Biomedical subjects

G Curzon

Publications and source records attributed to G Curzon.

At least 55 records · Page 3Linked to original sources

PubMed1989

8-OH-DPAT increases corticosterone but not other 5-HT1A receptor-dependent responses more in females.

The 5-HT1A receptor subtype agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (50-1000 micrograms/kg s.c.) dose dependently increased rat plasma corticosterone. Tube restraint for 30 min also increased plasma corticosterone; this effect was completely blocked by (-)-pindolol (1 mg/kg i.p.). Increases of corticosterone following either 8-OH-DPAT injection or restraint were significantly greater in female animals. The restraint stress-induced changes but not those due to 8-OH-DPAT were decreased by pretreatment with the tranquiliser chlordiazepoxide (10 mg/kg i.p.). In anaesthetized rats, restraint no longer significantly affected corticosterone levels but 8-OH-DPAT caused increases which (though much attenuated) were significantly greater in the females. Dose-dependent increases of plasma corticosterone also resulted on infusing 8-OH-DPAT (500-1500 ng) into the paraventricular nucleus of the hypothalamus; increases were significantly greater in the females. As mentioned in the discussion, these results may be relevant to the greater incidents of depression in women and the possible role of adrenal corticoids in the illness.

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

PubMed1989

Anxiogenic-like effects of mCPP and TFMPP in animal models are opposed by 5-HT1C receptor antagonists.

1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (0.1-1.0 mg/kg) reduce total interaction time in a rat social interaction test under low light familiar conditions and its following components; grooming, following, crawling over, fighting, sniffing. Locomotion was only reduced by the highest dose of mCPP. mCPP also reduced activity in the light but not total locomotion in a light/dark transition test. These results suggest that mCPP (and TFMPP) are anxiogenic but not sedative in these tests. The effect of mCPP on social interaction was blocked by three antagonists which share a high affinity for 5-HT1C and 5-HT2 receptors: mianserin, cyproheptadine and metergoline but not by the 5-HT2 antagonists ketanserin or ritanserin or the 5-HT1A and 5-HT1B antagonists cyanopindolol and (-)-propranolol. It was prevented by a low (0.05 mg/kg) but not by a high (1.0 mg/kg) dose of ICS 205,930 a specific 5-HT3 antagonist reported to be anxiolytic at low doses. It was also prevented by chronic pretreatment with the anxiolytic drug chlordiazepoxide. These results argue for an anxiogenic action of mCPP mediated by 5-HT1C receptors. Since the chronic chlordiazepoxide pretreatment did not prevent the hypolocomotion or hypophagia induced by mCPP at high dosage (5 mg/kg) these latter effects are unlikely to be secondary to anxiety.

Animals↗

PubMed1989

Hippocampal 5-HT synthesis and release in vivo is decreased by infusion of 8-OHDPAT into the nucleus raphe dorsalis.

Infusion of the serotonin-1A (5-HT1A) agonist, 8-hydroxy-2-di(n-propylamino)tetralin (8-OHDPAT) (0.5, 1.0 and 2.0 micrograms) into the dorsal raphe, decreased extracellular 5-HT as measured by dialysis in the ventral hippocampus and also decreased 5-HT synthesis in both the hippocampus and the rest of the brain as measured by 5-hydroxytryptophan (5-HTP) accumulation following decarboxylase inhibition by NSD 1015.

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

PubMed1989

5-Hydroxytryptamine and corticosterone in an animal model of depression.

