Biomedical subjects

C A Marsden

Publications and source records attributed to C A Marsden.

At least 73 records · Page 4Linked to original sources

PubMed1997

Cortical 5-HT-CCK interactions and anxiety-related behaviour of guinea-pigs: a microdialysis study.

Serotonin (5-HT) and cholecystokinin (CCK) are involved in the development of anxiety. There are only few data suggesting interactions between CCK and 5-HT under aversive conditions. In our study the cholecystokinin tetrapeptide (CCK-4) (10 microg/kg) induced 'anxious' behaviour and potentiated the increase of 5-HT release on the elevated plus maze (X-maze). The 'anxiolytic' 5-HT1A agonist 8-hydroxy-2-(di-n-propyl amino) tetralin (8-OH-DPAT; 0.3 mg/kg) reduced basal 5-HT and the increase in 5-HT release on the X-maze. 8-OH-DPAT given simultaneously with CCK-4, blocked the effects of CCK-4. The results demonstrate an interaction between CCK and 5-HT1A mechanisms via the influence on cortical 5-HT release.

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

PubMed1997

Effect of isolation-rearing on noradrenaline release in rat hypothalamus and hippocampus in vitro.

A fixed volume incubation method in conjunction with HPLC-ED analysis was employed to measure endogenous NA release in vitro in slices of hippocampus and hypothalamus from rats reared in either groups of five or in social isolation from weaning. NA in release supernatants from hippocampal slices was found to be increased in response to stimulation with high K+ (30 mM), an effect which was dependent on Ca2+. Basal NA release was also Ca2+ dependent. Isolation-rearing did not significantly alter either basal or K+-stimulated release. Clonidine (10 microM) caused an inhibition of basal NA release in both regions and in both rearing groups, however there was no significant effect of isolation-rearing for this response although the response tended to be greater in the hippocampus from isolates. Idazoxan (10 microM) significantly increased basal NA release in hippocampal and hypothalamic slices in both rearing groups, but this effect was significantly greater in the hippocampus from isolation-reared rats. These findings suggest there may be a region-specific change in the sensitivity of the alpha2-adrenoceptor in isolates. Taken together with previous findings, there is evidence to suggest that isolation-rearing alters the sensitivity of the presynaptic terminal alpha2-autoreceptor in the hippocampus.

Adrenergic alpha-Agonists↗

PubMed1997

Barakol, a natural anxiolytic, inhibits striatal dopamine release but off uptake in vitro.

The present study investigated the effects of barakol on the in vitro release of endogenous and radiolabelled dopamine from rat striatal slices in comparison with the dopamine receptor agonists, quinelorane dihydrochloride (1 microM) and pergolide methanesulfonate (100 microM), and the dopamine receptor antagonist, S(-)-eticlopride hydrochloride (10 microM) using a semi-superfusion method and high-performance liquid chromatography with electrochemical detector measurement of endogenous dopamine. Barakol (1, 10 and 100 microM) reduced K(+)-stimulated endogenous dopamine release as did the dopamine D2 receptor agonists but had no effect on [3H]dopamine release. The inhibition of barakol (10 microM) on K(+)-stimulated endogenous dopamine release was antagonised by a dopamine D2 receptor antagonist, eticlopride. Barakol (0.1 nM-10 microM) had no effect on [3H]dopamine uptake except at the highest concentration (100 microM) when inhibition was observed. The results indicate that barakol might act as a dopamine agonist to inhibit endogenous dopamine release without a change in dopamine uptake.

Animals↗

PubMed1997

Effect of imipramine treatments on the 5-HT1A-receptor-mediated inhibition of panic-like behaviours in rats.

