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Biomedical subjects

C A Marsden

Publications and source records attributed to C A Marsden.

At least 91 records · Page 5Linked to original sources
PubMed1996

Social isolation increases aggressive behaviour and alters the effects of diazepam in the rat social interaction test.

Isolation rearing in the early stages of life has been shown to modify a variety of behaviours in many animals and the responsitivity to psychotropic drugs. The aims of the present study were to investigate the effects of isolation rearing on anxiety using the social interaction paradigm and to compare the effects of diazepam on social interaction behaviours in isolation and socially reared rats. Male Lister hooded rats were reared from weaning either alone (isolation reared) or in groups of four (socially reared) for 6 weeks and then were tested for social interaction. Both isolation and socially reared rats were exposed to the social interaction test either without drug treatment or following saline or diazepam (1 and 2.5 mg/kg, i.p., 30 min before testing). The results demonstrate that under high light in an unfamiliar arena, the isolation compared to the socially reared rats showed a significantly (P < 0.01) higher level of social interaction, manifested as increases in aggressive and avoidance behaviours, and that this interaction occur for a greater length of time during the test period (10 min). However, when the light level was decreased or when the arena was familiar, active social interaction of isolation reared rats decreased but increased in the socially reared rats. In both conditions the isolation reared rats displayed more aggressive behaviours, in particular biting and boxing the partners which did not occur with the socially reared rats. Pretreatment of diazepam (1 and 2.5 mg/kg., i.p.) caused a dose-related reduction in aggressive behaviours in rats reared under both conditions but increased passive interactions in the socially reared rats. In contrast diazepam (2.5 mg/kg) reduced active interaction in the isolation reared rats but had no effect on passive interaction. These results indicate that isolation rearing increases aggressive behaviours and alters the effects of diazepam.

Aggression↗
PubMed1996

Effects of 8-OHDPAT and 5-HT1A antagonists WAY100135 and WAY100635, on guinea-pig behaviour and dorsal raphe 5-HT neurone firing.

1. The effects of 5-HT1A antagonists on guinea-pig behaviour and dorsal raphe neuronal activity were investigated. 2. WAY100135 (10 mg kg-1, s.c.) and WAY100635 (1 mg kg-1, s.c.) significantly reduced the behaviours induced by 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) (1 mg kg-1, s.c.) indicative of post-synaptic 5-HT1A receptor antagonism. WAY100635 (10 mg kg-1, s.c.) alone induced ear twitches, which were antagonized by ketanserin (1 mg kg-1, s.c.), but no other overt behaviours. 3. WAY100635 (0.125 mg kg-1, i.v.) produced a right-ward shift in the dose-related inhibition of neuronal firing by 8-OHDPAT (5-100 micrograms kg-1, i.v.) but did not affect the maximum inhibition induced by 8-OHDPAT indicating competitive antagonism between 8-OHDPAT and WAY100635 at the 5-HT1A somato-dendritic autoreceptor in the dorsal raphe nucleus of the guinea-pig. WAY100635 also produced a dose-related increase in the basal firing of 5-HT neurones in the dorsal raphe nucleus and restored the firing of dorsal raphe neurones previously inhibited by 8-OHDPAT (10 micrograms kg-1, i.v.). 4. The results indicate that WAY100635 is a competitive 5-HT1A antagonist in the guinea-pig. Furthermore WAY100635 can increase 5-HT neuronal firing, suggesting that it blocks a 5-HT1A receptor-mediated inhibitory tone acting on guinea-pig 5-HT neurones resulting in increased 5-HT release and 5-HT2 receptor-mediated behaviours.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Differential effects of phenytoin and sodium valproate on seizure-induced changes in gamma-aminobutyric acid and glutamate release in vivo.

The effects of intraperitoneal administration of the anticonvulsants phenytoin and sodium valproate were compared with ethosuximide on maximal electroshock seizure-related changes in rat hippocampal gamma-aminobutyric acid (GABA) and glutamate release in vivo as measured by microdialysis. There were immediate increases in GABA and glutamate in the 5 min post-ictal period, followed by a sustained reduction in GABA levels. Glutamate levels, however, were subsequently reduced until 20 min post-ictal before gradually increasing above basal. All animals displayed tonic hind-limb extension that was blocked by phenytoin (20 mg/kg) and sodium valproate (400 mg/kg) but not ethosuximide (150 mg/kg). Phenytoin attenuated the immediate post-ictal increase observed in glutamate whilst sodium valproate enhanced GABA release and prevented its secondary post-ictal inhibition. Ethosuximide was without effect on the post-ictal changes. These are the first data to show detailed seizure-induced amino acid changes and the in vivo effects of anticonvulsants on them in the seizure model.