1. Rat plasma corticosterone increases during 2 hr restraint stress. The animals then exhibit hypophagia and decreased locomotion occurs on placement 24 hr later in an open field. Repeating the restraint daily for 5-7 days leads to adaptation. Failure to adapt is the depression model which is associated with three factors implicated in the illness ie increased plasma glucocorticoid level, female sex and inadequate 5-HT function as revealed by behavioural response to the agonist 5-methoxy-N,N-dimethyl 5-HT. However, the greater stress induced rise of corticosterone in female rats may reflect a greater response to activation of hypothalamic 5-HT receptors mediating corticoid release. 2. The model responds appropriately to chronic antidepressant pretreatment. Single injections of 5-HT1A agonists (8-OH-DPAT, buspirone, ipsapirone, gepirone) but not of benzodiazepine anxiolytics have similar effects. Therefore, 5-HT1A agonists may have antidepressant activity. Both behavioural and neurochemical evidence indicates that the adaptive effects of 5-HT1A agonists on the depression model are associated with desensitisation of somatodendritic 5-HT1A autoreceptors.

Animals↗

PubMed1989

Concurrent determination of effects of p-chloroamphetamine on central extracellular 5-hydroxytryptamine concentration and behaviour.

1. The effects of p-chloroamphetamine (PCA) (5 mg kg-1, i.p.) on extracellular concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were monitored in the frontal cortex of conscious, freely moving rats by means of intracerebral dialysis. Concomitant behaviour comprising the 5-HT behavioural syndrome (reciprocal forepaw treading, headweaving, wet dog shakes) and locomotion and grooming was also recorded. 2. PCA markedly and transiently increased extracellular 5-HT but extracellular 5-HIAA values decreased to a moderate extent. 3. The time-course of 5-HT changes correlated positively (P less than 0.001) with those of the three components of the 5-HT syndrome but did not correlate significantly with locomotion and correlated negatively (P less than 0.01) with grooming. 4. As previous work using conventional methodology did not reveal clear relationships between the effects of PCA on 5-HT metabolism and behaviour, the present results emphasise the value of in vivo dialysis in the study of the neurochemical mediation of the behavioural effects of drugs.

Amphetamines↗

PubMed1989

An in vivo dialysis and behavioural study of the release of 5-HT by p-chloroamphetamine in reserpine-treated rats.

1. Reserpine (2.5 mg kg-1 i.p.) decreased rat brain 5-hydroxytryptamine (5-HT) by 86% 24 h later but most components of the 5-HT-dependent behavioural syndrome induced by p-chloroamphetamine (PCA, 5 mg kg-1 i.p.) or 5-methoxy-N,N-dimethyltryptamine (5-MeODMT, 5 mg kg-1 i.p.) over 1 h after administration were unaffected. However, Straub tail was increased after giving PCA or 5-MeODMT and head weaving was decreased after giving 5-MeODMT. 2. Frontal cortex extracellular 5-HT concentrations of vehicle pretreated rats before injection of PCA, as calculated from dialysate 5-HT concentrations, were about 1/1000th of corresponding brain values. Extracellular 5-hydroxyindoleacetic acid (5-HIAA) and brain values were comparable with each other. Dialysate 5-HT increased after PCA with peak values at 20-40 min. 3. Reserpine pretreatment reduced dialysate 5-HT concentration before PCA was given but the net increase (AUC) over the 1 h after PCA did not differ significantly from that seen in animals pretreated with vehicle. Dialysate 5-HIAA values slowly decreased after PCA injection in both reserpine and vehicle pretreated groups. 4. The results suggest that PCA causes the 5-HT syndrome by releasing 5-HT from the neuronal cytoplasm but that physiological release of 5-HT occurs from vesicular stores.

Amphetamines↗

PubMed1988

Adaptation of female rats to stress: shift to male pattern by inhibition of corticosterone synthesis.

