Search PubMed⌕ Search

Biomedical subjects

C R Freed

Publications and source records attributed to C R Freed.

At least 19 recordsLinked to original sources
PubMed1992

Survival of implanted fetal dopamine cells and neurologic improvement 12 to 46 months after transplantation for Parkinson's disease.

BACKGROUND AND METHODS: Patients with Parkinson's disease tend to have a reduced response to levodopa after 5 to 20 years of therapy, with "on-off" fluctuations consisting of dyskinesia alternating with immobility. In an effort to modify the motor disability of advanced Parkinson's disease, we implanted embryonic mesencephalic tissue containing dopamine cells into the caudate and putamen of seven patients. Two patients received unilateral grafts in the caudate and the putamen on the side opposite the side with worse symptoms. Five patients received bilateral grafts implanted in the putamen only. In six of the seven patients, the fetal tissue was obtained from a single embryo with a gestational age of seven to eight weeks. The tissue was injected by means of 10 to 14 needle passes. There were no surgical complications. Four of the seven patients underwent immunosuppression with cyclosporine and prednisone. RESULTS: All patients reported improvement according to the Activities of Daily Living Scale when in the on state 3 to 12 months after surgery (P < 0.01). Neurologic examination according to the Unified Disease Rating Scale showed that five of the seven patients improved when in the on state six months after surgery. The mean group Hoehn-Yahr score improved from 3.71 to 2.50 (P < 0.01). Computer and videotape testing in the home supported these findings. Fluctuations in clinical state were moderated, and periods of dyskinesia and off episodes were shorter and less severe than before implantation. Drug doses were reduced by an average of 39 percent (P < 0.01; maximum, 58 percent). The results of clinical evaluation and fluorodopa positron-emission tomography in one patient were compatible with transplant survival for as long as 46 months. Both immunosuppressed and nonimmunosuppressed patients improved. CONCLUSIONS: Fetal-tissue implants appear to offer long-term clinical benefit to some patients with advanced Parkinson's disease.

Activities of Daily Living↗
PubMed1992

Drug-induced changes in blood pressure lead to changes in extracellular concentrations of epinephrine, dihydroxyphenylacetic acid, and 5-hydroxyindoleacetic acid in the rostral ventrolateral medulla of the rat.

Neurochemical changes in the extracellular fluid of the rostral ventrolateral medulla (RVLM) were produced by changes in arterial blood pressure. Blood pressure was raised or lowered with systemic infusions of phenylephrine or nitroprusside and neurochemicals were recovered from RVLM by in vivo microdialysis. A dialysis probe 300 microns in diameter and 500 microns in length was stereotaxically implanted in the RVLM of the urethane-anesthetized rat. Sterile physiological Ringer's solution was perfused at a rate of 1.5 microliter/min. The perfusate was collected under ice-cold conditions every 15 min for the assay of epinephrine, dihydroxyphenylacetic acid (DOPAC), 5-hydroxyindoleacetic acid (5-HIAA), ascorbic acid, and uric acid. After stable baseline neurochemical concentrations were achieved, animals were infused with phenylephrine or nitroprusside intravenously to raise or lower the blood pressure. Increasing blood pressure 50 mm Hg above the baseline value by phenylephrine led to a significant reduction in heart rate and a reduction in extracellular epinephrine and DOPAC concentrations. The 5-HIAA concentration was increased during the hypertensive drug infusion. There were no changes in the concentrations of ascorbic acid or uric acid. Hypotension produced by nitroprusside (-20 mm Hg) led to neurochemical changes which were the reciprocal of those seen during hypertension. During hypotension, heart rate increased as did the extracellular fluid epinephrine concentration. The 5-HIAA concentration fell with hypotension and remained depressed following the nitroprusside infusion. Ascorbic acid and uric acid concentrations did not change during hypotension but ascorbic acid did increase after the nitroprusside infusion stopped. These data provide direct evidence that epinephrine release in RVLM is linked to changes in systemic blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1992

Alprazolam as a neuroleptic adjunct in the emergency treatment of schizophrenia.