Animals↗
PubMed1995

Detection of the lipid peroxidation product malonaldehyde in rat brain in vivo.

The extracellular concentrations of the lipid peroxidation product malonaldehyde (MDA) and the antioxidants ascorbic and uric acid were measured in rat brain in vivo using microdialysis coupled to HPLC with ultra violet spectrophotometry. Treatment with kainic acid at pH 4.1 (50 nmol) caused a significant increase in the sampled concentration of MDA but no significant changes in the antioxidants. Treatment with the same dose of kainic acid at pH 7.2 did not cause a significant increase in MDA, although some changes were noted in the antioxidants. The paper demonstrates the ability to monitor changes of a lipid peroxidation breakdown product as a measure of oxidative stress in vivo. Furthermore, the data suggests that the toxic action of kainic acid in acute preparations may be due to the elevation of hydrogen ions.

Animals↗
PubMed1995

Extracellular glutamate in the nucleus accumbens during a conditioned emotional response in the rat.

In vivo microdialysis combined with HPLC-EC analysis was used to monitor extracellular glutamate and GABA in the medial nucleus accumbens of Lister hooded rats during acquisition and expression of a conditioned emotional response. Footshock paired with tone (acquisition of conditioned emotional response) causes a significant decrease in extracellular glutamate during the period of footshock followed by a marked, but short lasting increase when the rats return to their home cage. Expression of the conditioned emotional response on exposure to the contextual cue produces no change in glutamate during exposure to the contextual cue, but a short lasting increase after. Thus, both the conditioned emotional response and footshock are associated with marked, but short lasting, increases in extracellular glutamate in the nucleus accumbens which, in both cases, occurred after the aversive stimuli, i.e., when the rats are returned to their home cage. In contrast, when control rats are exposed to the testing box without giving footshock there is an increase in extracellular glutamate during the exposure period and this is accompanied by exploratory behaviour. The conditioned emotional response (contextual cue), footshock and exposure of the control rats to the test box all resulted in increased extracellular GABA during exposure to the test situation. These results suggest that increases in extracellular glutamate in the medial nucleus accumbens caused by the conditioned emotional response or footshock are probably associated with relief from, rather than response to danger.

Animals↗
PubMed1995

Isolation rearing prevents the reinforcing properties of amphetamine in a conditioned place preference paradigm.

Social isolation has been demonstrated to alter individual reactivity to addictive drugs. The present experiments compared the effects of isolation rearing and socially rearing rats on the reinforcing properties of amphetamine. Male Lister hooded rats were housed from 21 days (weaning) either alone (isolation reared rats) or in groups of four rats per cage (socially reared rats). Six weeks later, the rats were tested for their sensitivity to d-amphetamine (1.5 and 5 mg/kg) using a conditioned place preference paradigm. The treatment quadrant was selected as that in which the rat spent least time during a preconditioning trial. After saline conditioning, the socially reared rats showed a significant (P < 0.05) aversion for the treatment quadrant relative to the opposite quadrant. Following amphetamine (1.5; 5 mg/kg) conditioning, socially reared rats spent significantly more time (P < 0.05) in the treatment quadrant relative to the opposite quadrant while isolation reared rats failed to display either the aversion effect of saline conditioning or amphetamine induced place preference. These results demonstrate isolation rearing prevents the reinforcing properties of amphetamine.

Age Factors↗
PubMed1995

Evidence for the involvement of the 5-HT1A receptor in CCK induced satiety in rats.

The present study was designed to examine possible interactions between exogenous CCK and the 5-HT1A receptor subtype mediated serotonergic effects on feeding in rats. The somatodendritic 5-HT1A receptor agonist 8-OH-DPAT (0.32 mg/kg sc) evoked feeding in freely feeding rats. This effect was attenuated by treatment with CCK-8 (1, 5 and 25 micrograms/kg ip). In food deprived rats, CCK-8 (40 micrograms/kg ip) significantly reduced the size of a test meal. Treatment with the 5-HT1A receptor antagonist WAY-100135 (10 mg/kg ip) antagonized this anorectic effect of CCK-8. WAY-100135 on its own did not affect food intake. These results suggest the involvement of the 5-HT1A receptor subtype in mediating 5-HT-CCK interactions in the control of food intake in rats.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Attenuation of CCK-induced aversion in rats on the elevated x-maze by the selective 5-HT1A receptor antagonists (+) WAY100135 and WAY100635.

