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Biomedical subjects

R B Mailman

Publications and source records attributed to R B Mailman.

At least 109 records · Page 6Linked to original sources
PubMed1984

Central neurotransmitter effects of organotin compounds: trials, tribulations and observations.

Administration of trimethyltin (TMT) or triethyltin (TET) compounds to rats during postnatal development has known behavioral and neuropathological consequences. By measuring the concentrations of dopamine, norepinephrine, homovanillic acid, dihydroxyphenylacetic acid, gamma-aminobutyric acid, acetylcholine, and choline in different brain areas of TMT and TET-treated animals, an attempt was made to correlate these functional deficits with changes in CNS neurotransmitter alterations in vivo. TET had no effect on any of the substances measured whereas TMT significantly decreased gamma-aminobutyric acid and dopamine levels, but only in hippocampus and striatum, respectively. All other neurotransmitter substances measured were not affected. These findings illustrate the complexity inherent in attempting to use neurochemical techniques alone as an index of toxicity in the absence of specific defined hypotheses.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Effects of thioridazine and its metabolites on dopaminergic function: drug metabolism as a determinant of the antidopaminergic actions of thioridazine.

The antidopaminergic properties of thioridazine (THD) and its major metabolites were evaluated using in vitro and in vivo estimates of dopaminergic function. THD-2-sulfone was more potent than, and THD-2-sulfoxide equipotent to, THD in displacing [3]spiperone from rat striatal membranes and in inhibiting dopamine-stimulated cyclic adenosine 3',5'-monophosphate synthesis in rat striatal homogenates. Other major THD metabolites were relatively inactive. These in vitro data suggest that THD, THD-2-sulfone and THD-2-sulfoxide are potent dopamine receptor blocking agents. Intraperitoneally administered THD antagonized amphetamine-induced locomotion and also increased the concentration of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in terminals of the nigrostriatal dopamine system. Conversely, THD administered i.c.v. into conscious animals, did not antagonize amphetamine-induced locomotion nor increase brain regional concentrations of DOPAC or HVA. On the other hand, the i.c.v. administration of THD-2-sulfone and THD-2-sulfoxide dose-dependently inhibited amphetamine-induced locomotion and also increased the concentrations of HVA and/or DOPAC in the striatum and olfactory tubercles. These apparently discrepant in vitro and in vivo data suggest that the biotransformation of THD is a major determinant in those actions of THD attributed to a blockade of dopamine receptors in the central nervous system.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1984

Greater potency of mesoridazine and sulforidazine compared with the parent compound, thioridazine, on striatal dopamine autoreceptors.

The electrically evoked overflow of dopamine (DA) from perfused rabbit striatal slices was used to assess the relative functional potencies of thioridazine, a phenothiazine antipsychotic agent, and two of its major metabolites, mesoridazine (thioridazine-2-sulfoxide) and sulforidazine (thioridazine-2-sulfone). Thioridazine (1000 nM) enhanced the electrically evoked overflow of DA by 18.3 +/- 4.6% (n = 4) at 0.3 Hz. Mesoridazine and sulforidazine likewise produced only small increases (5-20%) in evoked overflow of DA from slices stimulated at 0.3 Hz. At this frequency of stimulation, apomorphine (30 nM) inhibited the overflow of DA by 71.4 +/- 8.43% (n = 40). All three drugs antagonized, in a concentration-dependent fashion, the inhibitory effect of apomorphine (30 nM) on electrically evoked DA release at 0.3 Hz. The IC50 for thioridazine for antagonizing the effect of apomorphine was 130 nM, whereas that for mesoridazine was 14.4 nM and for sulforidazine was 6.1 nM. These results indicate that thioridazine and its two clinically active metabolites can block striatal DA autoreceptors involved in modulating DA release. The observation that mesoridazine and sulforidazine were significantly more potent than the parent drug is consistent with the hypothesis that a major part of the pharmacologic responses to thioridazine may be a consequence of its metabolism to active compounds.

Animals↗
PubMed1984

Thioridazine and the neuroleptic radioreceptor assay.

