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Biomedical subjects

H D Snoddy

Publications and source records attributed to H D Snoddy.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1984

Depletion of cardiac norepinephrine in rats and mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a commercially available chemical reagent. Although little has been known about its biological effects, recently MPTP has been reported to cause irreversible Parkinson's disease-like symptoms in humans and in monkeys. We describe here another pharmacologic effect of MPTP, the ability to deplete cardiac norepinephrine in rats and mice. In mice, cardiac norepinephrine concentration decreased within 1 hr, was maximally depleted at 24 hr, and recovered by 4-7 days after i.p. injection of a 32 mg/kg dose of MPTP. The depletion was antagonized by desipramine pretreatment, as was norepinephrine depletion by tyramine. In rats, cardiac norepinephrine depletion by 10-30 mg/kg, i.p., doses of MPTP was accompanied by depletion of cardiac dopamine and of norepinephrine in the mesenteric artery. In rats and in mice, norepinephrine in brain was affected to a smaller degree than was norepinephrine in heart, and dopamine in brain was depleted very little if at all. In spontaneously hypertensive rats, the depletion of cardiac norepinephrine was associated with a marked antihypertensive effect. The p-hydroxy analog of MPTP did not deplete cardiac norepinephrine in rats, indicating that its possible formation as a metabolite of MPTP was not involved in the depletion of cardiac norepinephrine. These findings extend the spectrum of known pharmacologic effects of MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1984

Interactions of trazodone with serotonin neurons and receptors.

Trazodone, 2-[3-[4-(m-chlorophenyl)-1-piperazinyl]propyl]-s- triazolo[4,3-a]pyridin-3(2H)one, was evaluated as an inhibitor of uptake into serotonin neurons in vivo in the brains of mice and rats by determining its ability to antagonize the depletion of brain serotonin by p-chloroamphetamine. In mice, trazodone was inactive under conditions in which many antidepressant drugs and other inhibitors of uptake are potent antagonists of the depletion of serotonin in brain induced by p-chloroamphetamine. Weak inhibition of uptake into serotonin-containing neurons in brain in vivo was demonstrated early after the injection of trazodone in rats, especially when the dose of p-chloroamphetamine was reduced to facilitate competitive inhibition of its effects. However, the effects of trazodone were short-lasting. Trazodone did not potentiate the elevation of serum corticosterone by L-5-hydroxytryptophan, in contrast to the effect of fluoxetine, a potent and selective inhibitor of the uptake of serotonin. Instead, trazodone antagonized a response mediated by a serotonin receptor, i.e. elevation of serum corticosterone by a serotonin agonist, quipazine, in rats. Trazodone also antagonized the serotonin-induced contraction of the rat jugular vein in vitro (a response mediated by 5-HT2 receptors), the pA2 being 8.79. These findings agree with previous reports that trazodone is a potent antagonist of serotonergic function. These data, together with earlier evidence, suggest it is unlikely that the inhibition of uptake of serotonin contributes to the clinical antidepressant effects of trazodone.

5-Hydroxytryptophan↗
PubMed1984

Central dopamine receptors mediating pergolide-induced elevation of serum corticosterone in rats. Characterization by the use of antagonists.

Fourteen dopamine antagonists were compared for their ability to antagonize the elevation of the concentration of serum corticosterone in rats by pergolide, a dopamine agonist. Clozapine did not antagonize the effect of pergolide at the largest dose (10 mg/kg) that could be tested without alteration of basal levels of corticosterone. For the other antagonists, calculation of ED50 values [dose antagonizing by 50% the elevation of corticosterone caused by a 0.3 mg/kg (i.p.) dose of pergolide mesylate] revealed the following order of potency: spiperone greater than loxapine greater than fluphenazine greater than perphenazine greater than flupentixol greater than haloperidol greater than cyclophenazine greater than zotepine greater than flumezapine greater than molindone greater than metoclopramide greater than chlorpromazine greater than sulpiride. All of these compounds caused increases in the concentration of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the brains of rats. The dose that increased the concentration of DOPAC to 200% of the control value (ED200) was calculated for each compound. The ratio of the ED50 value for antagonism of the elevation of corticosterone induced by pergolide to the ED200 value for the elevation of DOPAC in brain varied, probably related to differing selectivity for pre- versus postsynaptic dopamine receptors between the compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Central serotonin antagonist activity of ketanserin.

Ketanserin, given i.p. 1 hr before quipazine, antagonized the elevation of serum corticosterone by quipazine in rats. The relatively low ED50 value of ketanserin (0.9 mg/kg) supports other literature data showing that ketanserin is selective for the 5HT2 subtype of serotonin receptors, the data also suggest that 5HT2 receptors are involved in the elevation of serum corticosterone by the serotonin agonist, quipazine.