The present study determined the effect of pretreatment with "silent" selective 5-HT1A receptor antagonists on cholecystokinin (CCK)-mediated effects on rat behaviour in the elevated x-maze model of anxiety. In the absence of 5-HT1A receptor antagonists, non-sulphated cholecystokinin-octapeptide (CCK-8ns; 10 and 50 micrograms/kg, i.p.; 30 min prior to testing) produced an anxiogenic profile of behaviour on the x-maze, reducing the number of open arm entries and the number of exploratory head dips, while increasing the level of risk-assessment as measured by the number of stretched-attend postures. CCK-8ns did not, however, alter ambulatory activity. Two 5-HT1A receptor antagonists were employed in these experiments: (+)WAY100135 (the active enantiomer of N-tert-butyl-3-(4-(2-methoxyphenyl)piperzin-1-yl)- 2-phenylpropronamine) [sequence: see text] and WAY100635 (N-[2-[4(2-methoxyphenyl)-1-piperazinyl-1-piperazinyl]-N-2- pyridinyl)cyclohexanecarbonate [sequence: see text] trihydrochloride). When administered 10 min prior to CCK-8ns, (+) WAY100135 and 0.3 mg/kg s.c.) significantly attenuated profile of CCK-8ns. (+)WAY100135 was also demonstrated to significantly inhibit postsynaptic 5-HT1A receptor-mediated 8-OH-DPAT (8-hydroxy-2-(di-N-propylamino)tetralin)-induced 5-HT syndrome at the same dose used in the x-maze experiment. Neither (+)WAY100135 nor WAY100635 had any affects on ambulatory activity. These results support a CCK/5-HT1A receptor interaction in the modulation of aversion in rats exposed to the elevated x-maze.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Determination of in vivo amino acid neurotransmitters by high-performance liquid chromatography with o-phthalaldehyde-sulphite derivatisation.

The measurement of amino acid neurotransmitters by high-performance liquid chromatography (HPLC) has emerged as a reliable and sensitive method. This paper describes a method which employs electrochemical (EC) detection of amino acid derivatives formed by a reaction with o-phthalaldehyde (OPA) in the presence of sulphite ions. This is discussed in relation to the problems of previously reported methods based on OPA derivatisation. Precise separation of the following 7 amino acid standards is achieved using isocratic elution: serine, glycine, taurine, glutamate, arginine, alanine and GABA, in order of increasing retention time. Total elution time is 25 min. Derivatisation proceeds at room temperature and the derivatives are stable for up to 5 h. This technique has the sensitivity to determine the concentrations of amino acid neurotransmitters in cerebrospinal fluid (CSF) and an in vivo microdialysis method is discussed for the detection of basal and potassium-stimulated levels of gamma-aminobutyric acid and glutamate from rat hippocampus.

Animals↗
PubMed1995

Computer analysis and quantification of periaqueductal grey-induced defence behaviour.

The pharmacological study of midbrain-evoked aversive behaviours is commonly measured in terms of electrical escape thresholds, although studies which examine the actual expression of the behaviour are being introduced. A computer-driven automated tracking system has been developed to record and analyse the very rapid locomotor activity produced by the defence response. Stimulation of the midbrain periaqueductal grey (PAG) matter in rats with the excitatory amino acid D,L-homocysteic acid (DLH) produced very rapid and short-lasting escape behaviour which was tracked by computer. The system, VideoTrack, determines the speed and distance travelled by the animal and stores and statistically analyses the data. VideoTrack was able to detect a pharmacological modifications of the response; anti-aversive effects produced by intra-PAG pretreatment with the 5-HT1A agonist 8-hydroxy 2-(di-n-propylamino)tetralin (8-OHDPAT) and its reversal by peripheral pretreatment with the 5-HT1A antagonist N-[2-[-(2-methoxyphenyl)-1-piperazinyl]ethyl-N- (pyridinyl)cyclohexanecarboxanide (WAY 100635).

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1995

Conditioned dopamine release: dependence upon N-methyl-D-aspartate receptors.