When the neuroleptic radioreceptor assay (NRRA) has been used to monitor total neuroleptic-like activity (NLA) in the blood of patients taking thioridazine, the NLA values obtained from the NRRA are much lower than values calculated in the same sample by measuring the actual concentrations of parent drug and active metabolites and multiplying these values by the relative potency of each compound. The present report demonstrates that in the NRRA for thioridazine or its active metabolites, the normal displacement of [3H]-spiperone from striatal membranes by thioridazine is altered in the presence of sera. The inclusion of serum (50 microliter/ml) distorts the sigmoidal displacement curves, such the resulting log-logit (or Hill) slope is markedly decreased. Similar serum-induced changes in the log-logit slope are seen for two active metabolites of thioridazine, but not for chlorpromazine or haloperidol. As a consequence, when one of these latter drugs is used as a standard, the NRRA substantially underestimates the actual NLA (chlorpromazine equivalents) values for patients treated with thioridazine. Moreover, because of differences in the magnitude of the effect with serum from different individuals, it is not possible to control completely for this effect. Thus, these data reconcile discrepancies that have been reported for data from the NRRA versus that from direct analytical measurements, and demonstrate that the use of the NRRA as a quantitative tool in the clinical pharmacology of thioridazine may lead to erroneous estimations of active drug and metabolites in the blood.

Animals↗
PubMed1983

Lithium-induced polydipsia: dependence on nigrostriatal dopamine pathway and relationship to changes in the renin-angiotensin system.

The dependence of lithium-induced polydipsia (LIP) on central monoamine pathways was investigated using several pharmacological manipulations. Intracisternal administration of 6-hydroxydopamine (6-OHDA) in combination with pargyline or desipramine was used to deplete dopamine (DA), norepinephrine, or both catecholamines. Significant decreases in LIP were seen after treatments that depleted brain DA, whereas depletion of norepinephrine alone did not affect LIP. Site-specific injection of 6-OHDA into the substantia nigra or caudate nucleus, but not the nucleus accumbens or noradrenergic dorsal bundle, also caused a decrease in LIP. Depletion of serotonin by intracisternal administration of 5,7-dihydroxytryptamine also had no effect on LIP. Consistent with these findings, the DA receptor blocker haloperidol attenuated LIP. Thus, LIP appears to be dependent on intact nigrostriatal DA fibers, but not on other monoaminergic systems in the brain. Lithium also increased plasma renin activity (PRA) and angiotensin I and II immunoreactivity in plasma, though the time course of LIP onset did not directly parallel these latter changes in the renin-angiotensin axis. Neither the PRA or angiotensin II immunoreactivity in lithium-treated animals was sufficiently high to account for LIP. In addition, the 6-OHDA lesions of the caudate nucleus or substantia nigra that attenuated LIP did not affect the lithium-induced increases in PRA or in angiotensin I or II concentrations. Thus, LIP probably involves mechanisms other than just being a direct response to lithium-induced increases in PRA or angiotensin II concentration and simply may not be secondary to lithium-induced polyuria. Because of the similar pharmacological characteristics of angiotensin II and lithium-induced drinking, a role for angiotensin receptors in LIP cannot be ruled out.

Angiotensin II↗
PubMed1983

Calcitonin depresses amphetamine-induced locomotor activity.

Synthetic salmon calcitonin (sCT), given subcutaneously (6.4 micrograms/kg) or intracerebroventricularly (ICV, 30-600 ng), depressed amphetamine-induced locomotor activity in rats by more than 50%. ICV injection of sCT, either three hours or immediately before intraperitoneal amphetamine (1-3 mg/kg), significantly reduced the amphetamine-induced activity. In the absence of amphetamine, sCT had no effect on locomotor activity during the first 100 minutes after treatment. These results show sCT can act centrally to modify drug-induced behavior and may be related to reports of calcitonin receptors and calcitonin-like peptides in the brain.

Animals↗
PubMed1983

Effects of postnatal trimethyltin or triethyltin treatment on CNS catecholamine, GABA, and acetylcholine systems in the rat.