In a previous study, male rats showed behavioural deficits after a single restraint stress but not after 5 daily restraint periods (i.e. adaptation had developed): female rats although less affected by single restraint failed to adapt over the same time course. This sex difference was associated with the male but not the female rats showing enhanced behavioural responses to the 5-HT agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) after 5 restraint periods. In the present study, the role of the greater increases of plasma corticosterone in stressed females in these sex differences was studied. The corticosterone synthesis inhibitor metyrapone (75 mg/kg i.p.) was given to attenuate the rise of corticosterone to a level typical of stressed males. This resulted in the behavioural deficits of the female rats being shifted in the direction of the male pattern. Thus, their deficits in open field activity and food intake after single and repeated stresses were potentiated and opposed respectively. The latter effect was associated with increased responses to 5-MeODMT. Metyrapone alone was without significant effect. Brain regional 5-HT metabolism was unaffected. The results are consistent with corticosterone facilitating adaptation to single restraint but impairing adaptation to repeated restraint. As failure to adapt to repeated stress is an animal model of depression, results as a whole suggest that increased corticoid levels and decreased 5-HT functional activity may have a role in the development of the illness and its greater incidence in women.

Adaptation, Physiological↗

PubMed1988

Evidence that the hyperphagic response to 8-OH-DPAT is mediated by 5-HT1A receptors.

The 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) at a dose of 1 mg/kg s.c. increased food intake in free feeding rats. 8-OH-DPAT-induced feeding was blocked by metergoline which has comparable affinity for 5-HT1A, 5-HT1B, 5-HT1C and 5-HT2 receptors. This is consistent with the hyperphagia being mediated by an action at 5-HT receptors. Evidence against the involvement of 5-HT2 or 5-HT3 receptors was provided by the lack of effect of methysergide, ketanserin, MDL 72222 and ICS 205930 on the feeding response. Blockade of the hyperphagia by (-)- but not (+)pendolol which stereoselectively interacts with 5-HT1 receptors indicated an involvement of this receptor type. The lack of effect of ketanserin suggests that the 5-HT1C site is not involved as it has high affinity for both 5-HT2 and 5-HT1C receptors. Blockade of the hyperphagia by spiperone suggests mediation by 5-HT1A rather than 5-HT1B receptors. Although spiperone also blocks dopamine and alpha 2-adrenoreceptors, involvement of these sites is unlikely as neither the DA antagonist haloperidol nor the alpha 2-adrenoceptor antagonist idazoxan blocked 8-OH-DPAT-induced feeding. These results indicate that 8-OH-DPAT-induced feeding is mediated by 5-HT1A receptors.

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

PubMed1988

Infusion of the 5-hydroxytryptamine agonists RU24969 and TFMPP into the paraventricular nucleus of the hypothalamus causes hypophagia.

The 5-HT1B agonist RU24969 when given either systemically (1 mg/kg SC) or by infusion (0.5, 1.0, 2.0 micrograms) into the region of the paraventricular nucleus of the hypothalamus caused dose-dependent hypophagia in rats previously deprived of food for 18 h. Similar results were obtained at the above dosages of 1-[3-(trifluoromethyl) phenyl] piperazine (TFMPP), which acts on 5-HT1B and possibly also on 5-HT1C receptors. Neither drug significantly affected locomotion following central administration. Food intake was significantly decreased when the 5-HT1A agonist 8-OH-DPAT was given systemically (1 mg/kg SC) to rats previously deprived of food but was unaffected when 8-OH-DPAT (1 microgram) was infused into the paraventricular nucleus of both food-deprived and free feeding rats. Therefore, hypophagia occurs when hypothalamic 5-HT1B (and possibly 5-HT1C) but not 5-HT1A receptors are activated.

Animals↗

PubMed1988

Evidence that hypophagia induced by mCPP and TFMPP requires 5-HT1C and 5-HT1B receptors; hypophagia induced by RU 24969 only requires 5-HT1B receptors.

