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Biomedical subjects

R B Mailman

Publications and source records attributed to R B Mailman.

At least 145 records · Page 8Linked to original sources
PubMed1978

Behavioral and prolactin responses to 5-hydroxytryptophan in rats treated during development with 5,7-dihydroxytryptamine.

The serotonin precursor, 5-hydroxytryptophan (5-HTP), can induce a behavioral syndrome characterized by rigidity, splayed feet, tremor, head weaving, salivation and forepaw treading. This response to 5-HTP was markedly potentiated in adult rats treated intracisternally with 5,7-dihydroxytryptamine (5,7-DHT) during development. Prevention of the 5,7-DHT-induced reduction of brain norepinephrine with pargyline or desipramine did not diminish the potentiation of 5-HTP, suggesting that noradrenergic fibers are not contributing to the altered 5-HTP response. It was also found that treatments with 5,7-DHT potentiated the release of prolactin and the disruption of responding in a fixed-ratio operant task induced by 5-HTP. Other experiments indicated that 5,7-DHT treatments potentiated 5-HTP without affecting the action of L-dihydroxyphenylalanine. In addition, administration of the decarboxylase inhibitor, R0-4-4602, at a dose that inhibits enzyme activity in brain, blocked the 5-HTP-induced behavioral syndrome in 5,7-DHT-treated rats, indicating that 5-HTP must be converted to serotonin for 5-HTP to alter behavior. Thus, the present studies indicate that destruction of serotonergic fibers during development can produce permanent changes in central serotonergic mechanisms.

5,7-Dihydroxytryptamine↗
PubMed1978

Lead exposure during infancy permanently increases lithium-induced polydipsia.

Lead (200 milligrams per kilogram) was administered daily by intubation to Long-Evans rats on days 3 through 30 of life. Thirty to 180 days after cessation of lead administration, the lead-treated rats were consistently more polydipsic after lithium administration (2 millimoles per kilogram per day) than were pair-treated controls. Lithium increased the plasma renin activity equally in both the lead treated and the control groups. These data are evidence that there may be permanent neural changes induced by postnatal exposure to lead that are manifested by pharmacological challenge with lithium.

Animals↗
PubMed1978

Evaluation of the effects of nerve growth factor and anti-nerve growth factor on the development of central catecholamine-containing neurons.

Intracisternal NGF or anti-NGF has been found to produce no long-term major alterations in central norepinephrine (NE) or dopamine levels when administered to neonatal rats. While NGF and anti-NGF were found to produce significant changes in brain NE content within one week of treatment, changes in central NE were no longer detectable at 30 days of age. Modification of the growth response of the central adrenergic neurons following 6-OHDA treatment was also not affected by NGF or anti-NGF when evaluated 3 weeks after treatment. However, centrally administered anti-NGF did induce a loss of peripheral NE terminals, which was attributed to leakage of the anti-NGF from the central injection site.

Adrenergic Fibers↗
PubMed1975

The occurrence of multiple forms of cytochrome P-450 in hepatic microsomes from untreated rats and mice.

The hepatic microsomes of rat and mice were subfractionated by the procedure of Dallner. When a 1.3 M sucrose lower layer was used for the two-step discontinuous gradient, no differences in spectral characteristics were noted between subfractions, though the smooth fractions (SER) had higher oxidative activity towards the substrates tested. When lower layers of 1.05, 1.1 or 1.15 M sucrose were used, and the SER isolated contained cytochdrome P-450 with significantly different spectral characteristics from that of the rough fraction (RER). The SER cytochrome P-450 had a wavelength maximum in the carbon-monoxide reduced difference spectrum that was significantly lower (ca. 1.0 nm) than that in the RER. In addition, the type I:CO-reduced spectral ratio of these fractions is significantly elevated. These data indicate that liver microsomes from untreated rats and mice contain more than one cytochrome P-450 and that of these cytochromes may be located in different parts of the endoplasmic reticulum.

Animals↗
PubMedDate not supplied

Effect of ethanol on cyclic nucleotides in vivo: consequences of controlling motor and respiratory changes.

Many psychotropic drugs alter cerebellar cyclic guanosine-3',5'-monophosphate (cGMP) content. Whereas apomorphine increased levels, central depressants such as ethanol, chlordiazepoxide or barbiturates, reduce the content of cerebellar cGMP without altering levels of cyclic adenosine-3',5'-monophosphate (cAMP). Additional data indicate that tolerance develops to this reduction of cerebellar cGMP by ethanol. In paralyzed animals, the increase in cerebellar cGMP content induced by apomorphine and the decrease caused by ethanol were dramatically attenuated. Since relatively high doses of ethanol were needed to decrease blood CO2 tension in spontaneously moving rats, changes in respiratory function appear to be of only minor importance in the ethanol-induced decrease in cerebellar cGMP. It is concluded that ethanol-induced changes in content of cerebellar cGMP in vivo may be secondary to alterations in motor and, to a lesser extent, in respiratory function.

