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Biomedical subjects

G E Handelmann

Publications and source records attributed to G E Handelmann.

At least 19 recordsLinked to original sources
PubMed1992

Effects of apolipoprotein E, beta-very low density lipoproteins, and cholesterol on the extension of neurites by rabbit dorsal root ganglion neurons in vitro.

Previous studies suggest that during nerve regeneration apoE acts as a lipid transport protein that assists in the rapid initial extension of axons and then in their myelination. To determine whether apoE and/or apoE-containing lipoproteins can modulate axon growth, we assessed their effect on the out-growth of neurites from neurons in mixed cultures of fetal rabbit dorsal root ganglion cells in vitro. Incubation with beta-very low density lipoprotein (beta-VLDL) particles, which are rich in apoE and cholesterol, increased neurite outgrowth and branching. Unesterified cholesterol added to the cultures had a similar, but less pronounced, effect. These data suggest that cholesterol might be the component responsible for the enhanced neurite growth. In contrast, purified, lipid-free apoE added to the cultures reduced neurite branching. Neurite branching was also reduced when purified apoE was added along with beta-VLDL or cholesterol; however, the striking finding was that under these conditions the neurites extended farther from the neuronal cell body. Dorsal root ganglion cells were examined for the presence of receptors for native and apoE-enriched beta-VLDL. Immunocytochemistry, ligand blots, 45Ca2+ blots, and studies of the interaction of the cells with fluorescent lipoproteins provided evidence of two types of receptors for apoE-containing lipoproteins on neurons: the low density lipoprotein (LDL) receptor, which binds native beta-VLDL, and the LDL receptor-related protein, which binds apoE-enriched beta-VLDL. These findings indicate that apoE may play two complementary roles in neurite outgrowth. When complexed with lipoproteins, apoE stimulates neurite growth by the receptor-mediated delivery of cholesterol and perhaps other components necessary for neurite outgrowth. When apoE as a free protein is added together with apoE-containing lipoproteins, apoE decreases neurite branching and promotes neurite extension away from the cell body. These actions, which would be complementary in promoting target-directed nerve growth in vivo, provide the first direct evidence that apoE and apoE-containing lipoproteins can modulate the outgrowth of neuronal processes.

Animals↗
PubMed1989

Milacemide, a glycine prodrug, enhances performance of learning tasks in normal and amnestic rodents.

The N-methyl-D-aspartate receptor complex appears to play an important role in processes of learning and memory. The presence of a glycine modulatory site at this complex has recently been established and suggests that glycinergic neurotransmission may influence these cognitive functions. Increasing glycine concentrations in the brain by administration of a glycine prodrug, milacemide, is shown here to enhance performance of a shock-motivated passive avoidance task in rats, and to reverse drug-induced amnesia in a spontaneous alternation paradigm in mice. Prevention of the metabolism of milacemide to glycine by pretreatment with MAO-B inhibitors not only prevents the memory-enhancing effects of the drug, but appears to have a deleterious effect on memory formation suggesting an action of the prodrug itself on the brain. These studies indicate a role of glycinergic neurotransmission in memory processes, and support the therapeutic potential of glycinergic drugs in memory impairment.

Acetamides↗
PubMed1989

D-cycloserine, a positive modulator of the N-methyl-D-aspartate receptor, enhances performance of learning tasks in rats.

Glycine has recently been shown to positively modulate the N-methyl-D-aspartate (NMDA) subclass of acidic amino acid receptors which are important in neural pathways involved in learning and memory. We report that d-cycloserine (DCS), an antimycobacterial agent known to cross the blood-brain barrier, binds with high affinity to this glycine modulatory site, functions as a positive modulator, and facilitates performance of learning tasks in rats. In addition, DCS appears to be a potent cognitive enhancer at doses lower than those required for antibacterial activity. Based on these data, we propose that modulation of NMDA receptors via glycinergic mechanisms may be a means of influencing cognitive processes.

Animals↗
PubMed1987

Selective memory impairment by phencyclidine in rats.

Phencyclidine (PCP) users sometimes report lack of recall of events occurring while they are under the influence of the drug. The present experiment was designed to test whether rats remember information learned after PCP administration. Rats were trained to choose one arm of a T-maze to obtain a food reward. The following day they were injected with either PCP (1 mg/kg) or vehicle and trained to choose the opposite arm for a reward (reversal learning). A third group of rats received neither injections nor training on the second day. On the third day, all rats were tested for their preference of maze arms. Rats who had been injected with saline before reversal learning chose the arm rewarded during the reversal, while rats receiving PCP on the second day chose randomly. The rats which did not learn the reversal chose the arm learned on day 1. These results indicate that while PCP did not interfere with the rats ability to learn, it interfered with long-term storage of information.

