreased 5-hydroxytryptamine release and metabolism in rat suprachiasmatic nucleus after intravenous 8-hydroxy-2-(n-dipropylamino) tetralin.

The 5-hydroxytryptamine1A-receptor agonist 8-hydroxy-2-(n-dipropylamino) tetralin (8-OH-DPAT, 0.1 mg kg-1 i.v.) decreased the height of the extracellular 5-hydroxyindoleacetic acid (5-HIAA) oxidation peak recorded in the suprachiasmatic nucleus (SCN) of the anaesthetized rat by use of differential pulse voltammetry. The decrease in extracellular 5-HIAA produced by 8-OH-DPAT could be partially attenuated by prior administration of the non-selective 5-HT receptor antagonist methiothepin (1 mg kg-1 i.v.). The 5-HT2-receptor antagonist ritanserin (0.2 mg kg-1 i.v.) did not appear to block the effects of 8-OH-DPAT. The selective ligand for 5-HT1A recognition sites TVX Q 7821 (isapirone, 1 mg kg-1 i.v.) decreased the extracellular level of 5-HIAA in the SCN but to a lesser extent than 8-OH-DPAT. The response to 8-OH-DPAT was attenuated by prior administration of TVX Q 7821 to a level suggesting that TVX Q 7821 had blocked the effect of intravenous 8-OH-DPAT. Idazoxan (0.2 mg kg-1 i.v.) an alpha 2-adrenoceptor antagonist, completely blocked the effect of 8-OH-DPAT on the 5-HIAA oxidation peak recorded in the SCN, whilst having no effect on the 5-HIAA oxidation peak when given alone. At a dose of 0.5 mg kg-1 i.v. idazoxan induced a 120% increase in the height of the indole oxidation peak, suggesting that 5-HT release and metabolism in the rat SCN may be influenced by tonic adrenergic inputs. The data in this paper suggest that 5-HT1A- and alpha 2-receptors are involved in the effects of i.v. administered 8-OH-DPAT on 5-HT release and metabolism in the SCN in vivo.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1985

In vivo voltammetric and behavioural evidence for somatodendritic autoreceptor control of mesolimbic dopamine neurones.

Somatodendritic autoreceptor control of mesolimbic dopamine neurones was assessed using in vivo differential pulse voltammetry to monitor dopamine metabolism in the nucleus accumbens following infusion of haloperidol or dopamine into the ipsilateral ventral tegmental area (VTA) of chloral hydrate anaesthetized rats. Haloperidol (2.5 micrograms/0.5 microliters) produced an increase in dihydroxyphenylacetic acid (DOPAC) levels (45%) whilst dopamine produced a transient decrease (38%). In three experiments this decrease was smaller and was followed by a large increase in DOPAC levels (108-208%). However, the results of radiolabelled drug diffusion studies suggested that the secondary rise in DOPAC in the nucleus accumbens may be due to diffusion of dopamine following infusion into the VTA. In a separate set of experiments rats were injected with haloperidol (2.5 micrograms/0.5 microliters) bilaterally into the VTA and their behaviour monitored using doppler shift radar. Haloperidol infusion produced a phase of increased exploratory behaviour lasting approximately 30 min. Both sets of data support previous electrophysiological studies suggesting the presence of functional dopamine somatodendritic autoreceptors in the mesolimbic system. The results further demonstrate the applicability of in vivo voltammetry for study of the effects of drugs on discrete receptor populations.

Animals↗