The escape behaviour induced in rats by injecting D,L-homocysteic acid (DHL) into the dorsal periaqueductal grey area (DPAG) was used as an animal model of panic attacks to investigate the effect of imipramine, a drug used for the treatment of panic disorder, on the sensitivity of 5-HT1A receptors in the DPAG. Rats given imipramine (10 mg/kg per day SC for 3 weeks or IP for 2-3 days) received 250 nl saline or the 5-HT1A agonist 8-OH-DPAT (8.6 nmol) into the DPAG 10 min before inducing the escape response with DLH. As expected, 8-OH-DPAT produced a marked decrease in the average speed of the DLH-induced flight response. The short-term treatment with imipramine changed neither the DLH-induced escape behaviour nor the effect of prior 8-OH-DPAT administration on this response. In contrast, long-term treatment with imipramine enhanced the 5-HT1A-mediated inhibition, as the decrement in the amplitude of the flight response produced by 8-OH-DPAT was 96% after this treatment compared to 41% in controls. The injection of 8-OH-DPAT also significantly decreased the amplitude of the freezing behaviour observed at the end of the flight response in rats given imipramine for 3 weeks, but not in controls. The long-term imipramine treatment, however, did not significantly decrease the amplitude of DLH-induced flight and freezing behaviours in absence of prior 8-OH-DPAT administration. Finally, 8-OH-DPAT failed to inhibit the DLH-induced flight and freezing behaviours in rats withdrawn from imipramine after long-term treatment (10 mg/kg per day x 21 days). It is suggested that an alteration at the level of the DPAG-5-HT1A receptor system is implicated in the therapeutic and withdrawal effect of imipramine in panic disorder.

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

PubMed1997

Cholecystokinin increases extracellular dopamine overflow in the anterior nucleus accumbens via CCK(B) receptors in the VTA assessed by in vivo voltammetry.

Differential pulse voltammetry was used to investigate the extracellular dopamine (DA) and DOPAC signal in the anterior part of nucleus accumbens (N.acc.) after microinjection of cholecystokinin (CCK) derivatives into the ventral tegmental area (VTA). Both the mixed CCK(A)/CCK(B) receptor agonist CCK-8s and the selective CCK(B) receptor agonist CCK-4 caused a dose-dependent increase in the DA signal after doses of 10 ng and 100 ng while CCK-8s had no effect on the DOPAC signal. The CCK(A) receptor antagonist L 364,718 (25 microg/kg i.p.) as well as the CCK(B) receptor antagonist L 365,260 (25 microg/kg i.p.) were administered prior to microinjection of 100 ng CCK-8s and L 365,260, but not L 364,718, completely inhibiting the DA increase produced by CCK-8s. Analysis of the tissue levels of DA and its main metabolites in the anterior part of N.acc. revealed no changes after CCK-8s microapplication into VTA. The presented data indicate a CCK(B) receptor-mediated increase in extracellular DA in the anterior N.acc. after microapplication of CCK derivatives into the VTA.

Animals↗

PubMed1997

Social isolation in the rat enhances alpha 2-autoreceptor function in the hippocampus in vivo.

This study investigated the effects of isolation rearing from weaning in rats on extracellular noradrenaline in the dorsal hippocampus in vivo, measured using microdialysis. Male Lister hooded rats were obtained at weaning and reared in social isolation or in groups for six to eight weeks. Basal noradrenaline efflux did not differ between isolation- and group-reared rats. Local K+ stimulation (50 and 100 mM) increased noradrenaline efflux in the hippocampus of both groups of rats; however, this effect was greater in group-reared rats (50 mM K+). The alpha 2-adrenoceptor agonist, clonidine (0.3 mg/kg, i.p.), reduced noradrenaline efflux in both groups of rats, but this decrease was greater in isolates. Systemic (1.0 mg/kg, i.p.) and local (via the probe; 100 microM) administration of the alpha 2-adrenoceptor antagonist, idazoxan, increased noradrenaline efflux, but these responses were also greater in isolation-reared rats. The magnitudes of the idazoxan-induced increases in noradrenaline efflux were similar for both systemic and local administration, indicating that presynaptic terminal alpha 2-adrenoceptors were predominantly involved. Furthermore, although tail pinch increased noradrenaline efflux in both isolation- and group-reared rats, there was a significant/attenuation in the response in the isolation- compared to group-reared rats. Taken together with previous findings, the present results provide evidence in favour of an isolation-induced enhancement in the function of the presynaptic terminal alpha 2-autoreceptor in the dorsal hippocampus in vivo, resulting in decreased functional responsiveness of hippocampal noradrenergic nerve terminals.

