Biomedical subjects

H D Snoddy

Publications and source records attributed to H D Snoddy.

At least 19 recordsLinked to original sources

PubMed1994

Effects of duloxetine, an antidepressant drug candidate, on concentrations of monoamines and their metabolites in rats and mice.

Duloxetine, (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine, is an inhibitor of the serotonin and norepinephrine neuronal transporters (Wong et al., 1993). In mice, duloxetine antagonized the depletion of brain serotonin by p-chloroamphetamine (ED50 = 2.5 mg/kg, i.p.) and the depletion of heart norepinephrine by 6-hydroxydopamine (ED50 = 1.1 mg/kg, i.p.). Brain concentrations of 5-hydroxyindoleacetic acid were decreased by duloxetine at 2 hr after doses of 1, 3 and 10 mg/kg and at 1 to 8 hr (but not 24 hr) after a 10 mg/kg i.p. dose of duloxetine. Duloxetine antagonized norepinephrine depletion in frontal cortex, but not dopamine depletion in striatum, after treatment of mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. In rats, duloxetine decreased brain 5-hydroxyindoleacetic acid dose-dependently for up to 8 hr and decreased serotonin turnover measured by the accumulation of 5-hydroxytryptophan in rat hypothalamus after decarboxylase inhibition. In rats, duloxetine antagonized the depletion of brain serotonin by p-chloramphetamine and the depletion of norepinephrine and epinephrine in hypothalamus after i.c.v. injection of 6-hydroxydopamine. In vitro, duloxetine had little effect on either type A (serotonin as substrate) or type B (phenylethylamine as substrate) monoamine oxidase, IC50 concentrations being above 10(-5) M. These data extend evidence that duloxetine inhibits serotonin and norepinephrine transporters in vivo, actions that may lead to therapeutic efficacy in mental depression.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1993

Evaluation of nefopam as a monoamine uptake inhibitor in vivo in mice.

Nefopam antagonized 6-hydroxydopamine-induced depletion of heart norepinephrine in mice with an ED50 value of 12 mg/kg. Nefopam was ineffective in antagonizing p-chloroamphetamine-induced depletion of brain serotonin in our standard assay in mice, apparently due to a short duration of action. Brain concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) were decreased after a 32 mg/kg, i.p., dose of nefopam at 1 and 2 hr but not at 4 hr. When nefopam was injected simultaneously with p-chloroamphetamine, it prevented brain serotonin depletion initially, but by 6 hr the protective effect was essentially lost, suggesting that p-chloroamphetamine persisted in mouse brain longer than did nefopam. Nefopam caused a dose-related antagonism of brain serotonin depletion at 2 hr after injection of a low dose of p-chloroamphetamine hydrochloride (10 mg/kg, i.p.), with a calculated ED50 value of 11 mg/kg. The lowering of brain 5-HIAA concentration 2 hr after nefopam injection occurred after a 32 mg/kg dose but not after a 3 or 10 mg/kg dose. These data suggest that nefopam is effective as an inhibitor of norepinephrine and serotonin uptake at doses previously shown to be analgesic in mice, consistent with uptake inhibition being a postulated mechanism important in its analgesic effect. Nonetheless, nefopam is a relatively weak inhibitor of monoamine uptake with a short duration of action in mice.

Animals↗

PubMed1992

Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo.

Norfluoxetine, the N-desmethyl metabolite of fluoxetine, has been reported to resemble fluoxetine in being a potent and selective inhibitor of the serotonin uptake carrier. The enantiomers of norfluoxetine have now been compared as serotonin uptake inhibitors in vivo, based on their antagonism of p-chloroamphetamine-induced depletion of serotonin in brain and their lowering of concentrations of the metabolite of serotonin, 5-hydroxyindoleacetic acid (5-HIAA) in brain. In rats, S-norfluoxetine (ED50 3.8 mg/kg) was more potent than R-norfluoxetine (ED50 > 20 mg/kg) in blocking the depletion of serotonin by p-chloroamphetamine after intraperitoneal administration. The S enantiomer decreased concentrations of 5-HIAA in whole brain after doses of 2.5-20 mg/kg, whereas the R enantiomer did not. The concentrations of both enantiomers in brain increased in proportion to dose and the R enantiomer disappeared from the brain at a slightly slower rate than the S enantiomer. The relative inability of the R enantiomer to block the uptake of serotonin was therefore not a result of smaller concentrations of drug in the brain. In mice, S-norfluoxetine was also more potent than R-norfluoxetine in blocking depletion of serotonin by p-chloroamphetamine (ED50 values 0.82 and 8.3 mg/kg, respectively). Thus, in contrast to the relatively similar potencies of the enantiomers of fluoxetine in blocking the uptake of serotonin, the enantiomers of norfluoxetine have markedly different potencies as inhibitors of the uptake of serotonin.