OBJECTIVE: While neuroleptics remain the mainstay of drug intervention in the emergency management of psychosis, a variety of agents have received study as alternatives or adjuncts to these drugs in an attempt to improve the safety and efficacy of acute treatment. The purposes of this study were to investigate the efficacy and safety of alprazolam as a neuroleptic adjunct for schizophrenic patients in psychotic relapse and to clarify the effects of combination treatment on specific aspects of the psychotic process. METHOD: Twenty-eight acutely psychotic patients with schizophrenia who were admitted to an emergency psychiatric service were randomly assigned to treatment with either haloperidol and alprazolam or haloperidol with placebo under double-blind conditions. Drug administration lasted 72 hours. RESULTS: Both groups improved significantly. The combination-treated group required significantly less medication and had 56% fewer dystonic reactions. The addition of alprazolam was most effective for symptoms of excitement and uncooperativeness, particularly in the initial hours of treatment. CONCLUSIONS: The combination of alprazolam and haloperidol seems to be the most effective for agitated patients, particularly in the first 48 hours of treatment. It may also result in fewer dystonic reactions.

Adult↗
PubMed1990

Transplantation of human fetal dopamine cells for Parkinson's disease. Results at 1 year.

In an effort to improve the clinical signs of Parkinson's disease, we have implanted mesencephalic dopamine cells from a 7-week human embryo into the caudate and putamen of a 52-year-old man with Parkinson's disease. Fetal tissue was obtained from elective abortion. The woman and the patient with Parkinson's disease were unknown to each other. The woman gave specific consent and was not paid. The patient had a 20-year history of parkinsonism treated with multiple drug therapies including levodopa/carbidopa (Sinemet) every 2 1/2 hours. His symptoms were worse on the left side. For 5 months prior to transplantation, the patient underwent clinical evaluations by both a neurologist and a computer system installed in his home for daily measurement of walking and hand movements. Preoperative positron emission tomographic scanning with 6-L[18F]fluorodopa (fluorodopa) demonstrated severe dopamine depletion bilaterally. Fetal tissue was matched to the patient for ABO blood antigens, and maternal serum was screened for hepatitis B and human immunodeficiency virus type 1 prior to surgery. Fetal tissue was implanted stereotactically throughout the caudate and putamen on the right side of the brain via 10 needle tracks. The patient was not immunosuppressed. Results 12 months after surgery showed 42% improvement in left-hand speed before the first morning dose of drug and 40% greater response to drug therapy. Right-hand speed increased 15% before drug therapy and 23% after drug therapy. Reaction time was unaffected. Walking speed increased 33% after drug administration, although walking speed before the first morning dose of drugs declined 40%. Walking speed on an all-day basis improved 17%.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain↗
PubMed1990

Conditioned rotation: a behavioral analysis.

Rats trained to turn in circles have been used by a number of investigators to study brain dopamine metabolism. We report the results of a behavioral analysis of conditioned rotation and describe the apparatus used in our laboratory to train rats and monitor their performance. A novel discrimination procedure was used which required each rat to turn left in one training chamber with one set of stimulus conditions and right in a different chamber. Water-deprived animals were trained to circle for a water reward. Initial acquisition of this task required 11 days of training. At the end of acquisition, a discrimination test indicated that turning in the left and right directions was under stimulus control of the chamber environment. We found that trained turning had a highly stereotyped temporal organization with a rapid movement component during which the rat executed the turn, and a longer pause time component during which the rat consumed the water reinforcer.

Animals↗
PubMed1990

In vivo dialysis measurements of dopamine and DOPAC in rats trained to turn on a circular treadmill.

In vivo dialysis was used to measure extracellular fluid concentrations of dopamine and dihydroxyphenylacetic acid (DOPAC) in rats which were trained to run on a circular disk treadmill for water reinforcement. Turning resulted in bilateral increases in DOPAC in lateral striatum as well as nucleus accumbens/medial striatum. Dopamine release showed small but not significant increases at both sites. Changes in DOPAC release were not lateralized. Free drinking without circling also resulted in significant increases in DOPAC in these two brain areas. During free drinking, dopamine release was significantly increased in lateral striatum but not in nucleus/medial striatum. These experiments indicate that dopamine metabolism is increased in rat striatum and nucleus accumbens in animals running on circular treadmills as well as by free drinking.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1990

Unilateral dopamine depletion causes bilateral deficits in conditioned rotation in rats.