The effects on brain neurochemistry of two neurotoxic tin compounds, trimethyltin (TMT) hydroxide and triethyltin (TET) sulfate, were examined. Long-Evans rats were treated with TMT hydroxide (1 mg/kg, i.p.) on alternate days from day 2 to 29 of life. These treatments caused a weight deficit of 10-20% by the time the animals were killed on day 55 by head-focused microwave irradiation. These TMT treatments are known to cause severe neuronal loss in the hippocampus and lesser damage in other brain regions. Accordingly, the concentration of gamma-aminobutyric acid (GABA) was decreased in the hippocampus; however, acetylcholine and choline concentrations were unaffected. These data suggest that TMT-induced effects on GABA systems are greater than that due simply to generalized neuronal loss. The TMT treatments also caused a significant decrease in dopamine concentrations in the striatum, but did not alter the concentrations of dihydroxyphenylacetic acid or homovanillic acid, the acidic metabolites of dopamine. Conversely, concentrations of dopamine and norepinephrine in the brain stem and norepinephrine in the cerebellum were not altered. Despite reports in the literature of TMT-induced neuronal damage in areas of the cortex, no effects on GABA, acetylcholine, or choline levels were found in the cortical areas examined, or in the hypothalamus. TET sulfate (0.3 mg/kg/day) was administered for 6 consecutive days of every week during days 2-29 of life. This dose is lower than that needed to cause intramyelin edema, yet it does result in long-term behavioral changes. Despite this, no changes in the concentration of any of the measured neurotransmitters or their metabolites were detected. In concert, these data demonstrate that neurochemical methods should not be used as neurological "screens," but rather to define specific mechanisms suggested by detailed behavior, pharmacological, and/or physiological studies.

Acetylcholine↗
PubMed1983

N-oxides of phenothiazine antipsychotics: effects on in vivo and in vitro estimates of dopaminergic function.

Although it is known that N-oxidation is a major route for the metabolism of tertiary amine drugs in humans, the extent to which N-oxide (NO) metabolites of clinically used phenothiazine antipsychotics contribute to the neuropharmacology of the parent drug has been uncertain. After direct lateral ventricular injection of rats, both fluphenazine-NO and trifluoperazine-NO (piperazinyl-4-NO) had significant antidopaminergic activity as shown by their antagonism of amphetamine-induced locomotion and, to a lesser extent, of apomorphine-induced stereotypy. In vitro, fluphenazine-NO and trifluoperazine-NO inhibited both [3H]spiperone binding to rat striatal membranes and dopamine-stimulated adenylate cyclase activity in striatal homogenates. Conversely, chlorpromazine (CPZ)-NO (side-chain oxide) did not have significant antidopaminergic activity in either in vitro test, nor did it block amphetamine or apomorphine-induced behavior when centrally administered. These latter results were surprising because it had been reported that CPZ-NO had significant antidopaminergic activity when administered by i.p. injection. In our experiments, i.p. administration of CPZ-NO or CPZ resulted in increased concentrations in brain of the acidic metabolites of dopamine, 3,4-dihydroxyphenylacetic acid and homovanillic acid. However, for CPZ-NO, this was shown to occur concomitantly with the peripheral conversion of the NO back to the parent drug. This suggests that although CPZ-NO does not itself have antidopaminergic properties, it may be readily converted to CPZ or other active species that contribute to pharmacological responses. These data suggest that the NOs of the phenothiazines may contribute to the neuropharmacological actions of antipsychotic drugs via several mechanisms, and underscore the necessity of correlating metabolic and neuropharmacological data.

Adenylyl Cyclases↗
PubMed1983

Interactions of neurotensin with brain dopamine systems: biochemical and behavioral studies.

