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Biomedical subjects

R Freedman

Publications and source records attributed to R Freedman.

At least 163 records · Page 9Linked to original sources
PubMed1987

Transplantation in Parkinson's disease: two cases of adrenal medullary grafts to the putamen.

Autologous adrenal medullary tissue was transplanted unilaterally to the putamen in two patients with severe Parkinson's disease. The first patient exhibited a transient, two-day improvement of motor performance in the limbs contralateral to the implantation site. He also had significantly longer episodes of normal function for about two months. The second patient reported a minor improvement of balance and gait, again lasting for two months. Electrophysiological studies of the motor readiness and auditory evoked potentials were consistent with increased catecholaminergic activity in the basal ganglia after transplantation in both patients. Positron emission tomography showed no postoperative alteration of receptor density in the putamen. No significant adverse effects of the transplantation were observed in the patients' performance on neurological and psychological tests or in their quantitative electroencephalogram and cerebral blood flow recordings. Immediately after the grafting, one patient showed transient signs of sympathetic hyperactivity, probably caused by release of catecholamines from the implanted tissue into the peripheral circulation. We conclude that catecholamine-rich cellular implants in the basal ganglia have transient beneficial effects in patients with severe Parkinson's disease.

Adrenal Medulla↗
PubMed1987

Human fetal tissues grafted to rodent hosts: structural and functional observations of brain, adrenal and heart tissues in oculo.

The potential for growth and development of human tissue grafts was explored by transplantation to the anterior chamber of the eye of rats and mice. Tissues were obtained from therapeutic abortions, performed in the eighth to twelfth week of gestation, using a slight modification of routine vacuum aspirations. Recipients were either adult rats immunosuppressed with cyclosporin A and protected with antibiotics, or nude immunodeficient Balb C mice. Catecholamine-rich tissues such as chromaffin cells from the adrenal medulla, sympathetic ganglia, central dopamine neuroblasts from the substantia nigra, and noradrenaline neuroblasts from the locus coeruleus all survived grafting, and in many cases formed nerve fibers that invaded the host iris. Similarly, central serotonin neurons from developing raphe nuclei grafts were able to innervate host irides. Human fetal cerebellar and cerebral cortical transplants continued their development in rat host eyes. Extracellular recordings from such cerebellar and cortical grafts revealed spontaneously active cells with immature action potential waveforms. Spinal cord grafts also survived and contained substance P-immunoreactive neurons. Dorsal root ganglia were able to form nerve fibers invading the host iris, as evidenced by neurofilament immunohistochemistry. Heart tissue survived and manifested spontaneous rhythmic contractions in oculo. Both human cortex cerebri and heart tissue grafts became innervated by sympathetic adrenergic nerve fibers from the rat host iris. Thus both graft-to-host and host-to-graft neuronal connections may be established between man and rat. Taken together, these data suggest that transplantation of human fetal nervous tissues to the anterior chamber of immunosuppressed or immunodeficient rodent hosts yields a unique model system for studies of human brain development, developmental disturbances, connectivity, and the action of drugs.

Action Potentials↗
PubMed1987

Neurophysiological assessment of sensory gating in psychiatric inpatients: comparison between schizophrenia and other diagnoses.

Gating of auditory sensory responsiveness was examined in 75 psychiatric inpatients using a conditioning-testing paradigm with the P50 wave of the auditory evoked response, in which pairs of stimuli are presented to the subject. In previous studies, most schizophrenics did not decrement the second response to the extent seen in normals. Acutely ill patients, who were representative of patients admitted to a public university teaching service and a proprietary hospital, were used to examine the extent to which diminished sensory gating is found in diagnoses other than schizophrenia. About half of these patients showed diminished sensory gating that correlated with measures of severity of illness. The data, taken together with that from other studies using this paradigm, suggest that diminished sensory gating, like several other psychophysiological abnormalities, is a trait deficit in schizophrenia, but a state deficit in many other mental illnesses.

Adjustment Disorders↗
PubMed1987

Electrophysiological effects of phencyclidine in the medial prefrontal cortex of the rat.

The effects of local applications of phencyclidine (PCP) and dopamine (DA) on neurons of the medial prefrontal cortex were investigated using single unit recording techniques. The activity of the majority of cells in the deeper layers of the medial prefrontal cortex was depressed by both phencyclidine and DA, whereas increases, as well as decreases, in the firing rates were observed in cells located in the superficial cortical layers. The stereospecificity of the responses of deeper cells to phencyclidine was demonstrated using the enantiomers of 1-(-1-phenylcyclohexyl)-3-methylpiperidine (PCMP). Phencyclidine was found to be 1.5 times more potent than (+) PCMP and 3 times more potent than (-) PCMP. Finally, the DA receptor antagonist fluphenazine, blocked the phencyclidine-elicited depressions of unit activity in the deep prefrontal cortex. Taken together, the data indicate that the DA-like effects of phencyclidine on neurons of the medial prefrontal cortex are mediated by DA receptors and provide pharmacological support for the idea that psychomotor stimulant drugs have specific actions on targets of the ventral tegmental area (A10) dopamine system.