Male Sprague-Dawley rats deprived of food for 18 h were injected with the 5-HT agonists RU 24969, 1-(3-chlorophenyl)piperazine (mCPP) or 1-[3-(trifluoromethyl)phenyl)]piperazine (TFMPP) and 20 min later presented with their normal diet. Food intake was determined 1, 2 and 4 h later. All three drugs reduced intake over 1 and 2 h. Three out of four drugs with high affinity for 5-HT1C receptors (metergoline, mianserin, and mesulergine but not cyproheptadine) opposed hypophagia caused by mCPP. Another drug reported to have high affinity for the 5-HT1C site, 1-naphthyl-piperazine (1-NP), also blocked the hypophagic response to mCPP at doses which attenuated mCPP-induced hypolocomotion. Only one of the above drugs (metergoline) which also has high affinity for other 5-HT sites opposed hypophagia caused by RU 24969. Two out of three 5-HT1B receptor antagonists [(+/-) cyanopindolol, (-) propranolol, but not (-) pindolol)] which oppose hypophagia caused by RU 24969 (Kennett et al. 1987) also opposed hypophagia caused by mCPP. The 5-HT2 antagonists ketanserin and ritanserin, the 5-HT3 antagonist ICS 205-930 and the alpha 2 adrenoceptor antagonist idazoxan did not oppose the hypophagic effect of mCPP. In agreement with results for mCPP, hypophagia caused by TFMPP was opposed by both, mianserin and (+/-) cyanopindolol. Given alone, mianserin 1-NP and cyproheptadine but not ICS 205-930 increased food consumption of normally fed rats. The results suggest that RU 24969-induced hypophagia depends on 5-HT1B receptors but not on 5-HT1C receptors, while mCPP (and TFMPP)-induced hypophagia may depend on both receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Antagonists↗

PubMed1988

The antiemetic drug trimethobenzamide prevents hypophagia due to acetyl salicylate, but not to 5-HT1B or 5-HT1C agonists.

Pretreatment with the antiemetic agent trimethobenzamide (TMB) prevented the hypophagic response of rats to acetyl salicylate (a known emetic in man and dogs). However, it did not affect the hypophagic responses to the 5-HT1B agonist RU24969, or to the 5-HT1C/5-HT1B agonists mCPP and TFMPP. The results therefore suggest that the hypophagic effects of the 5-HT agonists do not involve a malaise-dependent mechanism similar to that mediating the effect of acetyl salicylate.

Animals↗

PubMed1988

Application of serial sampling of cerebrospinal fluid in pharmacodynamic studies with a drug active in the CNS: heptabarbital concentrations at onset and offset of loss of righting reflex in rats.

As cerebrospinal fluid (CSF) possesses unique characteristics in order to explore concentration-pharmacological response relationships of drugs active in the CNS, the practicability of serial sampling of CSF was tested in a study with heptabarbital. Concentrations in CSF and plasma were measured simultaneously in individual rats during and after an intravenous infusion for 30 min. At the end of the infusion, the distribution equilibrium was attained with a CSF/plasma concentration ratio of 0.38, roughly equal to the fraction unbound to protein. When concentrations in blood and CSF were determined at the onset and offset of loss of righting reflex concentrations in blood were significantly greater at onset (146 +/- 19 mg/l) than at offset (108 +/- 16 mg/l, n = 6), whereas concentrations in CSF were identical (39 +/- 5 and 38 +/- 5 mg/l, respectively). This confirmed the earlier observation that the CSF is pharmacokinetically indistinguishable from the site of action. When the duration of the loss of righting reflex was varied, concentrations of heptabarbital in CSF at onset and offset were similar, independent of the duration of the loss of righting reflex (1-5 hr). These findings demonstrate the absence of the development of acute tolerance and confirmed that no (inter)active metabolites interfered with the pharmacological response. In a total number of 26 rats the concentrations in CSF at onset and offset of loss of the righting reflex were compared. The interindividual variation was 13-15% and the intra-individual variation was only 4-6%. The results demonstrate the usefulness of serial sampling of CSF in pharmacodynamic studies with centrally acting drugs.

Animals↗

PubMed1988

Concurrent monitoring of central carbamazepine and transmitter amine metabolism and motor activity in individual unrestrained rats using repetitive withdrawal of cerebrospinal fluid.

