Biomedical subjects

G Curzon

Publications and source records attributed to G Curzon.

At least 73 records · Page 4Linked to original sources

PubMed1987

Single administration of 5-HT1A agonists decreases 5-HT1A presynaptic, but not postsynaptic receptor-mediated responses: relationship to antidepressant-like action.

The 5-HT1A agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), buspirone or TVXQ 7821 (ipsapirone) but not the 5-HT1B agonist RU 24969, attenuated the hyperphagic response to 8-OH-DPAT administered on the next day. Attenuation was still apparent on the fifth day after either 8-OH-DPAT or buspirone but not on the tenth day after 8-OH-DPAT administration. The ability of 8-OH-DPAT to reduce raphe 5-HIAA levels was also impaired by previous 8-OH-DPAT treatment. However, the 8-OH-DPAT or 5-methoxy-N,N-dimethyltryptamine-induced 5-HT syndromes were unaltered. The results indicate that a single pretreatment with 5-HT1A agonists rapidly desensitises 5-HT1A presynaptic receptor-mediated responses. This effect may mediate the antidepressant-like action of the drugs in an animal model of depression.

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

PubMed1987

Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression.

Previous results have suggested that behavioural adaptation to restraint might be promoted by post-restraint stimulation of 5-HT1A receptors. Therefore, rats were restrained for 2 h and injected with vehicle or 60-1,000 micrograms/kg of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) s.c. Vehicle-treated restrained rats showed reduced locomotor activity and increased defaecation in an open field test the day after the end of restraint. A single injection of 250 or 1,000 micrograms/kg 8-OH-DPAT attenuated these effects. The above locomotor deficits were also attenuated by chronic pretreatment with the antidepressants desipramine and sertraline but not by a single treatment with desipramine or the benzodiazepine anxiolytic drugs chlordiazepoxide and diazepam; none of these treatments unambiguously reversed stress-induced increases in defaecation. Evidence suggests that the above action of 8-OH-DPAT is mediated by 5-HT1A receptors since it was antagonised by the 5-HT1A antagonist spiperone but not by the 5-HT2 antagonist ketanserin and was not mimicked by the 5-HT1B agonist RU 24969. However, the 5-HT1A agonists buspirone and TVXQ 7821 (ipsapirone) and the non-specific 5-HT agonist quipazine all possess similar properties to 8-OH-DPAT in this test. The results suggest that 5-HT1A agonists may have rapid antidepressant properties.

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

PubMed1987

Immobilisation stress-induced anorexia is not due to gastric ulceration.

The relationship between the anorexia following immobilisation and the associated gastric pathology in male and female rats was investigated. Male rats were injected with saline or the histamine-H2. antagonist, ranitidine, which inhibits gastric acid secretion but does not readily enter the brain. Thirty minutes later, the animals were immobilised for 2 hours. Ranitidine pretreatment reduced the number of gastric lesions but had no effect on the degree of stress-induced anorexia. The number of gastric lesions did not correlate significantly with the degree of anorexia or weight loss. Previous studies have reported that female rats (unlike males) exhibit anorexia after repeated daily immobilisations and have greater gastric pathology following stress. Therefore, in a second experiment, female rats were pretreated with saline or ranitidine and immobilised for 2 hours/day for 4 days. The drug did not decrease the number of lesions observed after this treatment. However, as in the first experiment, the number of lesions did not correlate significantly with anorexia or weight loss. It is therefore unlikely that immobilisation stress-induced anorexia in either male or female rats is merely a consequence of gastric ulceration.

Animals↗

PubMed1987

Blockade of dopamine receptors explains the lack of 5-HT stereotypy on treatment with the putative 5-HT1A agonist LY165163.

