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I A Michaelson

Publications and source records attributed to I A Michaelson.

16 recordsLinked to original sources
PubMed1990

Effects of inorganic mercury on [3H]dopamine release and calcium homeostasis in rat striatal synaptosomes.

Inorganic mercury (Hg2+) in vitro increases spontaneous transmitter release from nerve terminals. The mechanisms of action are not well understood but may involve alterations in intraterminal Ca2+ dynamics. In this study we describe actions of Hg2+ in vitro on isolated mammalian CNS striatal nerve terminals (synaptosomes). Cobalt (2 mM) completely blocked the effect of 2 microM Hg2+ on spontaneous [3H]dopamine release. Cadmium (100 microM) was equipotent to Co2+ in blocking depolarization-dependent [3H]dopamine release, but did not alter the 2 microM Hg2(+)-induced spontaneous [3H]dopamine release. Depolarization-dependent [3H]dopamine release was not altered by 5 microM Hg2+. It appears that the site of action of Hg2+ on spontaneous [3H]dopamine release is not the Ca2+ channel. The effects of Hg2+ on intraterminal ionized Ca2+ [( Ca2+]i) were evaluated using the Ca2(+)-specific fluorescent probe, fura-2. Hg2+ (1-8 microM) had no effect on [Ca2+]i in 1.2 mM Ca2(+)-containing buffers. In nominal Ca2+ media, 4 and 8 microM Hg2+ significantly decreased [Ca2+]i. Following exposure to 4 and 8 microM Hg2+ the quenching of extrasynaptosomal fura-2 by Mn2+ was increased, suggesting that Hg2+ facilitated the leakage of fura-2. This apparent leakage was probably due to a nonspecific increase in membrane permeability since 2 microM Hg2+ produced a Co2(+)-insensitive increase in [3H]deoxyglucose phosphate efflux. Hg2+ did not increase the leakage of either lactate dehydrogenase or soluble protein from synaptosomes. Hg2+ produced a concentration-dependent (1-8 microM) increase in 45Ca2+ efflux from superfused synaptosomes which was insensitive to blockade either by 2 mM Co2+ or by 100 microM Cd2+. These data suggest that the transmitter releasing action of Hg2+ involves interactions with sites that also interact with Co2+ but not with Cd2+. Furthermore, Hg2+ may have direct transmitter releasing actions (i.e., Ca2(+)-mimetic properties), as well as nonspecific actions on plasma membrane permeability which may not necessarily be linked to [3H]dopamine release.

Animals↗
PubMed1989

Effects of mercuric chloride on [3H]dopamine release from rat brain striatal synaptosomes.

Electrophysiological studies employing amphibian neuromuscular preparations have shown that mercuric chloride (HgCl2) in vitro increases both spontaneous and evoked neurotransmitter release. The present study examines the effect of HgCl2 on the release of [3H]dopamine from synaptosomes prepared from mammalian brain tissue. Mercuric chloride (3-10 microM) produces a concentration-dependent increase in spontaneous [3H]dopamine release from "purified" rat striatal synaptosomes, in both the presence and absence of extra-synaptosomal calcium. The effects of HgCl2 on transmitter release from amphibian neuromuscular junction preparations resemble those produced by the Na+, K+-ATPase inhibitor ouabain. Experiments were performed to determine whether the HgCl2 effects on mammalian synaptosomal dopamine release are a consequence of Na+, K+-ATPase inhibition. Na+, K+-ATPase activity in lysed synaptosomal membranes is inhibited by HgCl2 (IC50 = 160 nM). However, mercuric chloride in the presence of 1 mM ouabain still increased [3H]dopamine release. The specific inhibitor of Na+-dependent, high-affinity dopamine transport, RMI81,182 inhibited ouabain-induced [3H]dopamine release whereas it had no effect on HgCl2-induced [3H]dopamine release. These data suggest that augmentation of spontaneous [3H]dopamine release by HgCl2 probably is not mediated by an inhibition of Na+, K+-ATPase and HgCl2 does not act directly on the dopamine transporter.

Animals↗
PubMed1988

Calcium efflux and neurotransmitter release from rat hippocampal synaptosomes exposed to lead.