Rats were trained to rotate for a water reward using a procedure which required each rat to turn in both the left and right directions. The rats were then lesioned with unilateral injections of 6-hydroxydopamine in the nigrostriatal bundle to produce unilateral dopamine depletion. Rats which had greater than 95% depletion had significant deficits in turning both ipsilateral and contralateral to the depleted side. Circling contralateral to the lesion was more impaired than circling ipsilateral to the lesion. All animals showed deficits in both the initiation of movement and in speed of turning. In addition, the rats displayed a chronic turning bias in the ipsilateral direction 16 weeks postlesion. These results indicate that unilateral dopamine depletion causes a variety of impairments in trained circling behavior. Although contralateral circling is most impaired, there is a significant decrease in ipsilateral performance. We conclude that normal conditioned circling behavior requires bilateral dopamine innervation.

Animals↗
PubMed1990

Nerve growth factor-dependence of herpes simplex virus latency in peripheral sympathetic and sensory neurons in vitro.

Previously, we reported that nerve growth factor (NGF) is required to maintain herpes simplex virus (HSV) latency in cultures of rat sympathetic neurons (Wilcox and Johnson, 1987, 1988). Here, we extend these results by showing that NGF was also required to maintain HSV latency in cultures of sensory neurons obtained from dorsal root ganglia of rats, monkeys, and humans. The interruption of the neuronal supply of NGF for 1 hr reactivated HSV, indicating that the latent virus was exquisitely sensitive to perturbations in the concentration or binding of NGF. A species-specific monoclonal antibody directed against the human NGF-receptor, which blocks NGF binding, reactivated latent HSV in human, but not rat, sensory neurons. In contrast, a monoclonal antibody against the rat NGF-receptor, which binds the receptor without blocking NGF action, did not produce reactivation. These results indicate that the effects of NGF on HSV latency are mediated via NGF binding to the NGF receptor. In addition, treatments that interfere with specific steps in the transduction of the NGF signal, including treatment with 6-hydroxydopamine and colchicine, reactivated latent HSV. Further, in neurons harboring latent virus, interruption of protein synthesis or RNA transcription for 1 hr resulted in viral reactivation, suggesting that a short-lived factor may be present in neurons which represses viral reactivation.

Animals↗
PubMed1989

Electrophysiological analysis of dopamine cells from the substantia nigra pars compacta of circling rats.

Extracellular single unit recordings were obtained from dopamine cells in the substantia nigra pars compacta during forced locomotion on a circular turntable treadmill. Stainless steel wire electrodes, 18 microns diameter, insulated with Parylene C were used. During the entire recording session the rat was in the treadmill apparatus. The device was stopped while a cell was being sought. A cell was identified as dopaminergic by a frequency of 3 to 10 Hz and a biphasic or triphasic action potential of greater than 2 ms in duration. An attempt was made to record from cells under the following conditions: animal at rest, animal turning in one direction, at rest again, turning in the opposite direction and finally, at rest. If the cell was still firing after these recordings, haloperidol was injected i.p. to see that the presumed dopamine cell increased its firing rate. A cell was held for all the observations in 4 animals. In an additional 10 rats, recordings were made before, during and after movement in one direction. Three animals were recorded only before and during movement. In 6 of the total of 17 animals haloperidol was administered. Results showed that firing patterns of cells in awake animals were similar to those reported from dopamine cells of anesthetized rats. During either contralateral or ipsilateral turning the firing frequency and burst activity significantly increased. These results indicate that the activity of dopamine cells in substantia nigra is increased bilaterally during circling.

Action Potentials↗
PubMed1989

Catechol and indole metabolism in rostral ventrolateral medulla change synchronously with changing blood pressure.

Catechol and indole metabolism in rostral ventrolateral medulla (RVLM or C1) was studied in response to changes in blood pressure across different rat strains. Sprague-Dawley, Wistar Kyoto normotensive and spontaneously hypertensive rats were anesthetized with urethane and had a 250 mu carbon paste in vivo electrochemical electrode implanted in RVLM area. Two electrochemical peaks were detected in this region. The first was at 0.12 V and the second at 0.28 V. To identify the electrochemical peaks, inhibitors of monoamine metabolism were administrated. alpha-Methylparatyrosine (tyrosine hydroxylase inhibitor), fusaric acid (dopamine-beta-hydroxylase inhibitor), pargyline (monoamine oxidase inhibitor) and LY 134046 (phenylethanolamine-N-methyltransferase inhibitor) showed that the first peak measured in the RVLM is likely to have multiple components including epinephrine, norepinephrine and 3,4-dihydroxyphenylacetic acid. The second peak most likely represents 5-hydroxyindole acetic acid. Phenylephrine or nitroprusside was infused to increase or decrease the blood pressure. Phenylephrine-induced hypertension reduced the catechol peak and increased the indole peak. By contrast, nitroprusside-induced hypotension produced reciprocal results. Hypotension led to an increase in the catechol peak and a reduction in the indole peak. The same pattern was observed in all three rat strains. We conclude that catechol and serotonin metabolism in RVLM changes in close relation to changes in blood pressure.