Animals↗
PubMed1987

Phencyclidine. Physiological actions, interactions with excitatory amino acids and endogenous ligands.

Phenycyclidine (PCP) produces many profound effects in the central nervous system. PCP has numerous behavioral and neurochemical effects such as inhibiting the uptake and facilitating the release of dopamine, serotonin, and norepinephrine. PCP also interacts with sigma, mu opioid, muscarinic, and nicotinic receptors. However, the psychotomimetic effects induced by PCP are believed to be mediated by specific PCP receptors, where PCP binds with greater potency than sigma compounds. Electrophysiological, behavioral, and neuro-chemical evidence strongly suggests that at least some of the many PCP actions result from antagonism of excitatory amino acid-induced responses via PCP receptors. The recent isolation and partial characterization of the alpha and beta endopsychosins and the identification of other endogenous ligands for the PCP and sigma receptors, is another promising area of research in the elucidation of the physiological role of an endogenous PCP and sigma system.

Animals↗
PubMed1987

A developmental influence of substance P on its receptors.

Events which alter the chemical environment of the developing nervous system have long-term consequences for neural function and behavior. Neonatal exposure to a peptide neurotransmitter, substance P (SP), increased the number of SP binding sites in the adult rat salivary glands, without altering their affinity. The neonatal treatment also increased the binding capacity for SP of several brain regions, but had no effect on SP levels in the brain. The increase in SP binding sites may be responsible for increases in sensitivity to SP in adults after neonatal treatment with the peptide.

Aging↗
PubMed1985

Modulation of brain development by morphine: effects on central motor systems and behavior.

Morphine administration to neonatal rats on days 1-7 after birth produced long-term changes in behavior and brain function. The pups were smaller than saline-treated littermates and showed retarded motor development. As adults, the morphine-treated rats had impaired motor coordination, altered gait, and altered patterns of activity in an open field. Several brain regions of the adult rats, including motor areas, had decreased metabolic activity as measured by the 2-deoxy-glucose technique, suggesting decreased functional activity in these areas. These results may be relevant to findings that children exposed in utero to narcotics tend to have impaired motor development.

Animals↗
PubMed1985

Neuropeptide effects on brain development.

Peptides which act as neurotransmitters or neuromodulators in the adult nervous system exert influences on brain development. Altering the levels of neuropeptide to which a developing animal is exposed produces a wide variety of physiological and behavioral effects which are apparent in adulthood. Many of the developmental effects involve neural systems in which the neuropeptide plays a role in the adult.

5,7-Dihydroxytryptamine↗
PubMed1984

Substance P administration to neonatal rats increases adult sensitivity to substance P.

Substance P (SP) administered subcutaneously to neonatal rats on days 1-7 after birth produced long-term physiological changes. The changes included altered pain perception and increased sialogogic response to SP, although the hypotensive response to SP was unchanged. Early exposure to the peptide therefore influenced development, particularly with respect to two systems in which SP is physiologically active. Both changes may reflect an increased sensitivity of these systems to the effects of SP.

Animals↗
PubMed1983

Effects of time and experience on hippocampal neurochemistry after damage to the CA3 subfield.

Bilateral injections of kainic acid into the hippocampal CA3 subfield destroyed the CA 3 pyramidal cells and produced a behavioral impairment, an inability to solve spatial maze problems. The behavior recovered, however, with daily experience in a maze task, and the rate of recovery was accelerated by additional daily experience. This recovery of function could be the result of compensatory changes in the distribution or function of the various hippocampal pathways. In the present experiment, this possibility was investigated neurochemically. Five putative neurotransmitters or their synthetic enzymes were measured in dissected regions of the hippocampal formation. Both the long-term effects of the lesions and the effects of behavioral training were determined. A number of alterations in hippocampal neurochemical systems were detected. Acute changes due to the lesions included a widespread loss of glutamate, and regionally specific decreases in glutamic acid decarboxylase (GAD) activity and cholecystokinin (CCK) and norepinephrine (NE) concentrations. Long-term changes included a decline in choline acetyltransferase (ChAT) activity throughout the hippocampal formation, and increases in NE in certain regions. Behavioral testing prevented the decline of ChAT activity, and increased the concentrations of GAD and CCK. The neurochemical conditions present at the time when trained rats recovered behavioral function may indicate the crucial conditions for the occurrence of the behavior.