Adrenergic alpha-Agonists↗

PubMed1997

Central c-fos expression following 20kHz/ultrasound induced defence behaviour in the rat.

Exposure of rats to aversive stimuli produces specific defence behaviour including the emission of 20-27kHz ultrasonic calls. Recent studies in this laboratory have shown that rats exposed to a 20kHz ultrasound tone display flight behaviour similar to that seen naturally, or following stimulation of brain regions associated with anxiety and defence. The present study examines the effect of ultrasound exposure on the central expression of the immediate early gene c-fos in the rat, in order to examine the brain structures activated by such behaviour. Ultrasound presentation produced rapid locomotor activity characteristic of defence behaviour, including brisk running and jumping behaviour. Animals showed dense c-fos like immunoreactivity in the dorsal periaqueductal grey matter, basolateral, medial, central amygdala, paraventricular thalamic nuclei and the dorsomedial nuclei of the hypothalamus, which was significantly greater than in either home-cage or arena control rats. These results suggest that exposure to artificially generated ultrasound can induce defence behaviour which is associated with activity in brain regions important in mediating aversion. This technique offers the potential of generating unconditioned aversive behaviour in rats in a non invasive way.

Acoustic Stimulation↗

PubMed1997

A simple method for measuring dopamine release from rat brain slices.

In many circumstances, rapid information is required about the effects of drugs on neurotransmitter release in brain, and a common method used is measurement of radiolabelled release from superfused brain slices or synaptosomes in vitro. However, the method requires expensive equipment and is not readily adapted to the measurement of endogenous release. The method described here uses readily available cheap chromatographic columns to measure both radiolabelled and endogenous dopamine (DA) release from striatal slices in repeated incubation samples. The results showed that the [3H]DA release is sensitive to temperature, K(+)-stimulation, and to both a DA agonist (pergolide) and an antagonist (eticlopride). Endogenous DA release was also stimulated by high K+ (20 mM) and sensitive to a DA agonist. Pergolide (100 microM) reduced both [3H]DA and endogenous DA release, while eticlopride (10 microM) increased [3H]DA, but not endogenous DA release. The results demonstrate an alternative cheap and quick way to study neurotransmitter release from brain in vitro.

Animals↗

PubMed1997

Studies of inositol phosphate export from neuronal tissue in vitro.

Recent in vivo microdialysis studies have demonstrated the presence of extracellular levels of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] that can be increased in a concentration-dependent manner by muscarinic receptor activation. The aim of the present study was to determine whether extracellular levels of Ins(1,4,5)P3 could be measured in vitro. Despite rapid increases in internal Ins(1,4,5)P3 levels after stimulation with 1 mM carbachol, there was no change in external levels in both rat brain cortical slices and human neuroblastoma SH-SY5Y cells. Suprafusion of myo-[3H]inositol-prelabelled hippocampal slices with 1 mM carbachol caused an increase in 3H-inositol phosphates over basal levels in the perfusate after 10 min, reaching a peak (223 +/- 56% of basal) 20 min after suprafusion with carbachol was started. This response to carbachol was potentiated in the presence of 30 mM K+. Analysis of the individual 3H-inositol phosphates in the perfusate revealed that levels of [3H]inositol monophosphate, [3H]inositol bisphosphate, [3H]inositol trisphosphate, and [3H]inositol tetrakisphosphate were all significantly increased. A similar increase in extracellular 3H-inositol phosphates was demonstrated in SH-SY5Y cells incubated with 1 mM carbachol for 30 min. This response was again enhanced by 30 mM K+, although the intracellular response was not potentiated. Possible roles for extracellular inositol phosphates are discussed.

