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Biomedical subjects

W J Freed

Publications and source records attributed to W J Freed.

At least 127 records · Page 7Linked to original sources
PubMed1985

Differences between calcium channel inhibitors in their effects on phencyclidine-induced behavioral stimulation in mice.

Sixteen calcium channel inhibitors (CCI's) were tested in a model utilizing phencyclidine (PCP)-induced behavioral stimulation in mice. There were marked differences in the effects of CCI's both within subclasses and between subclasses of CCI's. All of the dihydropyridines and possibly flunarizine were effective in blocking PCP-induced behavioral stimulation. Papaverine derivatives, including verapamil, and several other CCI's, were ineffective.

Animals↗
PubMed1985

GM1 ganglioside does not stimulate reinnervation of the striatum by substantia nigra grafts.

Ganglioside GM1 has been reported to promote reinnervation of the striatum by dopaminergic fibers following brain hemisection in the rat. In the present study, the possibility that chronic ganglioside GM1 (10 or 50 mg/kg day for 3 weeks) would promote reinnervation of the dopamine-denervated striatum by embryonic substantia nigra grafts was studied. No enhancement of the ingrowth of fibers from the grafts was observed. It is concluded that under this circumstance, the growth of catecholaminergic fibers is restricted by factors other than the availability of ganglioside GM1.

Animals↗
PubMed1984

Adrenal medulla grafts survive and exhibit catecholamine-specific fluorescence in the primate brain.

Parkinson's disease most consistently involves pathologic changes in the substantia nigra, which is the major source of dopamine to the striatum. It has been shown that either fetal substantia nigra or adrenal medulla tissue implanted into the rat brain survives, produces dopamine, and improves behavioral abnormalities induced by deprivation of the caudate nucleus of its dopaminergic innervation. Thus, catecholamine-containing grafts could be potential replacements for destroyed or damaged dopaminergic neurons in patients with Parkinson's disease. To explore the potential of this therapeutic approach, fetal substantia nigra or host adrenal medulla were grafted to the denervated caudate nucleus of the rhesus monkey. Under the specific conditions of our experiment, fetal substantia nigra did not survive in either of two animals tested. On the other hand, some tissue from adrenal medulla grafts survived in all four animals tested. These grafted cells contained catecholamines, as indicated by the presence of specific glyoxylic acid-induced catecholamine fluorescence. In two of the four animals, however, the grafts contained fewer than 10 surviving cells, and in the other two animals, about 190 and 300 cells were found, respectively. Despite the small numbers of cells, this is the first demonstration that peripheral tissue autografts can survive implantation into the nonhuman primate central nervous system.

Adrenal Medulla↗
PubMed1984

Genetic effects on PCP-induced stimulation in recombinant inbred strains of mice.

The stimulation of motor activity by phencyclidine was found to differ significantly in BALB/c and C57Bl/6By inbred strains of mice. Phencyclidine-induced stimulation was compared for these strains, their reciprocal F1 hybrids, and their recombinant inbred offspring. There were significant differences in responsivity among the strains, suggesting a genetic influence on the PCP response; however, the strains did not segregate into two distinct groupings, suggesting that this genetic influence was not carried by a single gene. In addition, there was no relationship between the responsivity of these strains of mice to PCP and their previously-reported responses to amphetamine or scopolamine, which suggests that PCP-induced stimulation is not a simple cholinergic or amphetamine-like response.

Amphetamine↗
PubMed1984

Hyperactivity induced by prenatal administration of methylazoxymethanol: association with altered performance on conditioning tasks in rats.

Methylazoxymethanol (MAM), an alkylating agent which kills dividing cells, produces microcephaly when administered to rats at 15 days gestation. Rats treated prenatally with MAM were tested on a variety of behavioral tests. The MAM-treated animals performed better than controls in the acquisition of a food-reinforced operant response, but poorer than controls on a passive avoidance procedure. When required to reverse the passive avoidance procedure by actively avoiding the portion of a chamber that was associated with shock, MAM-treated rats performed better than controls. The MAM-treated rats were microcephalic and were also hyperactive compared to controls. It was postulated that the behavioral changes observed in the conditioning tasks may be attributable to hyperactivity. A possible neurochemical basis for this hyperactivity is discussed.

Alkylating Agents↗
PubMed1984

Effects of neuroleptics on phencyclidine (PCP)-induced locomotor stimulation in mice.