Animals↗
PubMed1983

Choline acetyltransferase activity in the nucleus tractus solitarius: regulation by the afferent vagus nerve.

The influence of nodose ganglionectomy or transection of the peripheral branches of the afferent vagus nerve on choline acetyltransferase (ChAT) activity in the nucleus tractus solitarius (NTS) was studied. ChAT activity was reduced in the microdissected caudal and intermediate portions of the NTS in vagotomized as well as ganglionectomized rats. However, only the ganglionectomy resulted in the degeneration of medullary nerve fibers. These results suggest that the changes in ChAT activity in the NTS are independent of neuronal degeneration and may be due to transynaptic modulation of ChAT activity by afferent vagal impulses. The presence of ChAT in the sensory nodose projection to the NTS, however, cannot be ruled out.

Animals↗
PubMed1982

N-acetylation regulates the behavioral activity of alpha-melanotropin in a multineurotransmitter neuron.

A multineurotransmitter neuronal system that synthesizes and secretes both acetylated and deacetylated forms of alpha-melantropin and beta-endorphin is present in rat and human brain. The N-acetylated from of alpha-melanotropin had more potent behavioral effects than the deacetylated alpha-melanotropin. In the case of beta-endorphin, however, the deacetylated form has been shown to be more potent than the acetylated form. Enzymatic N-acetylation appears to be an important regulatory process for modulating the behavioral activity of peptides secreted from the opiomelanotropinergic multineurotransmitter neuron.

Acetylation↗
PubMed1981

Spatial memory following damage to hippocampal CA3 pyramidal cells with kainic acid: impairment and recovery with preoperative training.

The behavioral function of an intrinsic component of the hippocampus was investigated. Neurotoxic lesions of the CA3 region of the hippocampus impaired performance of a spatial memory task, and produced both hyperactivity and hyperreactivity to sensory stimulation. Both the magnitude and duration of these behavioral alterations depended on the amount of preoperative training received, and on the extent and locus of the lesion within the CA3 subfield. This study indicates that the CA3 subfield contributes to the performance of aat least three behavioral functions known to be mediated by the hippocampus. In addition, the lack of enduring deficits in the behavioral tests in which preoperative training was received suggests that, after loss of the CA3 subfield, some mechanism for recovery of function occurs within the hippocampus.

Animals↗
PubMed1981

Comparison of biological and behavioral activities of alpha- and gamma-melanocyte stimulating hormones.

The biological and behavioral activities of gamma-MSH (gamma-MSH) and alpha-MSH (alpha-MSH) were compared using three different tests: darkening of the skin of Anolis, grooming behavior of rats, and performance of a visual discrimination task by rats. When incubated with the Anolis skin, both peptides cause skin darkening. However, alpha-MSH is much more potent than gamma-MSH. The alpha-MSH effect is not antagonized by coincubation with gamma-MSH. When given intraventricularly to rats, alpha-MSH induces a marked grooming behavior. This effect was not noted upon administration of gamma-MSH. Injection of gamma-MSH with the alpha-MSH did not produce a grooming response significantly different from alpha-MSH alone. In the visual discrimination task, the two peptides had opposite effects on the rate at which rats learned the initial discrimination and a subsequent reversal. The peptides were injected intraperitoneally prior to behavioral testing. Following alpha-MSH, rats learned the discrimination and subsequent reversal faster than the control rats. Following gamma-MSH, rats learned the initial discrimination at approximately the same rate as controls, and learned the reversal much slower. These results are discussed in terms of the similarity and differences in the mechanisms of action of alpha-MSH and gamma-MSH.

Animals↗
PubMed1981

Evidence that N-acetylation regulates the behavioral activity of alpha-MSH in the rat and human central nervous system.

alpha-MSH immunoreactive peptides were fractionated and characterized in rat and human brain and rat pituitary by reversed phase high pressure liquid chromatographic techniques. alpha-MSH and deacetylated alpha-MSH were two major naturally existing peptides in both brain and pituitary gland. Subsequent experiments examined the roles of these two peptides in neuronal function. The alpha-MSH was clearly more effective than deacetylated alpha-MSH in improving performance on a visual discrimination task after intraperitoneal administration and in inducing excessive grooming after intraventricular administration. The difference in behavioral potency may be explained by the fact that alpha-MSH was much more resistant to peptidase degradation than was deacetylated alpha-MSH. N-acetylation of alpha-MSH may be an effective regulatory process for modulating the behavioral potency of the secretory product of alpha-MSH-containing pituitary cells and neurons.

Acetylation↗