Animals↗
PubMed1988

Brain acetaminophen measurement by in vivo dialysis, in vivo electrochemistry and tissue assay: a study of the dialysis technique in the rat.

After peripheral injections of the electrochemically active drug acetaminophen, striatal levels of the drug were measured in 3 different ways: in vivo electrochemistry, in vivo dialysis, and tissue assay. The time course of the acetaminophen concentrations measured by in vivo dialysis paralleled the in vivo electrochemistry curve and lagged behind the peak tissue concentration. This result suggests that dialysis and electrochemistry provide equivalent measurements of extracellular fluid acetaminophen. In vitro, dialysis recovery of acetaminophen was 28% of the beaker concentration.

Acetaminophen↗
PubMed1988

Changes in neurotransmitter turnover in locus coeruleus produced by changes in arterial blood pressure.

The effect of drug-induced hypertension and hypotension on neurotransmitter metabolism in the locus coeruleus (LC) of urethane anesthetized rats was studied using in vivo electrochemical methods. Peaks were seen at +0.15 V and +0.28 V. Studies with alpha-methylparatyrosine, fusaric acid and pargyline showed the first peak was produced by extracellular fluid dihydroxyphenylacetic acid (DOPAC) while the second peak was 5-hydroxyindoleacetic acid (5-HIAA). Phenylephrine was infused intravenously to raise the blood pressure by 50 mmHg, nitroprusside IV was used to reduce the blood pressure by 20 mmHg. During phenylephrine hypertension, the electrochemical signal for DOPAC showed an initial small reduction followed by a later significant increase which persisted even after the infusion was stopped. The signal for 5-HIAA rose with the onset of hypertension and remained elevated. Nitroprusside hypotension did not change the DOPAC peak but did lead to an immediate and persistent increase in the electrochemical 5-HIAA peak. To confirm the electrochemical findings, other groups of rats were decapitated during and after hypertensive and hypotensive drug infusions and the LC was assayed for norepinephrine, dopamine, DOPAC, serotonin, and 5-HIAA using HPLC with electrochemical detection. Changes in tissue DOPAC and 5-HIAA concentrations supported the electrochemical electrode observations. The effect of clonidine on the electrochemical recordings from LC was also studied. Clonidine reduced the catechol peak. No change was observed in the 5-HIAA peak during the infusion, but the 5-HIAA peak went up after the infusion was stopped. These experiments show that hypertension, hypotension, and alpha-2 agonists lead to changes in catecholamine and indoleamine metabolism in LC.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Plasma osmolality predicts extracellular fluid catechol concentrations in the lateral hypothalamus.

The lateral hypothalamus has an important role in regulating food and water intake. We have investigated the endogenous release of monoamines from the lateral hypothalamus during manipulations of plasma osmolality and circulating volume. Adult male Sprague-Dawley rats implanted with carbon paste in vivo electrochemical (EC) electrodes in the lateral hypothalamus were placed on a 72-h water deprivation schedule. Although the carbon paste EC electrode has an intrinsically ambiguous signal in which changes in ascorbic acid may appear as changes in catechol concentrations, pharmacologic studies in lateral hypothalamus indicated that the electrode most likely measured norepinephrine and possibly epinephrine. On the test day, the EC electrodes were scanned with linear sweep voltammetry from -0.2 to +0.4 V at a rate of 5 mV/s. Semiderivative signal processing showed catechol and hydroxyindole peaks at +0.11 and +0.23 V, respectively. Baseline recordings were made prior to rats drinking distilled water, 10% sucrose, 5% dextrose, 0.30% NaCl, 0.90% NaCl, or 10% d-mannitol. To control for the act of drinking, other implanted dehydrated rats were intraperitoneally injected with 5% dextrose, 0.30% NaCl, or 0.90% NaCl. To dissociate the effects of osmolality and circulating volume on the EC response, hydrated rats implanted with EC electrodes were subcutaneously injected with 12% NaCl or intraperitoneally injected with 35% polyethylene glycol. Other rats subjected to water deprivation and osmotic challenges were decapitated and trunk blood was collected for measurements of plasma osmolality and hematocrit. Similar experiments were conducted using homozygous Brattleboro rats which lack arginine vasopressin (AVP) but which preserve normal plasma osmolality with prodigious drinking.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Changes in arterial blood pressure lead to baroreceptor-mediated changes in norepinephrine and 5-hydroxyindoleacetic acid in rat nucleus tractus solitarius.