The study have investigated the effect of a conditioned emotional response using a contextual cue on dopamine release in the rat nucleus accumbens, measured with in vivo microdialysis, and its inhibition by N-methyl-D-aspartate antagonist dizocilpine maleate. The extracellular level of dopamine in the medial nucleus accumbens markedly increased for up to 40 min when rats were given mild footshock in the testing box. When the rats were returned to the testing box, but not given footshock (conditioned emotional response), there was an immediate and long-lasting (80 min) increase in extracellular dopamine. Dizocilpine maleate (50 mumol/l) administered into the nucleus accumbens through the dialysis probe had no significant effect on the immediate increase in dopamine induced by conditioned emotional response but completely prevented the later phase. Dizocilpine maleate had no effect on basal dopamine release in control rats but decreased basal dopamine in rats exposed to footshock 2 h previously. The alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate/kainate antagonist 6-cyano-7-nitroquinnoxaline-2,3-dione (100 mumol/l) had no effect on the increase in dopamine release in response to conditioned emotional response. The results indicate that the acquisition of conditioned emotional response causes long-lasting changes in the mechanisms involved in the glutamatergic control of dopamine release in the nucleus accumbens. Furthermore glutamate inputs into the nucleus accumbens may also regulate the delayed phase of conditioned dopamine release during expression of conditioned emotional response to a contextural cue through activation of N-methyl-D-aspartate receptors.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1995

Decreased GABA release following tonic-clonic seizures is associated with an increase in extracellular glutamate in rat hippocampus in vivo.

The effects of maximal electroshock, used as a model of generalized seizures, were studied on extracellular GABA and glutamate levels in the ventral hippocampus of the freely-moving rat, using in vivo microdialysis. Following a maximal electroshock there was a rapid decline in GABA levels (46 +/- 5%) in the 20 min immediately after the seizure and levels remained depressed for a further 60 min. However, although there was a transient small decrease (11 +/- 2%) in glutamate levels in the first 20 min post-ictally, there followed a more prolonged, larger increase in the next 40 min. Maximal electroshock, administered in the absence of extracellular calcium, did not change GABA levels, while glutamate levels were again increased (42 +/- 8%) in the 40-80 min after the shock. Local perfusion with nickel (1 mM) to block T-type calcium channels had no effect on basal GABA or glutamate levels but prevented maximal electroshock-induced changes in both amino acids. Experiments were carried out to test the hypothesis that the post-ictal increased glutamate release was due to the decrease in GABA release. Perfusion with the potent GABA re-uptake inhibitor NNC-711, for 60 min prior to administration of maximal electroshock, increased GABA levels (436 +/- 58%) and abolished the seizure-induced decrease. Basal glutamate levels were not affected by perfusion with NNC-711 but subsequent maximal electroshock also failed to affect levels. Local perfusion with the GABAA receptor antagonist bicuculline (1, 10 and 100 microM) had no effect on basal GABA levels but glutamate levels were increased (46 +/- 5%) after perfusion with 100 microM bicuculline.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1994

The influence of 5-hydroxytryptamine re-uptake blockade on CCK receptor antagonist effects in the rat elevated zero-maze.

In this study, the elevated zero-maze model of anxiety was used to investigate CCK receptor antagonist effects on the behaviour of male Lister-hooded rats and to demonstrate, by administering antagonists in the presence or absence of selective 5-hydroxytryptamine (5-HT) re-uptake inhibitors, the involvement of 5-HT in the mediation of these effects. Devazepide, a selective CCKA receptor antagonist, L-365,260 (3R(+)-N-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin- 3-yl-N1- (3-methyl-phenyl)urea) or CI-988 (4-([2-[[3-(1H-indol-3-yl)-2-methyl-1- oxo-2-[[(tricyclo[3.3.1.1.(3.7)]-dec-2-yloxy)-carbonyl]-amin o]- propyl]-amino]-1-phenylethyl]-amino)-4-oxo-[R-(R*,R*)]-butanoate- N-methyl-D-glucamine), both selective CCKB receptor antagonists, were administered 30 min prior to testing. Behavioural analysis during testing included measures of risk-assessment behaviours (e.g. stretched-attend posture) in addition to time spent on the open quadrants. Devazepide induced significant anxiolytic effects, whereas CI-988 produced inconsistent results and L-365,260 was ineffective. When administered simultaneously with the 5-HT re-uptake inhibitors zimelidine or Wy 27587 (N-[[[1-[(6- fluoro-2-naphthalenyl)methyl]-4-piperidinyl]amino] carbonyl]-3-pyridine carboxamide methyl sulphonate salt), the significant anxiolytic effect induced by devazepide was dose-dependently and significantly attenuated. Zimelidine and Wy27587 had little effect alone on zero-maze behaviour at the lower of two doses given. These data show that the elevated zero-maze, in conjunction with the analysis of 'risk-assessment' behaviours, is an anxiety model which is sensitive to the anxiolytic effects of CCK receptor antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Evidence for altered alpha 2-adrenoceptor function following isolation-rearing in the rat.