A variety of neuroleptics were compared for their ability to block phencyclidine (PCP)-induced behavioral stimulation in mice. Methiothepin, fluphenazine, trifluoperazine, and chlorpromazine were highly effective in blocking phencyclidine-induced stimulation at doses that did not decrease spontaneous behavioral activity. Clozapine, thioridazine and haloperidol were moderately effective, while sulpiride, molindone, and pimozide were completely ineffective. The effectiveness of the drugs was found to be correlated with their ability to block tryptamine-induced seizures and with several other measures of antidopaminergic and antiserotonergic potency. it is concluded that a combination of antidopaminergic and antiserotonergic activity is important for blocking the stimulating effects of phencyclidine.

Animals↗
PubMed1984

Eye-blinking and cerebral ventricular size in chronic schizophrenic patients.

Spontaneous eye-blinking, a possible measure of central dopaminergic activity, was studied in 55 drug-free chronic schizophrenic patients subdivided by cerebral ventricular size. Blink rates were higher in schizophrenic patients than in normal control subjects, regardless of cerebral ventricle size. Neuroleptics lowered blink rates in patients with normal ventricles but did not affect blink rates in patients with large ventricles. Insofar as blinking is a dopaminergic parameter, these findings suggest that the dopamine hypothesis of schizophrenia is most relevant in patients with normal ventricles.

Adult↗
PubMed1983

Normalization of spiroperidol binding in the denervated rat striatum by homologous grafts of substantia nigra.

Transplantation of embryonic substantia nigra into the adult rat brain decreases the motor asymmetry that is produced by dopamine receptor supersensitivity after a unilateral lesion of the substantia nigra. The authors report that this effect of transplantation is specific to grafts of substantia nigra. They also report that, in conjunction with the decrease in motor asymmetry, these grafts cause postsynaptic dopaminergic binding sites to return to normal density as measured by tritiated spiroperidol autoradiography. Thus, in animals with brain lesions, grafts of substantia nigra produce a long-term alteration in the functional status of host brain cell receptors that is associated with a reduction in the behavioral deficit.

Animals↗
PubMed1983

Catecholamine content of intracerebral adrenal medulla grafts.

The rotational behavior which is produced by substantia nigra lesions can be decreased by adrenal medulla grafts adjacent to the denervated striatum. Perhaps these grafts secrete dopamine that diffuses into the striatum. In the present study, we measured concentrations of catecholamines in adrenal medulla grafts as compared with the normal adrenal medulla. The grafts were found to have high but extremely variable concentrations of dopamine. In hosts with substantia nigra lesions, concentrations of dopamine in the adrenal medulla grafts were decreased. Substantia nigra lesions, however, tended to increase concentrations of epinephrine in the grafts, while norepinephrine and total catecholamine concentrations were not significantly affected. It is concluded that at least some adrenal medulla grafts contain concentrations of dopamine sufficient to account for their behavioral effects.

Adrenal Medulla↗
PubMed1983

Peripheral nerve reconnection: immediate histologic consequences of distributed mechanical support.

We tested the possibility of improving the quality of axonal repair after peripheral nerve transection by suppression of all mechanical stresses from the zone of repair. A method was developed involving mechanical support of the sciatic nerve from below in a grooved chamber with additional support provided by suturing the nerve to a rubber sleeve. Histological studies of silver-impregnated specimens from rabbit sciatic nerve using this technique revealed that the axons' tips were closely reconnected with minimal disruption in their direction or in the alignment of fibers and without extraneous material between the severed stumps. Comparison of these results with those of current microsurgical techniques showed the unequivocal superiority of this method in terms of immediate histologic aspects. The course of Wallerian degeneration was not modified.

Animals↗
PubMed1983

Peripheral nerve reconnection: mechanical, thermal, and ionic conditions that promote the return of function.

Current microsurgical techniques for repairing peripheral nerves do not take into account a number of factors that are of importance. A technique was developed that considered 17 factors, the major ones of which are proper alignment of the stumps, sharpness of cut, and prevention of physical and chemical damage. The clinical results after transection of rats' sciatic nerve were assessed in terms of functional recovery. When all 17 conditions were met, our technique was significantly superior to microsutures, suggesting the possible use of this method to improve the return of function after peripheral nerve injury.

Animals↗
PubMed1983

Peripheral nerve reconnection: improvement of long-term functional effects under simulated clinical conditions in the rat.