The results of several studies, employing various tissue preparations, have demonstrated that in vitro Pb exposure has similar effects on the release of several different transmitter substances. Pb has been observed to attenuate depolarization-evoked release and increase spontaneous (depolarization-independent) release. The current study confirms that Pb in vitro increases the spontaneous release of [3H]acetylcholine (ACh) from superfused synaptosomes prepared from rat hippocampus. Additionally, hippocampal synaptosomes, preloaded with 45Ca, were superfused under conditions similar to those used in the [3H]ACh-release studies. Exposure to 1-30 microM Pb produced a concentration-dependent increase in the efflux of 45Ca that was quantitatively and temporally related to the Pb-induced release of [3H]ACh from the hippocampal synaptosomes. Depolarization-evoked [3H]ACh release with high potassium did not produce a corresponding increase in 45Ca efflux. It is concluded that the Pb-induced increase in spontaneous transmitter release is apparently due to either an increase in intraneuronal ionized calcium or the stimulation by Pb of Ca-activated molecules mediating transmitter release.

Acetylcholine↗
PubMed1985

Altered central monoamine response to D-amphetamine in rats chronically exposed to inorganic lead.

Investigations of the mechanisms involved in the neurotoxicity resulting from chronic inorganic lead (Pb) exposure have centered on CNS biogenic amine function on the basis of behavioral and neurochemical findings. The following study examined the time course of the response of dopamine (DA) and 5-hydroxytryptamine (5-HT) neurons to d-amphetamine (AMPH) in rats chronically exposed to Pb from birth in order to further examine neurochemical mechanisms implicated by previous work. Offspring were exposed to 0.2% Pb acetate via the lactating dam and then weaned to the same drinking solution. At 120-140 days animals were injected with 1.0 mg/kg s.c. of the drug or with saline and sacrificed after various intervals. DA content in nucleus accumbens and corpus striatum in Pb-exposed animals was significantly higher than corresponding levels in controls at 20 minutes post-drug and remained significantly higher than baseline values at 80 minutes after the drug when DA concentrations in controls had returned to normal. These data suggest enhanced AMPH-induced DA synthesis in exposed rats. 5-Hydroxyindoleacetic acid (5-HIAA) content was significantly increased in three brain regions in exposed rats given AMPH compared to values in saline-injected exposed animals, indicating a compensation in these areas for the decreases in 5-HIAA values produced by Pb exposure alone. The results of this study reinforce the hypothesis that DA and 5-HT neurons are sensitive to relatively low levels of Pb exposure.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1985

A superfusion apparatus for the examination of neurotransmitter release from synaptosomes.

A superfusion apparatus for examining the release of neurotransmitter from synaptosomes is described. The apparatus provides for accurate temperature control, rapid switching and continuous gassing of superfusing buffers, short (i.e. 1-s) pulses of high-potassium-containing buffer for examining depolarized release, rapid collection of superfusing eluate, and low tissue chamber dead volume. Depolarization (high-potassium) evoked release and to some degree spontaneous release of [3H]dopamine from rat striatal synaptosomes are dependent on buffer calcium concentration. The putative calcium channel blocker nickel reduces both spontaneous and high-potassium-evoked [3H]dopamine release.

Animals↗
PubMed1979

Drug induced activity in lead-exposed mice.

Three interrelated studies were conducted to examine the locomotor activity of lead-exposed mice. The effects of lead were examined as a function of the dose and duration of exposure. Exposure during the first three weeks occurred via the maternal milk supply. Exposure following weaning was achieved via the water supply. Mice received challenges with various pharmaceutical agents, including d-amphetamine, methylphenidate, apomorphine and phenobarbital. The spontaneous activity prior to injection and the drug-induced activity were monitored. Lead-exposed mice usually displayed spontaneous activity which was indistinguishable from that of the control animals. In only one set of observations did lead exposure result in a modest increase in spontaneous activity. The drug-induced activity varied in a complex manner as a function of the magnitude and duration of the lead exposure. Depressed body weight, which was concurrent with high lead exposure (0.5% Pb(Ac)2) was also a significant parameter affecting both the spontaneous and drug-induced activity.

Age Factors↗
PubMed1979

Neonatal lead toxicity and in vitro lipid peroxidation of rat brain.

Neonatal rats were given aqueous lead acetate intragastrically from d 2--20 of life at doses of 0, 25, 75, and 225 mg Pb/kg.d. Blood Pb concentrations on d 21 were (mean +/- SE) 27 +/- 4 (control), 150 +/- 26, 263 +/- 63, and 518 +/- 97 microgram/100 ml, respectively. Growth was significantly depressed only in animals given the highest dose of Pb (225 mg/kg.d). Hematocrits were significantly decreased by d21 at all doses of Pb. Malondialdehyde (MDA) formation in 750 x g (10 min) brain supernatants induced spontaneously by aerobic incubation at 37 degrees C was not altered by Pb on d 7 and 14, but a slight decrease was observed on d 21. The extent of MDA formation induced by enzymatically generated superoxide anion was not altered by Pb toxicity during the first 21 d of life. Addition of Pb to 750 x g (10 min) brain supernatants in vitro significantly decreased MDA formation at Pb concentrations of 10(-5) M and higher. These results show that the central nervous system toxicity of Pb in neonatal rats is not associated with accelerated in vitro lipid peroxidation of brain tissue.