This study investigated central alpha 2-adrenoceptor function in differentially reared rats. Rats reared from weaning were either housed singly or in groups of five. Measurements of spontaneous ambulatory activity at 4 weeks postweaning showed that isolates were more hyperactive on exposure to a novel environment than grouped rats. alpha 2-Adrenoceptors were investigated using alpha 2-adrenoceptor agonist-induced behaviours, [3H]-idazoxan binding and measurement of forskolin-stimulated cyclic AMP accumulation. Clonidine (0.001-1.0 mg/kg IP) induced mydriasis in both groups with no difference observed in the response between the isolation and group-reared animals. Clonidine (0.01-0.5 mg/kg IP) induced hypoactivity in both groups, with the effect significantly greater in the isolation-reared rats. Idazoxan markedly attenuated both responses, confirming their induction by alpha 2-adrenoceptor stimulation. Clonidine-induced hypoactivity and mydriasis are mediated by pre- and postsynaptic alpha 2-adrenoceptors, respectively; therefore the results suggest rats reared in isolation have enhanced presynaptic but unchanged postsynaptic alpha 2-adrenoceptor function. Saturation binding experiments using [3H]-idazoxan were undertaken to determine alpha 2-adrenoceptor number (Bmax) and affinity (Kd) in membranes prepared from the frontal cortex and hippocampus. Analysis of binding data revealed an increase in receptor number in the hippocampus of isolates. Cyclic AMP accumulation was measured in hippocampal slices from differentially reared rats. Isolation-rearing did not affect cyclic AMP accumulation in response to stimulation by forskolin (30 microM). However, the selective alpha 2-adrenoceptor agonist, UK14304, produced a significantly greater inhibition of cyclic AMP accumulation in slices from isolated rats, confirming changes in alpha 2-adrenoceptor function following isolation rearing.

Adrenergic alpha-Antagonists↗
PubMed1994

Effect of the putative 5-HT1A antagonists WAY100135 and SDZ 216-525 on 5-HT neuronal firing in the guinea-pig dorsal raphe nucleus.

The selective 5-hydroxytryptamine1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OHDPAT, 0.5-35 micrograms kg-1 i.v.) produces a dose related reversible inhibition (ED50 = 6.5 micrograms kg-1 i.v.) of the firing of serotonergic neurones in the dorsal raphe nucleus of the guinea-pig. Administration of N-tert-butyl-3- (4-(2-methoxyphenyl)piperazine-1-yl)-2phenylpropanamide dihydrochloride (WAY100135, 0.5 mg kg-1 i.v.), a specific 5-HT1A antagonist, antagonized the 8-OHDPAT induced inhibition of neuronal firing whilst methyl 4-(4-[4-(1,1,3-trioxo-2H-1,2-benzoisothiazol-2-yl)butyl]-1- piperazinyl) 1 H-indole-2-carboxylate (SDZ 216-525, 0.1-0.5 mg kg-1 i.v.) (also a putative 5-HT1A antagonist) reduced the basal firing of 5-HT neurones and furthermore failed to antagonize the inhibition produced by 8-OHDPAT. These results indicate that WAY 100135 is a silent and selective 5-HT1A antagonist whereas SDZ 216-525 demonstrates a partial agonist activity at the somatodendritic 5-HT1A autoreceptor in the guinea-pig DRN.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1994

Serotonin 5-HT1A receptor activation increases cyclic AMP formation in the rat hippocampus in vivo.

In vivo microdialysis was used to examine the efflux of cyclic AMP (cAMP) into the extracellular fluid of the ventral hippocampus in the freely moving rat. The changes in extracellular cAMP concentration were monitored in response to forskolin and the serotonin 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT). The basal level of hippocampal extracellular cAMP was 2.3 +/- 0.2 pmol/ml (n = 6), after a 3-h postsurgery stabilisation period. Perfusion of forskolin (100 microM) through the probe for 30 min significantly increased the efflux of cAMP, which returned to baseline levels within 90 min. 8-OH-DPAT (0.3 mg/kg s.c.) also significantly increased cAMP efflux, whereas a similar volume of saline had no effect. Desensitisation of the 8-OH-DPAT-induced increase in cAMP efflux was observed following a second administration of 8-OH-DPAT after a 4-h interval. Administration of 8-OH-DPAT did not alter the efflux of cAMP when forskolin was perfused through the probe. Pretreatment with WAY 100135 [N-tert-butyl 3-4-(2-methoxyphenyl)piperazine-1-yl-2-phenylpropanamide dihydrochloride] (5 mg/kg s.c.), a specific 5-HT1A receptor antagonist, prevented the 8-OH-DPAT-induced increase in cAMP efflux. The data indicate that the 8-OH-DPAT-induced increase in cAMP efflux in vivo is mediated by a 5-HT1A receptor.

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