Intracisternal (i.c.) injection of neurotensin (NT) to rats or mice attenuated the locomotor hyperactivity induced by d-amphetamine, methylphenidate or cocaine, but not the increased activity induced by apomorphine or lergotrile. The reduction of methylphenidate-induced locomotor activity by i.c. NT was not due to an increased drug metabolism because i.c. NT did not change plasma methylphenidate concentrations. These actions of NT are distinct from those of the dopamine receptor antagonist haloperidol, which blocked the locomotor hyperactivity induced by all five stimulant drugs in rats. A further difference between NT and neuroleptics was demonstrated by the observation that i.c. NT did not block apomorphine-induced stereotypic behavior. In vitro, NT did not displace [3H]spiperone from its binding sites in homogenates of either the striatum or nucleus accumbens from rat brain. Moreover, i.c. injection of NT did not alter the subsequent in vitro binding of [3H]spiperone to membranes of the nucleus accumbens or striatum. In addition, NT did not alter basal or dopamine-stimulated adenylate cyclase activity in homogenates of the nucleus accumbens or striatum. However, i.c. injection of NT produced a significant increase in the concentrations of homovanillic acid, a major dopamine metabolite, in the nucleus accumbens, olfactory tubercles and striatum. In addition, the concentration of dihydroxyphenylacetic acid was increased in the nucleus accumbens and olfactory tubercles after i.c. NT. Peripheral injection of haloperidol produced qualitatively similar effects on dopamine metabolism, but the effects of haloperidol, unlike those of i.c. NT, were attenuated by apomorphine injection. Taken together, these data indicate that centrally administered NT affects certain brain dopamine systems without interacting directly with those dopamine receptors labeled by [3H]spiperone, coupled to adenylate cyclase or mediating the pharmacological effects of apomorphine.

Adenylyl Cyclases↗
PubMed1982

Simultaneous determination of thioridazine and its S-oxidized and N-demethylated metabolites using high-performance liquid-chromatography on radially compressed silica.

A method for simultaneously quantifying thioridazine, northioridazine, thioridazine-2-sulfoxide, thioridazine-2-sulfone and thioridazine-5-oxide in serum and plasma is described. Following solvent extraction these compounds were separated by high-performance liquid chromatography on radially compressed silica gel and detected by UV absorbance at 254 nm. Chromatography time is less than 7 min. The relative retention of these compounds as a function of the methanol and methylamine content of the mobile phase is discussed. Practical limits of detection, based upon on assayed plasma or serum volume of 1 ml, were 20 ng/ml for thioridazine-5-oxide and 10 ng/ml for the other compounds. The coefficient of variation for all compounds was less than 13%. The method is compared with more conventional high-performance liqiud chromatographic and gas chromatographic methodology.

Chromatography, Gas↗
PubMed1982

Serum concentrations of thioridazine, its major metabolites and serum neuroleptic-like activities in schizophrenics with and without tardive dyskinesia.

Two groups of elderly chronic schizophrenic patients, one with and one without tardive dyskinesia (TD), were studied. In addition to estimation of the neuroleptic-like radioreceptor activity (RRA) of the serum, serum concentrations of thioridazine (THD) and its major metabolites, THD-2-sulfoxide, THD-2-sulfone and THD-5-oxide, were measured with high performance liquid chromatography. Blood samples were collected at two different occasions when the patients were considered to be in a pharmacological "steady state". The concentrations of THD and its metabolites, as well as RRA values, were similar at both occasions. In general, THD-2-sulfoxide and THD-5-oxide were present in higher concentrations than the parent compounds, and the serum concentrations of THD, its metabolites and the RRA values were positively correlated with the administered daily dose of THD. However, no significant difference in serum levels of THD, its metabolites, or significant difference in serum levels of THD, its metabolites, or RRA values existed between the patients with and without TD. These data suggest that pharmacodynamic rather than pharmacokinetic differences may be more important in producing high risk for TD in patients on long-term neuroleptic treatment.

Aged↗
PubMed1982

Morphological and cytochemical characterization of neuroepithelial bodies in fetal rabbit lung. I. Studies of isolated neuroepithelial bodies.