Animals↗
PubMed1987

Desipramine and noradrenergic neurotransmission in aging: failure to respond in aged laboratory animals.

Deficiencies in noradrenergic neurotransmission have been found in the central nervous system of aged laboratory animals. The purpose of the present study was to determine if tricyclic antidepressants, such as desipramine, can overcome the diminished noradrenergic neurotransmission found in these animals. Using electrophysiological techniques, noradrenergic neurotransmission was examined in the cerebellar cortex of rats, a model system which has been used extensively to characterize the effects of norepinephrine in the central nervous system. The discharge rate of cerebellar Purkinje neurons is very sensitive to changes in the noradrenergic input from the nucleus locus coeruleus. In this model system in young rats, treatment with desipramine slowly augments noradrenergic neurotransmission over several weeks. Similar treatment in aged animals caused no increase in the age-related deficient noradrenergic neurotransmission. The decline in efficacy of desipramine with age could not be accounted for by differences between young and old rats in the distribution of the drug. Failure of desipramine to be effective in older rats may reflect the insensitivity of aged neurons to norepinephrine itself, so that treatment strategies which increase the amount of nerepinephrine released onto these neurons may be ineffective. The findings may have implications for the use of tricyclic antidepressants in aged depressed patients.

Action Potentials↗
PubMed1987

Selective antagonism of nicotine actions in the rat cerebellum with alpha-bungarotoxin.

Nicotine, locally applied to identified neurons in the rat cerebellar cortex, excites inhibitory interneurons, but depresses the discharge of Purkinje cells. Alpha-bungarotoxin blocked the excitatory actions of nicotine on the inhibitory interneurons. The antagonism of nicotine excitatory actions is largely irreversible and also insurmountable with higher doses of nicotine. The antagonism by alpha-bungarotoxin is, in addition, selective since there is no blockade of the inhibitory actions of nicotine on Purkinje neurons. The present data suggest that the excitatory actions of nicotine on inhibitory interneurons are mediated by neuromuscular-type nicotinic receptors in the cerebellum. Moreover, the present data also supports the hypothesis of multiple nicotinic sites of action in mammalian brain.

Action Potentials↗
PubMed1987

Premenstrual mood changes and gating of the auditory evoked potential.

To assess the effect of the menstrual cycle on a measure of brain physiology known to be affected in psychiatric illness, auditory-evoked electroencephalographic potentials were recorded from 12 women on the day prior to menstruation and nine days after the initiation of their cycle. Eight were normal college students, and four were patients in a premenstrual syndrome clinic. The women showed significant changes in self-ratings of mood between the two recordings. The P50 wave of the auditory-evoked response was evaluated in a conditioning-testing paradigm, in which stimuli were presented in pairs, allowing assessment of putative excitatory and inhibitory processes involved in the gating of central nervous system sensory responsiveness to auditory stimuli. The auditory-evoked potentials were unchanged between the two recording periods. There was also no difference between the women and age-matched male controls. The data suggest that these central nervous system functions are not responsive to hormonal fluxes in menstruation. Since inhibitory gating of the P50 wave is lost in the manic phase of manic-depressive illness, the data also suggest that premenstrual mood changes in normal women do not share electrophysiological properties of mania.

Adult↗
PubMed1987

Neurobiological studies of sensory gating in schizophrenia.

The sensory disturbance in schizophrenia is often described as an inability to filter out extraneous noise from meaningful sensory inputs. The neurobiological basis of this inability to filter has been examined using auditory evoked potentials, which are computerized averages of the brain's electrical response to sound. The sounds are presented in pairs to test the ability of the brain to inhibit, or gate, its response to a repeated stimulus. Schizophrenic patients lack the ability to gate the neuronal response shown by a particular wave, the P50 wave. The measurement of this deficit in human subjects and the exploration of its neurobiology in animals has produced evidence about several issues in the pathophysiology of schizophrenia: (1) the role of dopamine in improvement of sensory function in schizophrenic patients treated with neuroleptic drugs, (2) the interaction between familial or genetic deficits in sensory functioning in schizophrenic patients and possible abnormalities in dopamine metabolism, and (3) a mechanism by which noradrenergic hyperactivity in mania and other psychiatric illnesses might mimic some pathophysiological deficits in schizophrenia.

Antipsychotic Agents↗
PubMed1987

Effect of chronic nicotine administration on monoamine and monoamine metabolite concentrations in rat brain.