Animals↗

PubMed1992

Neuroendocrine evidence for antagonism of serotonin and dopamine receptors by olanzapine (LY170053), an antipsychotic drug candidate.

Olanzapine, 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-B] [1,5]benzodiazepine (LY170053), antagonized the quipazine-induced elevation of serum corticosterone concentration in rats with an ED50 value of 0.57 mg/kg i.p. LY170053 was less potent in antagonizing the pergolide-induced elevation of serum corticosterone concentration in rats, and increases in corticosterone elicited by olanzapine alone at higher doses complicated the precise estimate of an ED50 value, which was approximately 3 mg/kg. These relative potencies in blocking quipazine and pergolide effects are taken as indices of antagonism of serotonin 5HT2 and of dopamine D2 receptors, respectively. Olanzapine is more potent than clozapine in blocking 5HT2 and D2 receptors, and its ability to block these receptors supports its possible usefulness as an antipsychotic drug.

Animals↗

PubMed1992

Comparison of L-5-hydroxytryptophan and L-5-hydroxytryptophan inosinate as agents for increasing brain serotonin formation in rats.

The effects of L-5-hydroxytryptophan (L-5HTP) and L-5HTP inosinate injection on brain 5-hydroxyindoles in rats were compared. L-5HTP and L-5HTP inosinate caused indistinguishable dose-dependent increases in 5HTP and 5HIAA (5-hydroxyindoleacetic acid) but not serotonin concentrations in whole brain at 1 hr in rats. Our results do not substantiate a previous claim that L-5HTP inosinate is superior to L-5HTP itself in increasing brain serotonin formation.

5-Hydroxytryptophan↗

PubMed1991

Role of norfluoxetine in the inhibition of desipramine metabolism and in the inhibition of serotonin uptake after fluoxetine administration to rats.

Fluoxetine, a serotonin uptake inhibitor, is known to inhibit the metabolism of some drugs including desipramine, resulting in increased brain and blood levels of desipramine when the drugs are co-administered to rats. Norfluoxetine, the N-desmethyl metabolite of fluoxetine, was found to be less potent than fluoxetine in increasing brain and blood levels of desipramine in rats. Norfluoxetine was essentially equipotent to fluoxetine in decreasing brain concentrations of 5-hydroxyindoleacetic acid (5-HIAA) as a consequence of serotonin uptake inhibition. After the injection of fluoxetine into rats, brain levels of fluoxetine predominated over those of norfluoxetine at 1 hour, but at longer times (out to 24 hours), norfluoxetine levels were higher in brain (and in liver) than fluoxetine levels. Brain levels of 5-HIAA were decreased for at least 24 hours after fluoxetine injection, due apparently to the persistence of and inhibition of serotonin uptake by norfluoxetine. When desipramine was injected 16 hrs after fluoxetine injection, brain levels of desipramine were no longer elevated. The results suggest that norfluoxetine contributes in a major way to the inhibition of serotonin uptake after fluoxetine administration but contributes less, if at all, to the inhibition of desipramine metabolism.

Animals↗

PubMed1990

Serotonin receptor subtypes involved in the elevation of serum corticosterone concentration in rats by direct- and indirect-acting serotonin agonists.