The putative serotonin (5-HT)1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluormethylphenyl) piperazine (LY165163, PAPP) induces hyperphagia and hypothermia in rats, but unlike other 5-HT agonists, does not induce 5-HT stereotypy even at high doses (10 mg/kg sc). LY165163 (1 mg/kg) increased striatal DOPA accumulation in animals treated with the aromatic amino acid decarboxylase inhibitor 3-hydroxy-benzylhydrazine (NSD 1015) (100 mg/kg ip). This increase was also found when the drug was given to animals pretreated with parachlorophenylalanine (pCPA) (150 mg/kg ip daily for 3 days). LY165163 (2 and 4 mg/kg sc) inhibited stereotyped behaviour induced by the dopamine (DA) agonist apomorphine (2 mg/kg sc). LY165163 (2, 4, 10 mg/kg sc) also inhibited stereotyped components of the 5-HT syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 5 mg/kg ip) which previous studies (e.g. Andrews et al. 1982) suggested to require DA (head weaving, reciprocal forepaw treading). Thus, while other 5-HT1A agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) cause stereotypy, this does not occur with LY165163, probably because the drug blocks DA receptors.

Animals↗

PubMed1987

Enhancement of brain dopamine metabolism by tyrosine during immobilisation: an in vivo study using repeated cerebrospinal fluid sampling in conscious rats.

Central dopamine (DA) and 5-hydroxytryptamine (5-HT) metabolism was monitored in conscious, freely moving rats by determination of levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) in CSF samples withdrawn repeatedly from the cisterna magna and treated with acid to hydrolyse DOPAC and HVA conjugates. The effect of tyrosine on DA metabolism was investigated. Time courses of metabolite concentrations in individual rats in a quiet room showed that tyrosine (20, 50, or 200 mg/kg i.p.) was without significant effect; brain changes were essentially in agreement. However, the increases of CSF DOPAC and HVA levels that occurred on immobilisation for 2 h were further enhanced by tyrosine (200 mg/kg). The associated increases of 5-HIAA level were unaffected. The corresponding increases of DA metabolite concentrations in the brains of immobilised rats given tyrosine were less marked than the CSF changes and only reached significance for "rest of brain" DOPAC. The CSF studies revealed large interindividual variation in the magnitude and duration of the effects of immobilisation on transmitter amine metabolism. These results may help toward the elucidation of possible relationships between the neurochemical and behavioural effects of stress.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

CSF tryptophan and transmitter amine turnover may predict social behaviour in the normal rat.

Central 5-hydroxytryptamine (5-HT) and dopamine (DA) turnovers and tryptophan concentrations were estimated in individual male rats using repeated CSF withdrawal. On subsequent pairing, the major biters of each pair (neck + body bites) were predicted by their higher concentrations of the 5-HT precursor tryptophan but not by 5-HT turnover. However, bites/pair correlated highly significantly with the lower 5-HT and DA turnover values in each pair. The investigation illustrates a new and flexible approach to the neurochemistry of social behaviour.

Aggression↗

PubMed1986

Neurochemical and behavioural evidence for mediation of the hyperphagic action of 8-OH-DPAT by 5-HT cell body autoreceptors.

Administration of 60 micrograms/kg s.c. of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), a dose previously shown to cause hyperphagia in satiated rats (but not to cause the 5-HT behavioural syndrome) decreased 5-HIAA and 5-HIAA/5-HT ratio in several brain regions, the most marked effects being in pons + medulla oblongata, a region containing 5-HT cell bodies and ascending 5-HT axons. Micro-infusion of 8-OH-DPAT (250 and 500 ng) into the dorsal or medial raphe nuclei significantly increased food intake and feeding duration but did not produce the 5-HT behavioural syndrome. Results suggest that 8-OH-DPAT induced hyperphagia is mediated via a agonist action on somatodendritic 5-HT autoreceptors.

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

PubMed1986

Female rats are more vulnerable than males in an animal model of depression: the possible role of serotonin.