Animals↗
PubMed1983

Molindone: higher doses needed to block pergolide-induced elevation of serum corticosterone than to elevate dopamine metabolites in brain.

Molindone at a dose of 3 mg/kg i.p. in rats prevented pergolide-induced decreases in brain DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid), causing instead significant increases in these dopamine metabolites when given in combination with pergolide. Molindone alone at 3 mg/kg caused two-fold or greater increases in DOPAC and HVA and at doses as low as 0.3 mg/kg caused significant increases in these metabolites. However, molindone at 3 mg/kg and lower doses was without effect on pergolide-induced elevation of serum corticosterone, though a higher dose of molindone, 10 mg/kg, significantly antagonized this increase in corticosterone. These data support earlier findings with molindone, suggesting it has greater affinity for presynaptic dopamine autoreceptors than for postsynaptic dopamine receptors.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Elevation of serum corticosterone in rats by dopamine agonists related in structure to pergolide.

Two chemical analogs of pergolide were examined to test further the idea that pergolide elevates serum corticosterone concentration in rats by activation of brain dopaminergic receptors. LY116467, which contains an N-methyl substituent in place of the N-n-propyl substituent in pergolide, was less potent than pergolide in lowering brain levels of 3,4-dihydroxyphenylacetic acid (Dopac), the metabolite of dopamine. LY116467 increased serum corticosterone concentration in rats at a dose of 3 mg/kg (a higher dose than is required for pergolide), and the effect was prevented by spiperone pretreatment. LY141865, which has been reported to differ from pergolide in not activating dopamine-sensitive adenylate cyclase and which was found in this study to have much less affinity for serotonin receptors than does pergolide, increased serum corticosterone in much the same manner as pergolide, only slightly higher doses being required. The effect of LY141865 was prevented by pretreatment with haloperidol but not domperidone. Both haloperidol and domperidone increased serum prolactin concentration when given alone or in combination with LY141865, indicating they were both capable of blocking peripheral (pituitary) dopamine receptors. In contrast, haloperidol but not domperidone caused a marked elevation in brain levels of Dopac and of homovanillic acid and prevented the lowering of these brain dopamine metabolites by LY141865. The ability of LY141865 to increase serum corticosterone concentration was attenuated in rats that had received four daily injections of pergolide mesylate, indicating corss-tolerance had occurred. These results strengthen the hypothesis that activation of brain dopaminergic receptors leads to increased serum corticosterone concentration in rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1982

Dopamine accumulation after dopamine beta-hydroxylase inhibition in rat heart as an index of norepinephrine turnover.

Dopamine concentration in rat heart is normally very low, only a few percent of the concentration of norepinephrine. After treatment of rats with a dopamine beta-hydroxylase inhibitor, 1-cyclohexyl-2-mercapto-imidazole (CHMI), there was a rapid increase in dopamine concentration even before norepinephrine concentration had decreased perceptibility. This accumulation of dopamine was readily measured by liquid chromatography with electrochemical detection. Since the percentage change in dopamine was much greater than the percentage change in norepinephrine, especially at early times, measurement of dopamine accumulation rather than norepinephrine decline was considered as a useful measure of norepinephrine turnover. Drugs that act on noradrenergic receptors and are known to alter norepinephrine turnover were found to alter the rate of dopamine accumulation. Clonidine and guanabenz decreased dopamine accumulation after CHMI, whereas piperoxan (but not prazosin) increased dopamine accumulation after CHMI. Pergolide, a dopamine agonist whose lowering of blood pressure and cardiac rate has been suggested to be due to suppression of neurogenic release or norepinephrine, also decreased dopamine accumulation after CHMI. The results suggest that measuring dopamine accumulation may have advantages over measuring norepinephrine disappearance after dopamine beta-hydroxylase inhibition as an indicator of norepinephrine turnover in heart.

Animals↗
PubMed1982

Effect of cis and trans isomers of 1-amino-2-(p-chlorophenyl)cyclohexane, conformationally restricted analogs of p-chloroamphetamine, on 5-hydroxyindoles in rat brain.

Cis and trans isomers of 1-amino-2-(p-chlorophenyl)cyclohexane, conformationally restricted analogs of p-chloroamphetamine, did not decrease brain serotonin and 5-hydroxyindoleacetic acid concentrations at i.p. doses of .05 and .1 mmole/kg in rats, doses at which p-chloroamphetamine itself decreased the concentrations of these 5-hydroxyindoles to half or less of their initial values. These analogs of p-chloroamphetamine, unlike several others studied previously, apparently lack the ability of the parent compound to inhibit serotonin uptake or synthesis or to release serotonin from intraneuronal granular stores.

Animals↗