Animals↗

PubMed1997

The effect of central and systemic injection of the 5-HT1A receptor agonist 8-OHDPAT and the 5-HT1A receptor antagonist WAY100635 on periaqueductal grey-induced defence behaviour.

The effects of the selective 5-HT(1A) agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT) and the selective 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperzinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxamide trichloride (WAY100635) on periaqueductal grey (PAG)-stimulated defence behaviour were tested in the rat. Microinjection of the excitatory amino acid, D, L-homocysteic acid (DLH) into the dorsal region of the PAG produced overt aversive behaviour characteristic of the defence response, consisting of explosive motor behaviours which were quantified in terms of their duration and the number of arena revolutions and jumps made by the animal. Intra-PAG pre-treatment with 8-OHDPAT (3, 10 and 25 nmol in 250 nl) 10 min before DLH stimulation significantly attenuated the defence behaviour. This could be reversed by peripheral application of WAY100635 (0.1 mg/kg). In contrast, peripheral 8-OHDPAT (0.03, 0.1 and 0.3mg/kg) produced a significant potentiation of the DLH response which could also be blocked by peripheral WAY100635. When WAY100635 (10 nmol in 250 nl) alone was given into the PAG a significant increase in DLH induced behaviours was observed whereas peripherally applied WAY100635 (0.1 mg/kg) was without effect. These data support previous findings which indicate that serotonergic modulation of aversive behaviours such as defence can be mediated by 5-HT(1A) receptors. Furthermore there is evidence to indicate a differential involvement of pre- and postsynaptic 5-HT(1A) receptors.

Animals↗

PubMed1996

Behaviour of the transgenic (mREN2)27 rat.

The first model of genetically engineered hypertension, the transgenic rat TGR (mREN2)27, provides a unique opportunity to study the behavioural effects of an altered brain renin-angiotensin system. The TGR (mREN2)27 rats, characterised by fulminant hypertension, show differences in both the peripheral and central angiotensin systems. The behaviour of male transgenic TGR (mREN2)27 and male Sprague-Dawley rats were determined by 4 behavioural tests. While on the elevated X-maze the TGR (mREN2)27 rat showed a greater 'anxiogenic' profile (fewer open arm entries) than the control Sprague-Dawley rats, this 'anxiogenic' profile increased further during a second exposure to the elevated X-maze 24 h later. In comparison the behaviour of the male Sprague-Dawley rats was not different between the two exposures to the elevated X-maze. Locomotor activity did not differ between either the TGR (mREN2)27 or Sprague-Dawley rats when placed in a 1 m2 open-field for 10 min. A short period of fluid-deprivation (3 h) reversed the 'anxiogenic' profile of the TGR (mREN2)27 on the elevated X-maze. Administration of captopril (20 mg . kg-1 body weight) in the drinking water of the TGR (mREN2)27 rats and Sprague-Dawley rats reversed the anxiogenic profile of the TGR (mREN2)27 rat on the elevated X-maze but did not alter the behaviour of the Sprague-Dawley rats.

Animals↗

PubMed1996

Perinatal cocaine reduces responsiveness to cocaine and causes alterations in exploratory behavior and visual discrimination in young-adult rats.

Lister hooded female rats were exposed to either saline or cocaine (20 mg/kg s.c.) from gestational day 10 every other day until weaning (postnatal day 25). The effects of maternal cocaine exposure on novelty-induced exploration and on spontaneous and cocaine-induced motor activity were evaluated in young-adult male offspring (4 weeks after weaning). Rats exposed to cocaine during development spent less time exploring two novel objects. Lack of habituation upon the second presentation of the objects and failure in the ability to discriminate between the novel and familiar object were also found in cocaine exposed offspring. Moreover, maternal cocaine treatment did not affect spontaneous motor activity (active time, average speed and rearing) in rats subjected to an open field test. Furthermore, perinatal exposure to cocaine significantly attenuated acute cocaine (15 mg/kg i.p.)-induced hyperactivity. These data indicate that developmental exposure to cocaine, at dose levels below those producing gross malformations and/or overt signs of neurotoxicity, causes behavioral changes characterized by an altered responsiveness to environmental and pharmacological challenges.