Animals↗
PubMed1979

Brain lipofuscin concentration and oxidant defense enzymes in lead-poisoned neonatal rats.

Neonatal rats were given aqueous lead acetate intragastrically from d 2-20 of life at doses of 0, 10, 50, and 225 mg Pb/kg.d. Blood Pb concentrations on d 21 were (mean +/- SE) 23 +/- 3 (control), 63 +/- 19, 246 +/- 55, and 994 +/- 223 microgram/100 ml, and brain Pb concentrations were 14 +/- 2, 60 +/- 5, 114 +/- 15, and 275 +/- 26 microgram/100 g, respectively. Growth was significantly depressed only in rats given the highest dose of Pb (225 mg/kg.d). Solvent-extractable lipofuscin pigment concentration of brain tissue progressively decreased over the 21-d duration of the experiment but was not significantly altered at any dose of Pb. Brain glutathione peroxidase, glucose-6-phosphate dehydrogenase, and 6-phosphogluconate dehydrogenase activities were stimulated on d 20 at the maximal dose of Pb, but the activities of brain superoxide dismutases and catalase were not altered by Pb exposure. Locomotor activity was significantly increased in the male animals on d 20, but only at the highest dose of Pb. These results indicate that Pb toxicity in neonatal rats is not associated with accelerated in vivo lipid peroxidation in the brain, but that certain oxidant defense mechanisms in the brain are stimulated by Pb.

Aging↗
PubMed1979

Behavioral deficits in adult rats following neonatal lead exposure.

Rats exposed to lead via the maternal milk were tested at maturity on three different visual discrimination tasks. Starting at parturition the dams were given either tap water, 0.20% sodium acetate, 0.02% lead acetate, or 0.20% lead acetate in the drinking water. At weaning, the pups from all the groups were placed on normal chow and tap water. At 20 days of age, the concentration of lead in the blood and brain of the high lead-exposed offspring was approximately 6 times that of controls (11 microgram% vs 66 microgram%). A significant deficit was found in the ability of the high lead-exposed group to acquire a simultaneous visual discrimination task conducted in an operant chamber. No significant differences were observed in the ability of lead-exposed rats to acquire either a successive visual discrimination task or a cued go/no-go discrimination. Thee results suggest that early lead exposure can affect certain behavioral processes and that the effects may persist even after the rat has reached maturity.

Animals↗
PubMed1977

Behavioral effects of low level neonatal lead exposure.

Rats exposed to lead via maternal milk were tested at various stages of development on a number of behavioral tasks. Beginning at paturition, the dams were given either tap water, 0.02%, or 0.10% lead acetate in the drinking water. Pups from all three groups were weaned to normal chow and tap water at 21 days of age. The mean lead concentration of the dam's blood and of neonatal (20 days of age) brain and blood were all below 50 microgram/100 ml. No significant differences were found between the high lead-exposed group and controls in general as measured by wheel running over a 21 day period beginning at 30 days of age. However, there was a significant difference in wheel running behavior during the first three hr of testing. Both lead-exposed groups were found to display significantly less aggressive behavior as measured by the shock-elicited aggression test. Low level lead exposure had no discernable effect on the acquisition and subsequent reversal of a successive brightness discrimination task. Lead exposure under these conditions appears to affect some aspects of emotional behavior, while having little effect on general activity or cognitive function.

Aggression↗
PubMed1977

Technique for assessing visual discrimination learning in mice.

An automated technique for the study of visual discrimination learning in mice has been developed. The technique utilizes a nose-poke as the operant response. The nose-poke response requires no shaping, has a relatively high operant level and can be used to measure preacquisition exploratory behavior. CD-1 mice acquired a simultaneous brightness discrimination readily but a successive brightness discrimination proved more difficult. A 20 sec intertrial interval was optimal for acquisition of the simultaneous discrimination. Reversal learning was slow. This procedure should prove useful in the study of the effects of pharmacologic and toxic agents on learning and performance in both weanlings and adult mice.

Animals↗
PubMed1975

Growth, behavior, and brain catecholamines in lead-exposed neonatal rats: a reappraisal.

Daily oral administration of lead to newborn rats has no adverse effect on their body growth. Lead-treated rats were more active than age-matched controls. Endogenous levels of brain dopamine were unchanged, whereas norepinephrine was increased, suggesting a possible relationship between lead exposure during earliest developmental periods, increased motor activity, and brain norepinephrine, and not brain dopamine as previously postulated.

Animals↗