Neuroepithelial bodies (NEB) in 29-day fetal rabbit lung were examined by light microscopy and cytochemistry to demonstrate their structural and biochemical properties in situ. Longitudinal sections of NEB at airway bifurcations demonstrated their chemoreceptor-like appearance. Furthermore, the cytochemical presence of serotonin, acetylcholinesterase, formaldehyde-induced fluorescence, and silver-staining properties demonstrated the neural-like biochemical properties of NEB cells. Forty-one NEB and eight single neuroendocrine cells from whole fetal lungs were examined ultrastructurally. Juxtaluminal junctional complexes composed of tight and intermediate junctions, desmosomes, and cytoplasmic filaments were demonstrated in the corpuscular-shaped NEB. Basal bodies were apparent in NEB cell cytoplasm; cilia extended from NEB cells. Dense-core vesicles (DCV) were of at least three types: type 1, type 2, and enterochromaffin type. The majority of epithelial cells adjacent to NEB in near-term airway epithelium were undifferentiated, with large amounts of glycogen. However, ciliated cells were adjacent to some small NEB and single neuroendocrine cells; mucus or Clara-type cells were not observed. NEB isolated by collagenase treatment revealed an intact organoid structure, DCV, and desmosomes and retained their argyrophilia and formaldehyde-induced fluorescence. NEB were recovered in cell fractions separated by unit gravity that had cells in clumps of four or more. One to five NEB stained with silver in cytocentrifuge preparations of control, mixed cells, whereas up to 20 intact NEB were demonstrated in the clump-containing, separated fractions. We propose that isolated NEB retain certain biochemical and metabolic properties similar to those of their counterparts in situ. Serotonin and 5-hydroxyindole acetic acid were found by high-performance liquid chromatography analysis in the fractions containing NEB, and amine precursor uptake and decarboxylation (APUD) activity were demonstrated. Moreover, muscarinic cholinergic receptors were detected, consistent with the occurrence of acetylcholinesterase in NEB. The elution profile of bombesin radioimmunoactivity substantiated that isolated fetal rabbit NEB contained this neuropeptide and that NEB were enriched by unit gravity sedimentation. These studies suggest that NEB are structurally and functionally developed before other cell types in immature airway epithelium and can be isolated as intact organoids, which retain some of their structural and metabolic integrity.

APUD Cells↗
PubMed1982

Increase in dopamine metabolites in rat brain by neurotensin.

Neurotensin (NT), an endogenous tridecapeptide, is heterogeneously distributed in the central nervous system. The present study examined the effects of physiologically and behaviorally active doses of NT (1--100 micrograms intracisternally) on dopamine, serotonin and their primary metabolites as well as accumulation of dopa after inhibition of dopa decarboxylase. NT was shown to increase dopa accumulation when compared with saline treatment, suggesting that dopamine synthesis was increased. In accord with this view, NT also caused a dose-dependent increase in homovanillic acid and dihydroxyphenylacetic acid, the major metabolites of dopamine, in several brain areas (striatum, olfactory tubercles, nucleus accumbens, frontal cortex and hypothalamus). Interestingly, the increase in homovanillic acid was greater than that for dihydroxyphenylacetic acid. In striatum, an initial increase in dopamine content after 30 micrograms of NT was followed by an increase and a subsequent decrease of dopamine metabolites. Several other neuropeptides (Met-enkephalin, cholecystokinin-8, thyrotropin releasing hormone, substance P and d-Arg9-NT), at doses equimolar to 30 micrograms of NT, did not affect dopamine metabolites, whereas certain others (beta-endorphin and bombesin) increased their concentration in some brain areas. Except for the highest dose of NT, measures of serotonergic function were not affected by NT or any of the other neuropeptides.

Animals↗
PubMed1981

Simultaneous quantification of dopamine, 5-hydroxytryptamine and four metabolically related compounds by means of reversed-phase high-performance liquid chromatography with electrochemical detection.

A method for simultaneously quantifying dopamine, 5-hydroxytryptamine (5-HT) and four metabolically related compounds has been developed, permitting more efficient neurochemical examination of these often interrelated biogenic amine systems. The method uses high-performance liquid chromatographic separation of these compounds on a C18 reversed-phase column with a buffered mobile phase containing methanol as an organic modifier and heptanesulfonate as an ion-pair reagent. Using 5-hydroxy-N-methyltryptamine as an internal standard and electrochemical detection, chromatography time is less than 12 min. Sample preparation simply involves the addition of internal standard, homogenization in the mobile phase, centrifugation and injection of the supernatant into the chromatograph. The method is sensitive to a tissue content of these compounds of less than 1 ng. The utility of this method for neuropharmacological--neurochemical studies is illustrated with studies using inhibitors of monoamine oxidase (pargyline) and aromatic amino acid decarboxylase (RO 4-4602).

Animals↗