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G Curzon

Publications and source records attributed to G Curzon.

At least 19 recordsLinked to original sources
PubMed1992

Effect of milacemide on extracellular and tissue concentrations of dopamine and 5-hydroxytryptamine in rat frontal cortex.

1. Milacemide is a glycine prodrug which is both an inhibitor and a substrate for monoamine oxidase-type B (MAO-B) and also an inhibitor of MAO-type A (MAO-A). Its effects on dopamine and 5-hydroxytryptamine (5-HT) metabolism in rat frontal cortex tissue and dialysate were evaluated. 2. Dialysate dopamine concentrations increased linearly and dose-dependently after milacemide administration (100, 200, 400 mg kg-1, i.p.), peaking at 1 h. A concomitant dose-dependent decrease in dialysate 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) concentrations was observed but these changes were smaller (27% and 40% respectively) than the change in dopamine (125% after 400 mg kg-1 milacemide). 3. Dialysate 5-HT was significantly increased only at 1.5 h after giving milacemide 400 mg kg-1. Dialysate 5-hydroxyindoleacetic acid (5-HIAA) concentration was not affected. 4. Milacemide (400 mg kg-1) at 1.5 h post-administration significantly increased frontal cortex tissue concentrations of dopamine and 5-HT; the percentage increase in dopamine being about four times that of 5-HT. Metabolite concentrations, including 5-HIAA, decreased. Changes in tissue and dialysate dopamine, DOPAC and HVA were approximately proportionate to each other. 5. The results are explicable in terms of an inhibition by milacemide of MAO-A.

Acetamides↗
PubMed1992

Evidence for postsynaptic mediation of the hypothermic effect of 5-HT1A receptor activation.

1. The 5-HT1A ligand BMY 7378 (8-[2[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]8-azaspirol [4,5]-decane-7,9-dione dihydrochloride, 0.032-2 mg kg-1, s.c.) caused hyperphagia, a response to the activation of presynaptic 5-HT1A receptors. 2. BMY 7378 (8 mg kg-1, s.c.) and the 5-HT1A agonist (8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT), 0.10 and 0.25 mg kg-1 s.c.) also caused hypothermia. This was inhibited by (-)-pindolol (1-mg kg-1, i.p.) and not prevented by pretreatments with p-chlorophenylalanine which grossly depleted 5-hydroxytryptamine (5-HT) from terminal regions. The hypothermic effects are explicable by activation of postsynaptic 5-HT1A receptors. Infusion of BMY 7378 (8-64 micrograms) into the dorsal raphe was without convincing hypothermic effect. 3. BMY 7378 (8 mg kg-1, s.c.) inhibited another effect of activation of postsynaptic 5-HT1A receptors, i.e., the induction of components of the 5-HT syndrome by 8-OH-DPAT (0.5, 1.0 mg kg-1, s.c.) which suggests that BMY 7378 has antagonistic as well as agonistic effects at these sites. 4. Partial agonist properties of BMY 7378 at postsynaptic sites were also indicated by doses for hypothermia being much greater than those for hyperphagia i.e., ED50 (hypothermia) greater than 2 mg kg-1, ED50 (hyperphagia) = 0.010 mg kg-1. This contrasts with the similar ED50 values for both the hypothermic (ED50 = 0.08-0.10 mg kg-1) and hyperphagic (ED50 = 0.06-0.10 mg kg-1) effects of 8-OH-DPAT.5. The evidence obtained for mediation of the hypothermic response to 5-HTIA agonists by postsynaptic sites is relevant to the interpretation of the effects on it of antidepressant treatments and depressive illness.

Animals↗
PubMed1992

The effects of tianeptine and other antidepressants on a rat model of depression.

A model of depression based on measurements made after restraining rats for two hours has been developed. The model is associated with elevation in corticosterone, reflects the higher incidence of depression in women, and shows increased post-synaptic 5-HT function with adaptation. The effects of tianeptine and other antidepressants on the model were studied. Chronic pre-treatment with desipramine, sertraline (amine uptake inhibitors), and chlordiazepoxide normalised open field activity after restraint. Single high doses, post-restraint, of 8-OH-DPAT, gepirone (5-HT agonists), and tianeptine normalised open field activity, whereas desipramine, chlordiazepoxide, and diazepam did not. It is of considerable interest that tianeptine decreased the availability of 5-HT to receptors.

Animals↗
PubMed1991

Effects of tryptophan and of 5-hydroxytryptamine receptor subtype agonists on feeding.