Despite increasing precision of the microsurgical management of peripheral nerve injuries, measured by eventual return of function, there has been no clear improvement in the outcome. By taking into consideration a number of chemical and physical factors that could influence the condition of injured nerves, we developed a reconnection technique and have applied that technique under conditions mimicking those of human nerve injury. Within 4 weeks, all rats treated by reconnection had substantial return of motor function as measured by gait. Seventy-four days after surgery, performance of the animals receiving this reconnection treatment was 66% better than that of the animals treated by conventional microsuturing.

Animals↗
PubMed1983

Functional brain tissue transplantation: reversal of lesion-induced rotation by intraventricular substantia nigra and adrenal medulla grafts, with a note on intracranial retinal grafts.

Using a rotational behavior animal model, it has been found that embryonic substantia nigra (SN) can be homologously transplanted to the brain lateral ventricles to reverse the effects of SN lesions. These grafts were found to decrease the lesion-induced rotational behavior that was provoked either by apomorphine or amphetamine. This effect was not duplicated by grafts of other embryonic brain regions. The SN grafts produced a dopaminergic reinnervation of the dorsomedial striatum that appeared to be responsible for the behavioral amelioration. Long-term studies demonstrated that behavioral efficacy and survival continued for at least 6 months to 1 1/2 years. The catecholaminergic "chromaffin" cells of the adrenal medulla possess a remarkable ability to change morphologically and biochemically in response to their environmental hormonal milieu. This plasticity was exploited by transplanting adrenal medulla to the rat brain to reverse the effects of SN lesions. This tissue changed biochemically by producing large amounts of dopamine, and morphologically, by extending coarse fiber processes. Although these grafts appeared to secrete catecholamines, they did not reinnervate the striatum. Rotational behavior was reduced by these grafts, apparently as a consequence of the catecholamine secretion. When adrenal chromaffin tissue was obtained from 1- or 2-year-old donors, however, lesion-induced rotational behavior was not reduced. It is suggested that adrenal chromaffin cell grafts from young donors possess a biochemical plasticity that is the basis for the behavioral effect, but that this plasticity is lost with maturity of the tissue. An important issue for future applications of these procedures is the immunological privilege of the brain lateral ventricles. We found that both embryonic brain tissue and adult adrenal medulla "allografts" from Brown Norway rat donors consistently survived for at least 6 months in the ventricles of Fisher 344-strain rat hosts. These strains differ in major histocompatibility antigens and, as expected, Fisher 344 rats rapidly rejected Brown Norway skin grafts. Skin graft survival times were not influenced by the presence of established brain grafts, nor did brain grafts elicit systemic humoral immunity. Conversely, however, independent elicitation of systemic immunity by skin grafting resulted in the rejection of long-established brain grafts concomitant with rejection of the skin grafts. Rotational behavior in Fisher 344 hosts was reduced by brain grafts from Brown Norway donors; yet, after rotation had been reduced it could be brought back to baseline levels through systemic immunization and associated brain graft rejection.(ABSTRACT TRUNCATED AT 400 WORDS)

Adrenal Medulla↗
PubMed1982

The effect of local application of homocysteine on neuronal activity in the central nervous system of the rat.

Homocysteine, a monocarboxylic, sulfur-containing amino acid, produces convulsions in rats and mice when administered systemically. Convulsions and high serum concentrations of homocysteine are among the symptoms that characterize patients with homocystinuria, a hereditary disorder of amino acid metabolism. In order to evaluate the effects of homocysteine on the central nervous system directly, extracellular recordings were made from neurons in rat cerebral cortex, cerebellum and midbrain during local application of homocysteine by pressure ejection or iontophoresis. Both methods of drug delivery produced dose-dependent increases in the activity of neurons in every area tested. Activity was increased by D,L-homocysteine and L-glutamate in 67 percent of cells tested with both drugs. The doses required to produce equivalent excitations in this group of cells were similar, suggesting that homocysteine is at least as potent as glutamate. The excitatory effects of both homocysteine and glutamate were antagonized by local application of betaine, a biological methyl donor which blocks convulsions produced by systemic administration of pentylenetetrazol and electroshock as well as homocysteine. The effects of local application of homocysteine were also blocked by local application of the glutamate antagonist glutamate diethylester (GDEE). In 6 of 7 cells tested, GDEE appeared to preferentially affect homocysteine-induced excitations. These data indicate that homocysteine has an excitatory action on neurons, a finding which may account for some of the symptoms associated with certain disorders of amino acid metabolism.

Animals↗