Animals↗
PubMedDate not supplied

Mechanisms of CNS injury in behavioral dysfunction.

Advances in the neurosciences have led to a greater understanding of the anatomical, biochemical, and molecular loci involved in injury to, and adaptation of, the central nervous system. Recent research has permitted the elucidation of the mechanisms for some neurotoxicants whose actions have been studied for decades, as in the example of the pyrethroid insecticides. In contrast, the mechanism of the neurotoxicity of the organophosphate insecticides and nerve gases has been known for many years, but our understanding of the many resulting sequelae has been markedly increased by recent discoveries. Two examples illustrate the strengths and weaknesses of such methods in predicting neurotoxicity. Studies of the parkinsonian-like toxicity caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (a by-product of synthesis of illicit opiates) exemplify the best application of current methods in neurotoxicology. It has been shown that the expression of MPTP toxicity requires both metabolism of MPTP to the proximal toxicant 1-methyl-4-phenylpyridinium (MPP+) and active uptake into central dopamine neurons. The discovery of binding sites of MPP+ in these cells has clarified how dopamine neurons are destroyed, thereby causing neurological signs. This illustrates two key concepts: first, the bioconversion of compounds to proximal toxicants is often ignored, and second, these events are unlikely to be detectable by in vitro studies that focus on a few biochemical endpoints. Another useful example was that of erythrosin (FD&C Red No. 3), in which numerous in vitro studies suggested that this food color was a potential neurotoxicant. However, this was shown to be an artifact of the ability of this color to disrupt biomembranes at high in vitro concentrations, and this idea was supported by negative data from both behavioral and clinical studies. Thus, the plethora of possible molecular and biochemical targets in the central nervous system (receptors, second messenger events, transmitter-modulator synthesis, storage and release, membrane maintenance, etc.) preclude the likelihood of developing a single test or a battery of neurochemical or biochemical tests that will be able to screen for neurotoxicants randomly or efficiently. Use of in vitro methods is likely to detect both false positives and negatives. While the availability of theoretical or phenomenological data provides the best start to the application of available biochemical and molecular techniques, predictions of neurotoxicity best can come from theoretical comparison of the structure of suspect compounds (and hypothesized metabolites) with known target sites in the CNS.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Responses of dopaminergic and serotonergic systems to triethyllead intoxication.

Rats treated with triethyllead (TEL) exhibit a behavioral supersensitivity to challenge with dopamine agonists at 7 days following administration of TEL. In the present series of experiments, some neurochemical mechanisms which may affect this behavioral supersensitivity were detected. Administration of a single dose of TEL chloride (7.88 mg/kg, SC) to male Fischer-344 rats decreased the concentrations of dopamine in hippocampus, and of serotonin in olfactory tubercle, at Day 7 posttreatment. The ratio of 5-hydroxyindoleacetic acid/5-hydroxytryptamine (one estimate of serotonin turnover) was increased in nucleus accumbens (p less than 0.05), with a similar trend in olfactory tubercle and striatum (p less than 0.10). No changes were detected in binding of [3H]spiperone to D2 dopamine receptors in striatum or olfactory tubercle. However, although basal adenylate cyclase activity was unaltered in TEL-treated rats, the Vmax for dopamine-stimulated adenylate cyclase activity was significantly elevated in olfactory tubercle. Conversely, TEL at micromolar concentrations markedly attenuated both basal and dopamine-stimulated adenylate cyclase activity in vitro in striatal homogenates. These data suggest the hypothesis that administration of TEL to rats results in an up-regulation of D1 dopamine receptors in olfactory tubercle, and that the behavioral supersensitivity of TEL-treated animals to dopamine agonists may, in part, be a result of this receptor supersensitivity.

Animals↗
PubMedDate not supplied

Temporal changes in dopaminergic and serotonergic function caused by administration of trimethyltin to adult rats.

Previous studies have demonstrated that at day 7 following treatment, administration of 3 or 7 mg/kg trimethyltin (TMT) to male Long-Evans rats caused decreases in the concentrations of DA in nucleus accumbens, and perturbed serotonergic function in regions of brain that receive serotonergic innervation from the raphe nuclei. The present series of experiments extended these observations by examining the time course of these events from 14 to 28 days after treatment. Following a dose of 7 mg/kg, changes in serotonergic function, as evidenced by increased turnover and decreased concentrations of 5-HT, were present in striatum, olfactory tubercle, septum and frontal cortex. In nucleus accumbens, concentrations of DA were decreased up to 21 days, while in frontal cortex concentrations of DOPAC and HVA were elevated only at 14 days. In concert with our previous studies, these data indicate that administration of TMT continues to affect serotonergic systems up to 28 days, and dopaminergic systems up to 21 days after exposure, with striatum, nucleus accumbens, olfactory tubercle and septum exhibiting persistent effects due to administration of this neurotoxicant. These prolonged alterations in serotonergic function suggest that this system may play an important role in the response to intoxication with TMT.

3,4-Dihydroxyphenylacetic Acid↗