Feeding or food withdrawal can affect the supply of tryptophan to the brain and hence (in some circumstances) 5-HT synthesis therein. Also fenfluramine which releases 5-HT to postsynaptic receptors suppresses appetite and there are reports that tryptophan can have a similar effect. Furthermore, feeding is reported to release hypothalamic 5-HT. Therefore 5-HT could have a role in the normal termination of feeding and perhaps also in disorders of appetite. The recognition of various 5-HT receptor subtypes has stimulated research in this area. We have now investigated the involvement of the subtypes in the pharmacological control of feeding. Thus, 5-HT1A agonists (8-OH-DPAT, buspirone, gepirone etc.) stimulate intake in freely feeding rats, probably by activating autoreceptors on the cell bodies of 5-HT neurons so that 5-HT release at terminals is decreased. The hyperphagia is not explicable by increased activity or gnawing and is strikingly manifest against carbohydrate in carbohydrate vs. protein choice experiments. Feeding in previously food deprived rats is decreased by the 5-HT agonists RU 24969, 1-(3-chlorophenyl)piperazine (mCPP) and 1-[3-(trifluoromethyl) phenyl]piperazine (TFMPP). Effects of antagonists suggest that RU 24969-induced hypophagia depends on 5-HT1B receptors only while mCPP and TFMPP induce hypophagia at 5-HT1C sites, though this effect also requires 5-HT1B receptors for its expression. Responsible sites occur in the paraventricular nucleus of the hypothalamus as infusing either RU 24969 or TFMPP therein causes hypophagia. On systemic injection, the hypophagic drugs are particularly active in female rats, an effect of conceivable relevance to human anorexic illness.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1991

Effects of tianeptine on stress-induced behavioural deficits and 5-HT dependent behaviour.

The novel tricyclic antidepressant drug tianeptine had an antidepressant-like effect on a rat model of depression based on the deficit in open field activity observed on the day after 2 h restraint. Thus, when tianeptine (10 mg/kg IP) was given 2 h after the end of the restraint to either untreated rats or to animals previously given 10 mg/kg of the drug per day for 13 days, then the deficit was opposed. Tianeptine, given acutely but not chronically, moderately enhanced the 5-HT1C receptor-dependent hypolocomotor effect of m-chlorophenylpiperazine (mCPP) but did not alter other 5-HT1 receptor subtype-dependent behaviour. Acute but not chronic tianeptine also decreased 5-HT2 receptor-dependent body shakes induced by 5-hydroxytryptophan. Shakes induced by the 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2 aminopropane (DOI) were unaffected. The results are discussed in relation to the possible mechanism of antidepressant action of tianeptine.

Animals↗
PubMed1991

The effect of the novel antidepressant tianeptine on the concentration of 5-hydroxytryptamine in rat hippocampal dialysates in vivo.

Tianeptine is a novel tricyclic antidepressant which, in marked contrast to other antidepressants, increases the uptake of 5-HT in brain tissue and blood platelet preparations ex vivo. In the present study it was shown, by microdialysis, that tianeptine (10 mg/kg i.p.), whether given as a single dose or as daily doses for 14 days, attenuated the K(+)-evoked rise of extracellular 5-HT in the hippocampus in vivo. Tianeptine (10 mg/kg i.p.), given acutely, did not reduce basal levels of 5-HT in hippocampal dialysates in the presence of the 5-HT reuptake inhibitor, citalopram. These results suggest mutually opposing effects of tianeptine and citalopram on neuronal uptake of 5-HT. Their significance in relation to the role of 5-HT in the action of antidepressants is discussed.

Animals↗
PubMed1991

Effect of tryptophan on extracellular concentrations of tryptophan and 5-hydroxyindoleacetic acid in the striatum and cerebellum.

The effects of L-tryptophan (50 mg/kg i.p.) on extracellular concentrations of tryptophan and the 5-hydroxytryptamine (5-HT) metabolite 5-hydroxyindoleacetic acid (5-HIAA) were determined in the rat striatum and cerebellum, regions with rich and poor 5-HT innervation, respectively. Determinations were on perfusates from dialysis probes in the brains of conscious, freely moving rats. The pharmacokinetic profiles of dialysate tryptophan after tryptophan load (peak concentration, time to peak concentration, area under curve, and half-life) in the two regions did not differ significantly. The dialysate 5-HIAA concentration in the striatum rose two- to threefold after the administration of tryptophan. Therefore, as 5-HIAA was undetectable in the cerebellum either before or after the administration of tryptophan, the increase of 5-HIAA in the striatum is unlikely to depend appreciably on its production within the cerebral vasculature or outside the brain or on its entering the striatum through a blood-brain barrier damaged by placement of the dialysis probe. Overall, the findings strengthen previous evidence that extracellular 5-HIAA concentrations determined by cerebral dialysis are a valid measure of the metabolism of 5-HT of brain neuronal origin.

Animals↗
PubMed1991

Effect of p-chlorophenylalanine on release of 5-hydroxytryptamine from the rat frontal cortex in vivo.