The serum corticosterone concentration in rats was increased by injection of quipazine, a relatively nonselective serotonin (5-hydroxytryptamine; 5-HT) agonist, or 8-hydroxy-2-(di-n- propylamino)tetralin (8-OH-DPAT), a serotonin agonist selective for the 5-HT1A subtype of receptor. The quipazine-induced increase in serum corticosterone was antagonized by 17 different serotonin antagonists; of these, MDL 11939, pirenperone, setoperone, mianserin, LY 281067, ketanserin, ritanserin and clozapine have relatively selective affinity for the 5-HT2 subtype of receptor. The 8-OH-DPAT-induced increase in serum corticosterone was not antagonized by metergoline, the most potent antagonist of the quipazine effect, but was antagonized by pindolol or penbutolol, 5-HT1A receptor antagonists. Pindolol did not block the effect of quipazine. The results support earlier evidence that serum corticosterone concentration in rats can be increased by activation of either 5-HT1A or 5-HT2 receptors. Indirect-acting serotonin agonists - fluoxetine, L-5-hydroxytryptophan and p-chloroamphetamine - also increased serum corticosterone concentrations. The increases elicited by those agents, which earlier had been reported not to be blocked by metergoline pretreatment, also were not blocked by pretreatment with pindolol or with the combination of metergoline and pindolol. Thus, an involvement of a specific serotonin receptor subtype in the actions of these indirect agonists has not been established.

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

PubMed1989

Lack of a difference between ketanserin and ritanserin in central vs. peripheral serotonin receptor antagonism.

Ketanserin and ritanserin antagonized with similar potency the pressor response to serotonin in pithed rats, a measure of antagonism of vascular 5HT2 receptors. Both compounds also antagonized the elevation of serum corticosterone concentration by quipazine, a centrally acting serotonin agonist; higher doses of both antagonists were needed, but ketanserin was not less potent than ritanserin. Earlier suggestions that ketanserin mainly blocks peripheral serotonin receptors and that ritanserin mainly blocks central serotonin receptors seem unfounded.

Animals↗

PubMed1988

Mechanisms of effects of d-fenfluramine on brain serotonin metabolism in rats: uptake inhibition versus release.

d-Fenfluramine is an anorectic drug believed to act by enhancement on serotonergic function in the brain. d-Fenfluramine (or the racemate) releases serotonin through a carrier-dependent mechanism, and serotonin release is the mechanism usually thought to produce its serotonergic effects. However, d-fenfluramine also inhibits serotonin uptake in vitro, and serotonin uptake inhibition is sometimes suggested to contribute to its mechanism of anorectic activity. Neurochemical experiments were done to examine serotonin release and serotonin uptake inhibition as mechanisms of action of d-fenfluramine in rats and to compare d-fenfluramine to fluoxetine, a serotonin uptake inhibitor. d-Fenfluramine decreased serotonin concentration in rat brain as early as 1 hr; at 1 hr 5-hydroxyindoleacetic acid (5HIAA) concentration was slightly increased, but at later times 5HIAA was also decreased. Fluoxetine, in contrast, did not change serotonin concentration in whole brain but decreased 5HIAA concentration at all time points. At all time intervals studied, the 5HIAA/serotonin ratio was increased by d-fenfluramine (and by Ro 4-1284, a nonspecific serotonin releaser) but was decreased by fluoxetine, a serotonin uptake inhibitor. No decrease in 5HIAA concentration or in the 5HIAA/serotonin ratio was apparent at any time or after any dose of d-fenfluramine studied. The possibility that doses of d-fenfluramine below those needed for serotonin release might inhibit serotonin uptake was tested by determining whether d-fenfluramine could block the acute depletion of brain serotonin by p-chloroamphetamine, or the long-term neurotoxic effect of p-chloroamphetamine on brain serotonin neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

2H-Benzo(a)quinolizin-2-ol, 2-Ethyl-1,3,4,6,7,11b-↗

PubMed1988

Ergolines as selective 5-HT1 agonists.

The synthesis and serotonin receptor subtype affinity of a series of ergolines are described. High selectivity for the 5-HT1 subtype was found with a number of 8-substituted (3 beta, 5 beta)-9,10-didehydro-6-methylergolines. The more potent and selective of these compounds increased the concentration of serotonin and decreased the concentration of 5-HIAA in rat brain and increased corticosterone concentration in rat serum. Oral administration of 13, (3 beta)-2,3-dihydrolysergine, produced long-lasting decreases in serotonin turnover. Compound 13 lacked substantial dopaminergic activity as measured by its effects on dopamine turnover in whole brain or striatum and its affinity for alpha-adrenergic binding sites was significantly less than for 5-HT1 binding sites. The increases in serum corticosterone concentrations produced by 13 were not blocked by the serotonin uptake inhibitor fluoxetine or by the serotonin synthesis inhibitor p-chlorophenylalanine, suggesting that 13 exerts its effects through direct stimulation of serotonin receptors.