Catecholamine and indoleamine metabolism in nucleus tractus solitarius were studied during drug-induced hypertension and hypotension. Urethane-anesthetized normotensive male Sprague-Dawley rats implanted with a 250-mu carbon paste in vivo electrochemical electrode were infused with phenylephrine to raise blood pressure 50 mm Hg. Other animals were given nitroprusside to lower pressure 20 mm Hg. Phenylephrine-induced hypertension was associated with a 30% reduction in the electrochemical peak corresponding to norepinephrine. The electrochemical peak which was identified as 5-hydroxyindoleacetic acid (5-HIAA) was increased 25% with the onset of hypertension and remain elevated after the phenylephrine infusion was stopped. Nitroprusside-induced hypotension resulted in a 20% reduction in the norepinephrine peak during the infusion followed by an additional 10% reduction after the infusion. 5-HIAA concentration did not change during the hypotensive phase but showed a 40% increase after the nitroprusside was stopped as blood pressure rebounded to levels higher than the control period. Direct tissue assays of norepinephrine and 5-HIAA confirmed the electrochemical findings. These experiments were repeated in rats which had undergone sinoaortic denervation. The electrochemical changes in norepinephrine and 5-HIAA associated with hypertension and hypotension were attenuated in these animals indicating that the brain neurotransmitter changes were a consequence of baroreceptor input to the brain. We conclude that 5-HIAA in nucleus tractus solitarius appears to be a marker for elevated blood pressure, whereas norepinephrine falls with either an increase or a decrease in pressure.

Animals↗
PubMed1987

Nucleus tractus solitarius: an evaluation by in vivo voltammetry.

Nucleus tractus solitarius (NTS) is a brainstem nucleus known to play an important role in baroreceptor mediated cardiovascular regulation. As part of our study of the role of monoamines in the function of NTS, we have characterized pharmacologically the in vivo electrochemical signal recorded from the nucleus using carbon paste electrodes and linear sweep voltammetry with semiderivative signal processing in awake, freely moving rats. Two peaks were recorded by these techniques, one at 0.14 V and a second at 0.28 V. The tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine led to a significant reduction in the peak recorded at 0.14 V whereas it had no effect on the higher potential peak at 0.28 V. The dopamine-beta-hydroxylase inhibitor fusaric acid resulted in a large reduction in the 0.14 V peak and led to a 30% increase in the 0.28 V peak height. Pargyline, a monoamine oxidase inhibitor, did not change the low potential peak but did significantly reduce the 0.28 V peak. Tissue assays provided further support for the interpretation of in vivo electrochemical recordings. Norepinephrine concentration was reduced with fusaric acid. Tissue serotonin was not affected by any of the drugs while the 5-HIAA content was increased with fusaric acid and reduced with pargyline. These experimental findings lead to the conclusion that the first peak in the voltammogram most likely represents norepinephrine with a possible contribution by dopamine but not by DOPAC. The second peak appears to be 5-HIAA.

Animals↗
PubMed1987

In vivo electrochemical recording of acetaminophen in non human primate brain.

In vivo electrochemical recordings were obtained from the caudate nucleus of three young adult pigtail monkeys (M. nemestrina) following the oral administration of acetaminophen (APAP) (75 mg/kg). Using linear sweep voltammetry, electrodes in the right and left caudate were scanned alternately every five minutes. The electrochemical peak resulting from the APAP was monitored for at least 140 minutes following drug administration. Maximum APAP levels were detected in the monkey caudate 40 minutes following drug administration. Both right and left caudate displayed an identical time course, with oxidation potentials (Eox) similar on both sides of the brain. Blood samples were collected from one monkey by means of an intravenous catheter. Samples were obtained at approximately 5-minute intervals and over a period of 140 minutes following oral administration of APAP. Concentration of APAP in serum peaked 25 minutes after administration. In this animal the maximum electrochemical peak height was detected 40 minutes following APAP administration. These findings demonstrate the ability to measure APAP in the caudate nucleus of awake monkeys by means of electrochemical detection. This method may be useful for calibrating electrochemical electrodes in vivo, and it also provides a model system for studying drug kinetics in the brain.

Acetaminophen↗