1. Rats were given p-chlorophenylalanine (PCPA, 150 mg kg-1, i.p.) to inhibit partially 5-hydroxytryptamine (5-HT) synthesis so that its concentration in the frontal cortex fell by about half. The effects of this treatment on frontal cortex dialysate 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) concentrations were determined before and after stimulation by increasing K+ concentration in the perfusion fluid by 100 mM for 20 min. Rates of 5-HT synthesis as indicated by the effects of 3-hydroxybenzylhydrazine (NSD 1015, 150 mg kg-1, i.p.) on frontal cortex tissue and dialysate 5-hydroxytryptophan (5-HTP) and dialysate 5-HIAA were also measured in rats that had not been stimulated with K+. 2. Dialysate 5-HT and 5-HIAA concentrations of both vehicle- and PCPA-treated rats fell into major (group 1) and minor (group 2) populations statistically distinguishable from each other by the high 5-HT and low 5-HIAA values of the latter group. 3. In group 1 animals, PCPA decreased both the dialysate 5-HT concentration and its rise following stimulation by K+ in proportion with the decrease of 5-HT in frontal cortex tissue. 5-HIAA fell more markedly than 5-HT and in similar proportion in both tissue and dialysate. The fall of dialysate 5-HIAA on stimulation by K+ was also attenuated to the same degree. The elevated 5-HT/5-HIAA ratios after PCPA treatment imply increased conservation of the depleted 5-HT stores. 4. PCPA decreased the above 5-HIAA values and the effects of NSD 1015 on tissue 5-HTP or dialysate 5-HIAA concentrations in similar proportion. However, PCPA had little effect on corresponding dialysate 5-HTP values. 5. The results are discussed with respect to relationships between synthesis, storage and release of 5-HT. They indicate that (under the conditions of the present study) the availability of 5-HT to receptors is directly proportional to total vesicular stores under both basal conditions and during neuronal firing.

5-Hydroxytryptophan↗
PubMed1991

Potencies of antagonists indicate that 5-HT1C receptors mediate 1-3(chlorophenyl)piperazine-induced hypophagia.

1. 1-3(Chlorophenyl)piperazine (mCPP) (5 mg kg-1, i.p.) inhibited 2 h food intake in rats previously deprived of food for one day. Ten 5-hydroxytryptamine (5-HT) antagonists given s.c. opposed this hypophagic response. Calculated ID50 values correlated significantly with reported affinities (r = 0.81, n = 10, P less than 0.01) for 5-HT1C but not for 5-HT2, 5-HT1A, 5-HT1B or 5-HT1D receptors. 2. ID50 values of the ten antagonists against 5-hydroxytryptophan (5-HTP) + carbidopa-induced head shakes (a 5-HT2-mediated response) correlated significantly (r = 0.81, n = 10, P less than 0.01) with their affinities for 5-HT2 but not for 5-HT1A, 5-HT1B, 5-HT1C or 5-HT1D receptors. 3. ID50 values for inhibition of hypophagia and head shakes did not correlate significantly with each other. 4. Ratios of ID50 values against hypophagia and 5-HT2-mediated head shakes gave indices of relative in vivo potencies independent of differences in drug metabolism and disposition. These ratios correlated highly significantly (r = 0.91, n = 10, P less than 0.001) with the ratios of the affinities of the drugs for 5-HT1C (but not for 5-HT1A, 5-HT1B or 5-HT1B or 5-HT1D receptors) and with their affinities for 5-HT2 receptors. These results strongly support the hypothesis that mediation of mCPP-induced hypophagia is by stimulation of 5-HT1C receptors and the mediation of 5-HTP-induced head twitches by 5-HT2 receptors.

Animals↗
PubMed1990

A single dose of 8-OH-DPAT reduces raphe binding of [3H]8-OH-DPAT and increases the effect of raphe stimulation on 5-HT metabolism.

8-Hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT) has antidepressant-like effects in rats and selectively reduces presynaptic 5-HT1A function a day after administration. In the present study, the effect of 8-OH-DPAT (1 mg/kg s.c.) pretreatment on presynaptic (raphe nuclei) and postsynaptic (frontal cortex and hippocampus) [3H]8-OH-DPAT binding was studied. Bmax values were markedly reduced in the raphe, but not in the hippocampus and frontal cortex. Kd values were unchanged. Electrical stimulation of the dorsal raphe (300 microA, 1 ms, 20 Hz, 30 min) significantly increased 5-hydroxyindoleacetic acid in the frontal cortex, but not in the amygdala or the nucleus accumbens and caused smaller increases in the rest of the brain. The increase in the frontal cortex was significantly potentiated one day after giving 8-OH-DPAT. These results confirm the ability of 8-OH-DPAT to desensitise presynaptic 5-HT1A receptors and suggest that this may lead to a loss of feedback control so that, on neuronal stimulation, the increase of 5-HT function is enhanced. This effect may underlie the antidepressant-like action of 8-OH-DPAT pretreatment, i.e. its ability to oppose restraint-induced defects in locomotion on placement in an open field one day later. A requirement of presynaptic 5-HT for this behavioural effect is consistent with its prevention by the 5-HT synthesis inhibitor parachlorophenylalanine.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Hippocampal 5-hydroxytryptamine synthesis is greater in female rats than in males and more decreased by the 5-HT1A agonist 8-OH-DPAT.