Animals↗

PubMed1988

Metabolism of fenfluramine to norfenfluramine in guinea-pigs.

After injection of fenfluramine into guinea-pigs, the N-dealkylated metabolite norfenfluramine was present in brain at higher concentrations and persisted longer than the parent drug, fenfluramine. Contrary to a claim in previous literature, the guinea-pig does metabolize fenfluramine to norfenfluramine, hence the ability of fenfluramine to cause acute and long-term depletion of brain 5-hydroxytryptamine in this species does not prove that fenfluramine, instead of nonfenfluramine, can produce these effects.

Animals↗

PubMed1987

p-Chloroamphetamine formation responsible for long-term depletion of brain serotonin after N-cyclopropyl-p-chloroamphetamine injection in rats.

After the injection of N-cyclopropyl-p-chloroamphetamine (N-cyclopropyl-PCA) into rats, p-chloroamphetamine (PCA) was identified in brain by high performance liquid chromatography with UV detection and was quantitated by that method and by spectrofluorometric analysis involving reaction with fluorescamine. The identity of PCA in brains of rats treated with N-cyclopropyl-PCA was confirmed by mass spectrometry. The peak concentrations of PCA in brain occurred 4 hrs after N-cyclopropyl-PCA injection. Brain concentrations of PCA and of N-cyclopropyl-PCA were measured at 1 or 4 hrs, respectively, after the injection of various doses of PCA or of N-cyclopropyl-PCA into rats. The depletion of brain serotonin and 5-hydroxyindoleacetic acid (5-HIAA) was measured 1 week after injection of those same doses of PCA or N-cyclopropyl-PCA. Comparing peak concentrations of PCA with the degree of depletion of brain serotonin supported the interpretation that PCA formed metabolically accounted for the long-term depletion of brain 5-hydroxyindoles after injection of N-cyclopropyl-PCA in rats.

Amphetamines↗

PubMed1987

Influence of route of administration on potency of the selective 5HT-1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin, in rats.

8-Hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) decreased the concentration of 5-hydroxyindoleacetic acid (5HIAA), the deaminated metabolite of serotonin, in rat brain. 8-OH-DPAT was much more potent when injected subcutaneously than when injected intraperitoneally, the potency difference being approximately 17-fold. The important influence of route of administration on the potency of 8-OH-DPAT must be considered in interpreting the various functional effects that have been reported with it.

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

PubMed1986

Fluoxetine enantiomers as antagonists of p-chloroamphetamine effects in rats.

The dextrorotatory enantiomer of fluoxetine was slightly more potent than the levorotatory enantiomer in antagonizing the depletion of brain serotonin by p-chloroamphetamine in rats. The time course of the depletion of brain serotonin at times out to 24 hr after the injection of p-chloroamphetamine was determined with or without simultaneous administration of one of the fluoxetine enantiomers. The dextrorotatory enantiomer prevented the depletion of brain serotonin at any time after p-chloroamphetamine. The levorotatory enantiomer prevented the initial depletion of brain serotonin at 2 and 4 hr, but by 8 hr brain serotonin concentration was decreased and by 24 hr the depletion of serotonin was almost as great as in rats treated with p-chloroamphetamine alone. The elevation of serum corticosterone that occurred acutely after injection of a low dose of p-chloroamphetamine was significantly antagonized by both enantiomers of fluoxetine, the dextrorotatory enantiomer being slightly more potent. In contrast, the lowering of DOPAC (3,4-dihydroxyphenylacetic acid) concentration in rat brain by p-chloroamphetamine was not antagonized by either enantiomer of fluoxetine, indicating this effect is not secondary to serotonin release by p-chloroamphetamine. The results are consistent with other evidence that both enantiomers of fluoxetine are potent inhibitors of serotonin uptake, the dextrorotatory enantiomer being longer-acting than the levorotatory enantiomer in rats.

Amphetamines↗

PubMed1986

Effect of fluoxetine pretreatment on the neurochemical changes induced by amfonelic acid combined with spiperone in rats.