Animals↗

PubMed1996

Effects of social isolation rearing on learning in the Morris water maze.

Impaired learning has been shown as a consequence of isolation-rearing in a variety of paradigms. However, there are situations in which learning in isolation-reared rats is enhanced or unimpaired compared to socially reared rats. The present experiments investigated the effects of isolation rearing on place navigation in the Morris water maze. Two complementary paradigms were studied: isolation and socially reared rats were exposed to the water maze either without drug pretreatment or following systemic administration of scopolamine. Two conditions were examined: place learning and reversal learning. Male Lister hooded rats were either housed singly (isolation reared) or in groups of four (social reared) from weaning at 21 days of age. Six weeks later place learning and reversal learning were determined using the Morris water maze. The time taken to locate the submerged island (escape latency) was used as the measure of learning ability. The results showed that place learning, and reversal learning were enhanced in isolation reared rats compared to socially reared controls. Pretreatment with scopolamine (0.3 and 0.5 mg/kg, i.p.) produced a dose-related cognitive deficit as shown by an increase in the escape latency. Scopolamine (0.3 mg/kg) impaired both place and reversal learning but this was less pronounced in isolation compared to socially-reared rats. These results suggest that rearing in isolation may enhance spatial learning though central cholinergic mechanisms.

Animals↗

PubMed1996

Acute acidosis elevates malonaldehyde in rat brain in vivo.

Oxidative stress in brain tissue was measured experimentally in situ using microdialysis to sample the extracellular environment for a lipid peroxidation breakdown product and antioxidants. The extracellular concentrations of the lipid peroxidation product malonaldehyde (MDA) and the antioxidants ascorbic acid (AA) and uric acid (UA) were measured in rat cortex and striatum in vivo using microdialysis coupled to HPLC with UV detection. Tissue acidosis following ischaemia and epileptic seizures may contribute to neuronal damage, which may be mediated by reactive oxygen species. Perfusion of microdialysis probes with acidic artificial cerebrospinal fluid (pH 6) led to a significant increase in the sampled concentration of MDA and the antioxidant ascorbic acid. Simultaneous perfusion of ascorbate (5 mM) with acidic ACSF (pH 6) completely attenuated the rise in lipid peroxidation. This study provides in vivo evidence for acidosis induced oxidative stress in brain tissue and an antioxidant action of ascorbate. The methodology described here can provide direct in vivo information in respect of oxidative stress in experimental situations. The method could equally be applied to the assessment of oxidative stress in a number of pathological models not necessarily confined to the CNS.

Acidosis↗

PubMed1996

Increased 5-HT2C receptor responsiveness occurs on rearing rats in social isolation.

To investigate whether isolation rearing alters 5-hydroxytryptamine2C (5-HT2C) receptors, the effect of the serotonin agonist m-chlorophenylpiperazine (mCPP) was examined on elevated plus-maze behaviour, plasma corticosterone and brain 5-HT2C receptor protein levels in rats. There was no distinction between behaviour or corticosterone levels in drug-free isolates or socially housed rats exposed to the elevated plus-maze. The anxiogenic response to mCPP (decrease in open arm entry and time and an increase in stretch attend postures) on the elevated plus-maze was greater in isolation than in socially reared controls without any concomitant difference in the hypolocomotor effect of mCPP in the two groups. mCPP produced a greater elevation in plasma corticosterone in isolates than in group-housed controls. Hippocampal 5-HT2C receptor protein-like immunoreactive levels were significantly lower following mCPP than saline only in rats reared in isolation. These results indicate that increased 5-HT2C receptor responsiveness accompanies isolation-rearing and may contribute to the enhanced response to stress and the increased neophobia seen in this animal model of trait anxiety/depression. In isolation reared rats, rapid down-regulation of supersensitive 5-HT2C receptors may occur in the hippocampus following 5-HT agonist challenge.