A method for repeated withdrawal of cerebrospinal fluid (CSF) from the cisterna magna was used in a pharmacokinetic and behavioural study of conscious, freely-moving rats, given the antiepileptic drug carbamazepine (35 mg/kg i.p.). Pharmacokinetic constants (i.e. time to peak concentration, peak concentration, area under the curve and t 1/2) for the drug and its primary metabolite carbamazepine-10,11-epoxide and also concentrations of acidic metabolites of 5-hydroxytryptamine and dopamine were obtained for the CSF of individual rats. A pharmacodynamic constant, the effective concentration of drug in CSF for 50% inhibition of motor activity was also determined for each animal. The above data provides good indices of the corresponding values for carbamazepine and its metabolite in brain insofar as a separate experiment showed good correlations between CSF and brain for concentrations of both the drug and its metabolite. Carbamazepine appeared to be largely responsible for the depression of motor activity as the metabolite, at the levels attained, seemed to have little effect. The changes in motor activity were not associated with altered concentrations of the metabolites of 5-hydroxytryptamine or dopamine in the CSF. While the investigation did not reveal major advantages in monitoring the drug under study in CSF rather than in serum it illustrates the potential of the CSF method as a simple way to obtain neuropharmacokinetic and neuropharmacodynamic profiles of the action of drugs in individual rats.

Animals↗

PubMed1988

Evidence that mCPP may have behavioural effects mediated by central 5-HT1C receptors.

1. The effects of 1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl)phenyl] piperazine (TFMPP) on activity of rats in a novel cage, and on the rotorod and elevated bar co-ordination tests was examined. 2. Peripherally administered mCPP and TFMPP dose-dependently reduced locomotion, rearing, and feeding scores but not grooming of freely fed rats placed in a novel observation cage. Yawning behaviour was increased. Similar effects were also observed after injection of mCPP into the 3rd ventricle. 3. Co-ordination on a rotating drum of both untrained and trained rats was impaired following mCPP but co-ordination on an elevated bar was not. 4. The hypoactivity induced by mCPP was opposed by three antagonists with high affinity for the 5-hydroxytryptamine (5-HT1C) site; metergoline, mianserin, cyproheptadine and possibly also by a fourth antagonist mesulergine. Metergoline, mianserin and cyproheptadine also opposed the reduction in feeding scores. However, neither effect of mCPP was antagonized by the 5-HT2-receptor antagonists ketanserin or ritanserin, the 5-HT3-receptor antagonist ICS 205-930, the 5-HT1A and 5-HT1B-receptor antagonists (-)-pindolol, (-)-propranolol and (+/-)-cyanopindolol or the 5-HT1A-, 5-HT2- and dopamine receptor antagonist spiperone. The specific alpha 2-adrenoceptor antagonist idazoxan was also without effect. 5. Hypoactivity induced by TFMPP was similarly antagonized by mianserin but unaffected by (+/-)-cyanopindolol. 6. These results suggest that the hypoactivity is mediated by central 5-HT1C-receptors and that mCPP and possibly TFMPP may be 5-HT1C-receptor agonists. 7. As mianserin, cyproheptadine and mesulergine in the absence of mCPP did not increase locomotion but increased the number of feeding scores, the activation of 5-HT1C-receptors may be of physiological importance in the control of appetite. The possible relevance of these results to the therapeutic and side-effects of clinically used antidepressants (particularly trazodone and mianserin) and anorexigenic drugs is discussed.

Animals↗

PubMed1988

Serotonergic mechanisms of depression.

Data gathered for the past 30 years suggest 5-HT abnormalities in depression, but it is still unknown whether serotonin has a major causal role. Depression is often regarded as a result of defective serotonergic function, but it is also possible that this defect is an indication of an ineffective compensatory response to abnormally high serotonergic function. Abnormal 5-HT function could be a result of disturbances at various pre- and postsynaptic levels. The disturbances reported at most of these levels are largely subject to dispute. Specific abnormalities can occur in specific subgroups and can be either state or trait dependent. Nevertheless, 5-HT hypotheses have been helpful for the development of drugs, although even here there is disagreement as to their actual mechanism of action. Two recent developments can help to clear up these uncertainties. First, the discovery of many types of 5-HT receptors and the increasing availability of drugs specifically related to them provides new adaptable research tools as well as the possibility of new therapies. Second, data provided by studies of humans and by animal models suggest that vulnerability to depression depends on disturbances of both 5-HT and the hypothalamohypophysial axis.