Combined treatment with amfonelic acid plus spiperone caused large increases in 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) and a decrease in dopamine in rat striatum. 5-Hydroxytryptamine (5-HT) was decreased in striatum (but not in hypothalamus), and 5-hydroxyindoleacetic acid (5-HIAA) was increased in the striatum. Pretreatment with fluoxetine, an inhibitor of uptake into 5-HT neurons, antagonized the decrease in 5-HT and the increase in 5-HIAA and in the ratio 5-HIAA/5-HT but did not antagonize the changes in dopamine or its metabolites. The amfonelic acid-spiperone combination apparently causes increased release of dopamine in striatum, and the released dopamine is accumulated by 5-HT nerve terminals via the membrane uptake carrier. Inhibition of that carrier by fluoxetine prevents the release of 5-HT caused by the dopamine influx.

Animals↗

PubMed1986

1-(1-Naphthyl)piperazine, a central serotonin agonist.

1-(1-Naphthyl)piperazine (1-NP) had high affinity for tritiated serotonin, tritiated LSD (lysergic acid diethylamide) and tritiated spiperone binding sites in rat brain cortex in vitro. 1-NP at doses of 3-30 mg/kg i.p. decreased 5-hydroxyindoleacetic acid (5-HIAA) concentration in whole brain of rats in vivo. The 30 mg/kg dose caused a significant increase in serum corticosterone concentration. At doses of 3-30 mg/kg i.p., 1-NP reduced the accumulation of 5-hydroxytryptophan following decarboxylase inhibition by NSD 1015 in rat hypothalamus and striatum. Reduced serotonin turnover and elevated serum corticosterone concentrations are interpreted as evidence of central serotonin receptor activation by compounds of this structural class. 1-NP has previously been reported to antagonize vascular serotonin receptors, suggesting that it, like 1-(m-trifluoromethylphenyl)piperazine, behaves as an antagonist at peripheral (vascular) serotonin receptors despite being an agonist at central serotonin receptors.

Animals↗

PubMed1986

Central serotonin agonist actions of LY 165163, 1-(m-trifluoromethylphenyl)-4-(p-aminophenylethyl) piperazine, in rats.

1-(m-Trifluoromethylphenyl)-4-(p-aminophenylethyl)piperazine (LY 156163), reported previously to have selective affinity for the 5-HT1A subtype of serotonin receptor in vitro, was studied at doses of 1.25 to 20 mg/kg i.p. in rats to determine if it had properties characteristic of centrally acting serotonin agonists. LY 165163 decreased whole brain concentrations of the serotonin metabolite, 5-hydroxyindoleacetic acid, but not of serotonin itself, decreased the rate of accumulation of 5-hydroxyindoleacetic acid after probenecid administration to block its efflux from brain, decreased the rate of decline in serotonin concentration after inhibition of serotonin synthesis with alpha-propyldopacetamide and decreased the accumulation of 5-hydroxytryptophan after decarboxylase inhibition by m-hydroxybenzylhydrazine. LY 165163 also decreased 5-hydroxyindoleacetic acid concentrations in two specific brain regions, striatum and hypothalamus. Serum concentrations of corticosterone and prolactin were increased by doses of LY 165163 that reduced serotonin turnover. These effects are all consistent with evidence from other studies that LY 165163 is a centrally acting serotonin agonist. LY 165163 also increased the concentrations of two dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, measured in whole brain as well as in striatum and hypothalamus, but did not alter dopamine concentration. The accumulation of dopa after decarboxylase inhibition was accelerated by LY 165163. The increases in hormone concentrations in serum and of dopamine metabolite concentrations in brain were not antagonized by pretreatment with metergoline, a serotonin antagonist. The mechanisms of those effects require further study.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1985

Flumezapine and zotepine: 5-hydroxytryptamine antagonism not involved in the lack of synergism of these antipsychotic drugs with amfonelic acid in rats.

Two antipsychotic drugs, flumezapine and zotepine, resembled clozapine, not spiperone, in not acting synergistically with amfonelic acid to elevate striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) in rats. Since flumezapine, zotepine and clozapine antagonize 5-hydroxytryptamine (5-HT) receptors with potency similar to their potency in antagonizing dopamine receptors, the possibility that 5-HT receptor blockade prevented their synergism with amfonelic acid was considered. Methiothepin, a potent 5-HT antagonist and dopamine antagonist, mimicked spiperone in causing a marked increase in striatal DOPAC in amfonelic acid-treated rats, indicating that 5-HT antagonism is not involved in the lack of synergism of flumezapine and zotepine with amfonelic acid.

3,4-Dihydroxyphenylacetic Acid↗