Animals↗

PubMed1996

Pharmacological manipulation of ultrasound induced defence behaviour in the rat.

Rats exposed to aversive stimuli display species specific defence behaviour as part of their natural survival strategy. one component of this behaviour is the production of ultrasonic calls in the 20 to 27-kHz range, which are thought to serve a communicative role. The present study has examined the behavioural effects of exposing rats to artificially generated ultrasound and the ability of three distinct pharmacological agents to modify this response. Single tone 20 kHz ultrasound exposure for 1 min produced intensity-related locomotor behaviour, characteristic of defence behaviour, which could be measured using a computer tracking system. This was significantly reduced by peripheral pretreatment with the benzodiazepine, diazepam (0.3 and 3.0 mg/kg IP). Pretreatment with the 5-HT agonist 1-(3-chlorophenyl) piperazine (mCPP) (0.5-2.0 mg/kg IP) produced a dose-related reduction in the ultrasound-induced response. The alpha 2 adrenoceptor antagonist, yohimbine (0.5-5.0 mg/kg IP), caused an increase in the response at the lower dose (0.5 mg/kg) and a decrease at the two higher doses (2.0 and 5.0 mg/kg). The present findings suggest that defence behaviour in the rat can be artificially produced by 20 kHz ultrasound; this is sensitive to pharmacological manipulation and may offer a novel animal model of aversive behaviours that are associated with human panic.

Adrenergic alpha-Antagonists↗

PubMed1996

Effect of social isolation on the reinforcing properties of morphine in the conditioned place preference test.

It is widely accepted that early environmental influences may affect the behaviour of the adult animal and the responsivity to psychotropic drugs. Isolation rearing is an important variable in this regard. The present experiments compared the effects of isolation and social rearing of rats on the reinforcing properties of morphine. Male Lister hooded rats were raised from weaning either alone (isolation reared rats) or in groups of four rats per cage (socially reared rats). Four weeks later, the rats were tested for their sensitivity to morphine using a conditioned place preference test. Comparisons were made between socially and isolation-reared rats with respect to preconditioning and postconditioning following either saline or morphine (1 and 5 mg/kg SC) pretreatment. The results from the preconditioning phase demonstrated that rats reared either socially or in isolation had least preference for one quadrant that was then selected as the treatment quadrant. After saline conditioning, the socially reared rats still showed a significant (p < 0.05) less preference for the treatment quadrant relative to the opposite quadrant. Following morphine (1 and 5 mg/kg) conditioning, socially reared rats spent significantly more time (p < 0.05) in the treatment quadrant relative to the opposite quadrant, whereas isolation-reared rats failed to display morphine-induced place preference. These results demonstrate that social isolation decreases the reinforcing properties of morphine.

Animals↗

PubMed1996

Barakol: a potential anxiolytic extracted from Cassia siamea.

The behavioural effects of an extract of Cassia siamea, a plant used in Thai traditional medicine, and barakol, its active chemical, were studied on an elevated plus-maze compared with diazepam. An aqueous extract of C. siamea (1, 6, and 12 g/kg body wt., orally) produced a small increase in the percentage of the open: total number of arm entries and time, time spent on the end of the open arms, total number of arm entries, and number of rears/min. Barakol [10 mg/kg, intraperitoneally (IP)] significantly increased all of these behavioural parameters in a manner similar to diazepam (1 mg/kg, IP, 30 or 60 min before testing), except that barakol and not diazepam increased both the number of rears and total arm entries. Barakol at 25 and 50 mg/kg increased the percentage of the open: total number of arm entries and time and number of rears. The results indicate that barakol has anxiolytic properties similar to diazepam but differs from diazepam in that it also increases exploratory and locomotor behaviour, as shown by the number of rears and total arm entries.

Animals↗