The effects on rat brain tissue monoamine and monoamine metabolite concentrations of chronic nicotine administration at two doses (3 and 12 mg/kg/day) using constant infusion were studied. After 21 days of treatment, tissue concentrations of dopamine (DA), norepinephrine (NE), 5-hydroxytryptamine (5-HT), and several metabolites in striatum, hypothalamus, and frontal cortex were determined by high performance liquid chromatography with electrochemical detection. Compared with a control group, nicotine treatment significantly decreased NE in frontal cortex but not in other regions. The concentration of 5HT also was decreased in frontal cortex but increased in the hypothalamus at the higher dose of nicotine. The 5HT metabolite 5-hydroxyindoleacetic acid (5-HIAA) was not significantly altered in any region. The 5HT index (5-HIAA/5-HT) was significantly decreased in the hypothalamus and increased in frontal cortex at the higher dose. Concentrations of DA and the metabolite homovanillic acid (HVA) were not significantly altered by nicotine. Nevertheless, significant decreases in the DA metabolite dihydroxyphenyl-acetic acid (DOPAC) were observed in both striatum and hypothalamus. Moreover, the DA index [(DOPAC + HVA)/DA] was significantly decreased in all three brain regions. In contrast to other studies using acute dose and in vitro perfusion paradigms that have reported increased CNS catecholamine release stimulated by nicotine, chronic administration appears to be associated with decreased catecholamine turnover in some brain regions.

Animals↗
PubMed1987

Growth of Campylobacter pylori in liquid media.

Until recently, broth cultivation techniques for Campylobacter pylori were unavailable. We developed a method to cultivate bacterial cells within 24 h in liquid media. Cultivation in broth depended on the adequate dispersion of appropriate gases. A static broth at 37 degrees C in a GasPak jar (BBL Microbiology Systems, Cockeysville, Md.) with a CampyPak (BBL) envelope did not support growth after 5 days of incubation. A broth placed in a flask on a Gyrotory water bath shaker (150 rpm; New Brunswick Scientific Co., Inc., Edison, N.J.) fitted with a gassing hood connected to a gas mixture of 10% CO2, 5% O2, and 85% N2 supported good growth. An initial inoculum of 10(5), 10(3) to 10(4), or 10(2) CFU/ml resulted in greater than or equal to 10(8) CFU/ml after incubation for 24, 48, or 72 h, respectively. Under these conditions, the bacteria grew as motile, spiral bacilli rather than the oval and coccal bacilli occasionally reported. Several bases supported good growth when supplemented with serum. For the determination of basal growth conditions, brucella broth base was used. Fetal calf serum (1%) provided maximum growth. Vitox was not necessary for growth and did not augment growth. C. pylori grew over a wide optimal pH range of 5.5 to 8.5.

Campylobacter↗
PubMed1987

The yeast ARD1 gene product is required for repression of cryptic mating-type information at the HML locus.

Mutations in the ARD1 gene prevent yeast cells from displaying G1-specific growth arrest in response to nitrogen deprivation and cause MATa haploids (but not MAT alpha haploids) to be mating defective. Analysis of cell type-specific gene expression by examination of RNA transcripts and measurement of beta-galactosidase activity from yeast gene-lacZ fusions demonstrated that the mating defect of MATa ard1 mutants was due to an inability to express genes required by MATa cells for the mating process. The lack of mating-specific gene expression in MATa cells was found to be due solely to derepression of the normally silent alpha information at the HML locus. The cryptic a information at the HMR locus was only very slightly derepressed in ard1 mutants, to a level insufficient to affect the mating efficiency of MAT alpha cells. The preferential elevation of expression from HML over HMR was also observed in ard1 mutants which contained the alternate arrangement of a information at HML and alpha information at HMR. Hence, the effect of the ard1 mutation was position specific (rather than information specific). Although the phenotype of ard1 mutants resembled that of cells with mutations in the SIR1 gene, both genetic and biochemical findings indicated that ARD1 control of HML expression was independent of the regulation imposed by SIR1 and the other SIR genes. These results suggest that the ARD1 gene encodes a protein product that acts, directly or indirectly, at the HML locus to repress its expression and, by analogy, may control expression of other genes involved in monitoring nutritional conditions.

Diploidy↗
PubMed1987

Heterogeneity of nicotine actions in the rat cerebellum: an in vivo electrophysiologic study.