A single 2-h restraint stress reduces locomotion and increases defaecation of male rats placed in an open field 24 h later. After daily 2-h restraints for 5 days these effects were no longer observed. This adaptation was associated with enhanced sensitivity to the serotonin agonist 5-methoxy-N,N-dimethyltryptamine. Female rats were less affected by a single restraint but failed to adapt to the repeated stress procedure and did not exhibit enhanced sensitivity to 5-methoxy-N,N-dimethyltryptamine. Furthermore, females but not males killed 24 h after the final restraint period had decreased brain regional 5-hydroxyindoleacetic acid concentrations particularly in the frontal cortex. No sex differences in hypothalamic and striatal dopamine metabolism were observed. The above differences between male and female rats were unaffected by adult gonadectomy. Similar differences could be involved in the higher incidence of depressive illness in women.

Animals↗

PubMed1986

Para-chlorophenylalanine prevents feeding induced by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT).

The effects of para-chlorophenylalanine pre-treatment (PCPA, 150 mg/kg IP daily for 3 days) on feeding and stereotyped behaviour elicited by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) in rats were investigated. PCPA depleted brain serotonin and 5-hydroxyindoleacetic acid concentrations by 90% and increased feeding during a 2-h day-time test. 8-OH-DPAT (60-4000 micrograms/kg SC) increased food intake in control animals but decreased it in PCPA-treated animals during the 2-h test. PCPA treatment had no effect on 8-OH-DPAT-induced locomotion or serotonin-related stereotyped behaviour (i.e. forepaw treading, headweaving, wet dog shakes, etc). Since PCPA prevents the operation of pre-synaptic serotonergic mechanisms, the failure of 8-OH-DPAT to increase food intake in PCPA-treated rats suggests that 8-OH-DPAT-induced hyperphagia is autoreceptor mediated.

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

PubMed1986

5-Hydroxytryptamine-mediated behaviour in male and female rats.

The responses of male and female rats to drugs causing the behavioural syndrome induced by 5-hydroxytryptamine (5-HT) were compared. Preliminary experiments showed that females had largely similar responses to the releaser of 5-HT, p-chloroamphetamine (PCA) and the 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) at different stages of the oestrus cycle. The behavioural responses to 5-MeODMT (with and without the monoamine oxidase inhibitor pargyline) or to p-chloroamphetamine were not significantly different to those of males except for tremor after p-chloroamphetamine which was more marked in the females. However, concentrations of p-chloroamphetamine in brain in these animals, when killed immediately after behavioural recording were greater in the females. When rats, pretreated with the monoamine oxidase inhibitor, pargyline, were given the precursor of 5-HT, tryptophan, the females showed substantially greater hypothermia and larger scores for components of the 5-HT syndrome than the males. This sex difference may have been due to the moderately but significantly higher levels of 5-HT (and possibly tryptamine) in brain attained by the female rats, than by similarly-treated males. The results as a whole therefore suggest that the greater behavioural response of female rats to pargyline and tryptophan reflects a greater effect of this treatment on the synthesis of indoleamines than that occurring in males.

Animals↗

PubMed1986

Biopterin and neurotransmitter amine metabolism in children with acute lymphoblastic leukemia receiving methotrexate therapy.

To test the hypothesis that some of the neurologic sequelae of treatment for acute lymphoblastic leukemia (ALL) might be related to abnormalities in biopterin metabolism associated with methotrexate (MTX) therapy, total biopterin levels in cerebrospinal fluid (CSF) and plasma, and homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) were measured in a cross-sectional study of 80 children with ALL. For comparison, biopterins were also measured in a group of children of similar age undergoing investigation for neurologic disease. In children with ALL studied before therapy, no significant difference was found between the means of plasma biopterin or CSF biopterin concentrations and the means in the control group. In children receiving MTX, plasma biopterin values were higher in the group given maintenance therapy than in children observed before treatment. CSF levels were significantly increased only in those patients who had completed 2 years of maintenance therapy. CSF concentrations of HVA and 5HIAA in patients with ALL who had received no treatment (median values 52 and 18 ng/ml, respectively) showed a wide scatter and were inversely related to age. In patients receiving MTX, concentrations of these metabolites were higher than in the untreated group, again reaching a peak in patients just completing 2 years of treatment (median HVA 110 ng/ml, 5HIAA 34 ng/ml). These results provide no support for the idea that neurotransmitter amine deficiency occurs in children with ALL receiving MTX, and indicate, rather, that amine and biopterin synthesis increases in such patients.