Brain regional 5-hydroxytryptamine (5-HT) and/or 5-hydroxyindoleacetic acid (5-HIAA) concentrations tended to be slightly higher in female rats than in males but differences were substantial only in the hippocampus where female values were 34% and 36% higher respectively. These findings were consistent with the synthesis rates of 5-HT as this was 53% greater in the female than in the male hippocampi. Other regions did not show significant sex differences. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT, 1 mg/kg sc) caused comparable decreases of 5-HT synthesis rate in both sexes and in all regions studied except the hippocampus where the percentage decrease was twice as large in the females (-64%) as in the males (-32%) so that the sex difference in 5-HT synthesis in this region largely disappeared. The results are discussed in relation to sex differences in behaviour and hippocampal function.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1990

Anxiogenic-like effect of infusing 1-(3-chlorophenyl) piperazine (mCPP) into the hippocampus.

1-(3-Chlorophenyl) piperazine (mCPP) was previously shown to have an anxiogenic-like effect, i.e., it decreased total interaction in a rat social interaction test. Evidence indicated mediation by activation of 5-HT1C receptors with an ED50 of approximately 500 micrograms/kg IP (Kennett et al. 1989). A comparable effect is now shown on infusing 4 micrograms of the drug ICV or infusing 0.5 microgram into the hippocampus. Both responses were dose dependent. Infusion of 1 microgram mCPP into the amygdala had no effect. None of the above treatments significantly reduced locomotion. Results are consistent with the postulated role of the hippocampus in anxiety.

Amygdala↗
PubMed1990

Effect of transient cerebral ischaemia and cardiac arrest on brain extracellular dopamine and serotonin as determined by in vivo dialysis in the rat.

The effects of 20-min transient, global, forebrain ischaemia and cardiac arrest on extracellular concentrations of dopamine (DA), serotonin (5-HT), and their respective metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), were measured in vivo by dialysis of rat striatum and hippocampus. During the ischaemic period, striatal DA content increased (250-fold basal concentrations) with parallel but much less marked increases of both striatal and hippocampal 5-HT content (eight- to 10-fold). Baseline values were restored during reperfusion. Subsequent increases of DA and 5-HT levels on cardiac arrest were comparable after both sham operation and ischaemia. Significant decreases of HVA and 5-HIAA levels were observed following ischaemia or cardiac arrest. The differential effects of ischaemia on DA and 5-HT suggest selective alterations in disposition or metabolism of the two transmitters and that dopaminergic neurones may be more vulnerable to ischaemic insults.

Animals↗
PubMed1990

Serotonin and appetite.

Feeding or food withdrawal can affect the supply of tryptophan to the brain and hence (in some circumstances) 5-HT synthesis therein. Also fenfluramine which releases 5-HT to postsynaptic receptors suppresses appetite, and there are reports that tryptophan can have a similar effect. Furthermore, feeding is reported to release hypothalamic 5-HT. Therefore 5-HT could have a role in the normal termination of feeding and perhaps also in disorders of appetite. The recognition of various 5-HT receptor subtypes has stimulated research in this area. We have now investigated the involvement of the subtypes in the pharmacological control of feeding. Thus, 5-HT1A agonists (8-OHDPAT, buspirone, gepirone, etc.) stimulate intake in freely feeding rats, probably by activating autoreceptors on the cell bodies of 5-HT neurons so that 5-HT release at terminals is decreased. The hyperphagia is not explicable by increased activity or gnawing and is strikingly manifest against carbohydrate in carbohydrate vs. protein choice experiments. Feeding in previously food-deprived rats is decreased by the 5-HT agonists RU 24969, 1-(3-chlorophenyl) piperazine (mCPP) and 1-(3-trifluoromethyl) phenyl) piperazine (TFMPP). Effects of antagonists on these properties suggest that RU 24969-induced hypophagia depends on 5-HT1B receptors only, while mCPP and TFMPP induce hypophagia at 5-HT1C sites, though this effect also requires 5-HT1B receptors for its expression. Responsible sites occur in the paraventricular nucleus of the hypothalamus as infusing either RU 24969 or TFMPP therein causes hypophagia. On systemic injection, the hypophagic drugs are particularly active in female rats, an effect of conceivable relevance to human anorexic illness.

Animals↗
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↗