Much controversy surrounds the actions of nicotine on mammalian central neurons, especially with respect to the question of presence of multiple nicotine receptors and with respect to similarities of responses to those induced by acetylcholine (ACh). To resolve some of these complexities, the authors determined the effects of pressure-ejected nicotine on identified neurons in the cerebellar cortex of Sprague-Dawley rats under urethane anesthesia. Purkinje cells and interneurons were identified by their anatomical localization, discharge characteristics and responses to electrical stimulation of superficial parallel fibers. Locally applied nicotine altered single-unit activity in a manner strictly dependent on cell type. Pressure-ejected nicotine inhibited Purkinje cells (50/51) and excited cerebellar interneurons (22/22). The effects of nicotine on cell discharge rate were probably receptor mediated because "classical" nondepolarizing nicotinic antagonists selectively blocked the agonistic actions of nicotine. A curare-sensitive site (neuromuscular type) was found to mediate the excitatory effects of nicotine, and a hexamethonium-sensitive site (ganglionic type) was found to mediate the inhibitory effects of nicotine. ACh mimicked the effects of nicotine on both cell classes although muscarinic interactions were also observed. The inhibitory effects of ACh on Purkinje cells were antagonized by the ganglionic blocker hexamethonium only if muscarinic receptors were simultaneously blocked via systemic administration of scopolamine. The excitatory effects of ACh on interneurons, on the other hand, were antagonized by the neuromuscular blocker curare even in the absence of a muscarinic antagonist. No interactions of curare and hexamethonium were observed with the amino acid transmitters gamma-aminobutyric acid (Purkinje cells) and glutamate (interneurons).

Acetylcholine↗
PubMed1986

Diminished interaction of norepinephrine with climbing fiber inputs to cerebellar Purkinje neurons in aged Fischer 344 rats.

The ability of norepinephrine (NE) to modulate climbing fiber activation of complex spike discharge in cerebellar Purkinje neurons was compared in young (3-6 months) and aged (18-20 months) Fischer 344 rats. In young rats, NE selectively inhibits spontaneous activity while climbing fiber evoked activity remains intact or increased. NE also increases the probability of observing 4 bursts of full-sized action potentials rather than partially inactivated action potentials in the complex spike. In older rats, both of these modulatory actions of NE on climbing fiber complex spike activation are markedly diminished. These data support the concept that age-related reductions in catecholamine modulation of synaptic inputs may contribute to CNS dysfunction found in senescence.

Aging↗
PubMed1986

Neurophysiological studies of sensory gating in rats: effects of amphetamine, phencyclidine, and haloperidol.

Central mechanisms of sensory gating were assessed in Sprague-Dawley rats by an evoked potential technique similar to one that we have previously used to show diminished sensory gating in psychotic patients. Middle latency (15-50 msec) auditory evoked potential responses were recorded at the skull in unanesthetized freely moving animals. Gating mechanisms were assessed in a conditioning-testing paradigm by measuring the suppression of response to a 74 dB click test stimulus following an earlier identical conditioning stimulus at 0.5-sec intervals. The rats demonstrated significant suppression of the N50 response to the second auditory stimulus. Amphetamine treatment significantly interfered with the suppression of the response to the second stimulus; haloperidol, injected after the amphetamine, returned the conditioning-testing ratio toward normal values. Phencyclidine caused a similar decrease in suppression and was similarly antagonized by haloperidol. During some periods of hyperarousal, animals showed spontaneous loss of suppression; this condition could be reversed by haloperidol treatment. These results with psychotomimetic drugs in an animal model parallel abnormalities in sensory gating previously observed in psychotic human subjects.

Animals↗
PubMed1986

Structure-activity relationships of phencyclidine derivatives in rat cerebellum.

The depressant effects of phencyclidine [1-(1-phenylcyclohexyl) piperidine, PCP] and three of its analogs (m-amino-PCP, m-nitro-PCP, and PCP-methyliodide) on the spontaneous action potential discharge of cerebellar Purkinje neurons in urethane-anesthetized rats were examined in this study. Both intraperitoneal injection and micro-pressure ejection were employed as routes of drug administration. The relative potency after parenteral administration corresponded closely with previous findings in behavioral test paradigms. PCP and m-amino-PCP were equipotent, m-nitro PCP was less potent than either PCP or m-amino-PCP, and PCP-methyliodide showed almost no activity. After local administration onto neurons, m-amino-PCP was significantly more potent than PCP, while PCP, m-nitro-PCP, and PCP-methyliodide were equipotent. Tritiated PCP, m-nitro PCP, and m-amino PCP have similar distribution and metabolism in cerebellum. PCP-methyliodide, a quaternary ion, does not cross the blood brain barrier. M-nitro PCP is appreciably less ionized at pH 7.4 than PCP or m-amino-PCP and, therefore, may be more easily sequestered into lipids. Differences between PCP and its analogs found in experiments which employ parenteral administration may reflect differences in drug distribution. These differences are minimized when these drugs are administered directly onto neurons via pressure microejection.

Action Potentials↗