Adolescent↗

PubMed1986

8-OH-DPAT-induced hyperphagia: its neural basis and possible therapeutic relevance.

The pharmacological and neurochemical bases of hyperphagia induced by the serotonin agonist 8-OH-DPAT were examined. In addition, the possible therapeutic potential of 8-OH-DPAT and related drugs in the treatment of anorexic pathology was assessed in an animal model of anorexia (as induced by acute immobilization stress). In normal rats 8-OH-DPAT elicited feeding after peripheral injection and after intracerebral application to the brainstem raphé nuclei. Feeding elicited by peripheral injection of the drug was attenuated by pretreatment with the serotonin synthesis inhibitor para-chlorophenylalanine. Following a hyperphagic dose of 8-OH-DPAT, brain serotonin metabolism was reduced, particularly in midbrain and pons-medulla. Our interpretation of these data is that 8-OH-DPAT elicits feeding via an agonist action on serotonin autoreceptors in the raphé nuclei. These receptors are probably of the 5-HT1A subtype as 8-OH-DPAT has a high affinity for this receptor and other putative 5-HT1A agonist (i.e. buspirone, TVX Q 7821) also elicit feeding. In contrast, putative 5-HT1B agonists (i.e. RU-24969 and quipazine) decrease feeding and cause anorexia. 8-OH-DPAT and other 5-HT1A agonists attenuated the anorexia and body weight loss caused by immobilization stress. Therefore, it seems possible that 5-HT1A agonists may be clinically useful in the treatment of anorexia.

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

PubMed1986

Amino acid analysis demonstrates that increased plasma free tryptophan causes the increase of brain tryptophan during exercise in the rat.

Rats were trained to run on a horizontal treadmill for 2 h at 20 m/min. This activity considerably increased plasma free tryptophan (TRP) (+70%) but did not alter plasma total TRP levels and had little or no effect on plasma concentrations of the other large neutral amino acids (LNAAs) that compete with TRP for entry into the brain. Brain TRP levels increased by 80%. The only other brain LNAA to be affected by exercise was threonine, which rose moderately. The results indicate that increased plasma free TRP was specifically responsible for the increase of brain TRP after 2 h of exercise. Brain lysine was also increased whereas glycine, alanine, and gamma-aminobutyric acid were decreased. The differences between the present findings and those previously obtained following 2 h immobilization stress are discussed.

Alanine↗

PubMed1986

Dopamine metabolites in rat cisternal cerebrospinal fluid: major contribution from extrastriatal dopamine neurones.

The interpretation of central 3,4-dihydroxyphenylethylamine (dopamine, DA) metabolism, as indicated by determinations in rat cisternal CSF, was investigated using intrastriatal injection of the DA neurotoxin 6-hydroxydopamine (6-OHDA) and intraperitoneal injection of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4). DA turnover was subsequently determined by measurement of the rate of accumulation of total 3,4-dihydroxyphenylacetic acid and homovanillic acid (DOPAC + HVA) in the CSF after probenecid was given. Two days later the rats were killed, and metabolism of DA and 5-hydroxytryptamine (5-HT) was investigated by determining levels of the amines and their metabolites in brain regions. Although 6-OHDA greatly decreased striatal DA metabolism, this was not paralleled by DA turnover as indicated by CSF, as this fell only moderately and approximately in parallel with results for the brain as a whole. 5-HT metabolism was essentially unaltered. DSP4 considerably depleted noradrenaline and caused smaller decreases of 5-HT metabolism in some regions. However, DA metabolism was not significantly affected, either in brain or CSF, which suggests that noradrenaline neurones make only a small contribution to central DA metabolism. Results as a whole suggest that DOPAC and HVA concentrations in rat cisternal CSF reflect whole brain DA metabolism and derive predominantly from DA neurones in extrastriatal regions of the brain.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Immobilization decreases amino acid concentrations in plasma but maintains or increases them in brain.