Depressive Disorder↗

PubMed1987

Hypothermia induced by the putative 5-HT1A agonists LY165163 and 8-OH-DPAT is not prevented by 5-HT depletion.

The putative 5-HT1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (LY165163, PAPP) (1, 2, 4, 10 mg/kg s.c.) caused a significant and dose-dependent hypothermia in rats, 30 and 60 min after injection. The decreases of temperature were less marked than that caused by 8-OH-DPAT 1 mg/kg s.c.). Depletion of brain serotonin (5-HT) by 91% following pretreatment with p-chlorophenylalanine (pCPA) (150 mg/kg i.p. on three successive days) significantly enhanced the hypothermic effects of both 8-OH-DPAT (0.25 mg/kg s.c.) and LY165163 (4 mg/kg s.c.). LY165163-induced hypothermia was also somewhat enhanced following depletion of hypothalamic 5-HT by 76% after infusion of 5,7-dihydroxytryptamine (5,7-DHT) (150 micrograms) into the third ventricle. Results indicate that the hypothermia induced by the putative 5-HT1A agonists LY165163 and 8-OH-DPAT in the rat is not dependent on presynaptic 5-HT stores and is therefore probably mediated by postsynaptic 5-HT receptors.

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

PubMed1987

5-HT1B agonists induce anorexia at a postsynaptic site.

Ru 24969 and two other putative 5-HT1B agonists 1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl) phenyl]piperazine (TFMPP) and RU 24969 dose-dependently decreased food intake over 4 h (and in the case of RU 24969 also over 24 h) in free-feeding male Sprague-Dawley rats. Decreasing the doses of the agonists below the range eliciting anorexia did not cause hyperphagia. The anorexic effect of RU 24969 over 4 h was antagonised by metergoline, (-)pindolol and (+/-)cyanopindolol, but not by ketanserin, spiperone or haloperidol. Metergoline and (+/-)cyanopindolol also antagonised the anorexic effect of RU 24969 over 24 h. This data is consistent with an action mediated by 5-HT1B receptors. Locomotor activity induced by RU 24969 was markedly antagonised by haloperidol despite its lack of effect on the anorexic response. Persistence of the anorexic effect of RU 24969 after p-chlorophenylalanine (pCPA) pretreatment suggests that 5-HT1B agonists induce anorexia at a postsynaptic 5-HT receptor.

Animals↗

PubMed1987

Neurochemical and behavioural evidence for an agonist action of 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (LY 165163) at central 5-HT receptors.

1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (LY 165163, PAPP) (1 mg/kg s.c.) significantly decreased 5-hydroxytryptophan (5-HTP) accumulation in cortex, hippocampus, striatum, septum, pons + medulla and midbrain and increased DOPA accumulation in the cortex and striatum following inhibition of aromatic amino acid decarboxylase with NSD 1015. LY 165163 increased food intake in non-food-deprived rats over 2, 4 and 24 h after administration. Depletion of brain 5-hydroxytryptamine (5-HT) by parachlorophenylalanine (pCPA) prevented the hyperphagic effect over 2 and 4 h after treatment with LY 165163 (1 mg/kg). Components of the postsynaptically mediated 5-HT behavioural syndrome were not detected at doses of LY 165163 between 1 and 10 mg/kg, although locomotion was increased at lower doses and the rats were inactive at the highest dose. Results in general indicate that LY 165163 is a centrally active agonist at 5-HT presynaptic receptors.

5-Hydroxytryptophan↗