Immobilization for 2 h significantly decreased plasma concentrations of 13 of 16 amino acids assayed, including the transmitter amine precursors tyrosine and total tryptophan. The level of plasma free tryptophan, however, was increased. Despite the reduced plasma levels, corresponding brain concentrations of many large neutral amino acids (LNAAs) were increased (tryptophan, phenylalanine, valine, leucine, and isoleucine). Brain concentrations of tyrosine and the other amino acids measured were unaltered. The results for the LNAAs were not explained by calculated brain influx rates. Therefore, altered influx kinetics or perhaps altered brain protein metabolism or efflux may be responsible. Comparison of calculated brain influxes and brain concentrations of LNAAs suggests that the rise in level of plasma free tryptophan during immobilization is not responsible for the increase in level of brain tryptophan and that the mechanism responsible for the maintenance of or increase in brain concentrations of the other LNAAs is probably involved. Maintenance of brain concentrations of basic amino acids is explicable by reduced competition for brain uptake.

Amino Acids↗

PubMed1986

Characteristics of analgesias induced by brief or prolonged stress.

Some characteristics of the effects of brief and prolonged stress on tail-flick latency are described. The pharmacological profiles of the latency responses to 30 sec and 30 min footshock are strikingly different. Thus, the increase of tail-flick latency after 30 sec shock is unaffected by naloxone and enhanced by drugs which decrease 5HT or DA-dependent transmission, while the increase after 30 min shock is blocked by naloxone and also by the above drugs. The increased tail-flick latency after 30 sec shock only occurs if tail-flick latency is also determined before shock. This finding, together with the attenuation or enhancement of the post-shock response by drugs that similarly affect conditioned avoidance behavior, suggests that the increased latency after brief shock occurs through a mechanism that is related to passive avoidance learning. Finally, a new approach to the investigation of stress-induced analgesia is described in which neurochemical changes during prolonged immobilization stress are repeatedly monitored using cisternal CSF samples taken in parallel with tail-flick latency measurements.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Monitoring dopamine metabolism in the brain of the freely moving rat.

Determination of DOPAC and HVA in cisternal CSF taken repeatedly from freely moving rats provides a useful means of monitoring central DA metabolism. A large proportion of both metabolites occurs in cisternal CSF as conjugates from which they are liberated by acid hydrolysis. The method enables DA turnover values to be determined for individual rats. Drug experiments indicate that these values reflect brain DA metabolism and that most of this occurs in extrastriatal DA neurons. Concurrent determination of 5HT turnover on the same CSF samples revealed a significant positive correlation between the turnovers of the two transmitters together with considerable inter-individual differences. The turnover method was particularly convenient when investigating daily variations of turnover. Repeated CSF withdrawal also appears to be useful in the analysis of stress-provoked changes of the metabolism of DA and other transmitters. For example, it was used to show that central DA metabolism becomes highly responsive to tyrosine availability if rats are subjected to immobilization stress. The method can also be used to compare the time dependencies of both metabolic and behavioral responses to the stress in the same animal. Preliminary results suggest that the increase of 5HT metabolism during immobilization (rather than that of DA) may oppose the suppression of open field activity that occurs 24 hr later.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1986

Monitoring 5HT metabolism in the brain of the freely moving rat.

The techniques of repeated CSF withdrawal and intracerebral dialysis are described. They were used to monitor 5HT metabolism in the brains of freely moving rats. Evidence indicates that results obtained proportionately reflect changes of 5HT metabolism in whole brain (CSF method) and in the striatum (intracerebral dialysis). The potential value of the methods is illustrated by two behavioral studies. The first suggested that 5HT turnover values (determined two weeks prior to behavioral testing by the CSF method) were predictive for neck + body biting in a social interaction test. The second study showed a consistent pattern of change of hypothalamic dialysate 5HIAA concentration associated with feeding in rats on a restricted food intake schedule.

Animals↗