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Biomedical subjects

N S Sharpless

Publications and source records attributed to N S Sharpless.

At least 37 records · Page 2Linked to original sources
PubMed1982

Dopamine receptor sensitivity following nigrostriatal lesion in the aged rat.

This investigation sought to determine whether the ability to regulate dopamine receptor sensitivity following removal of dopaminergic innervation is altered during aging. Aged (24-26 months old) Fisher 344 rats compared with young (6 months old) rats had lower levels of dopamine and dopamine receptor binding ([3H]ADTN), but no change of dopamine-stimulated adenylate cyclase activity. Unilateral lesion of the nigrostriatal pathway produced equivalent dopaminergic denervation in rats of both age groups. The denervated striata of young rats had greatly enhanced dopaminergic sensitivity as evidenced by apomorphine induced rotational behavior and increased dopamine stimulated adenylate cyclase activity and [3H]ADTN binding. Old rats responded similarly with a very high degree of increased dopaminergic sensitivity in both the behavioral and biochemical parameters, demonstrating that the ability to regulate dopamine receptors remains basically intact. However, deficits of supersensitivity occurred in apomorphine induced rotational behavior and [3H]ADTN binding and there was a large deficit in the guanine nucleotide sensitive subcomponent of [3H]-ADTN binding. Supersensitivity of dopamine stimulated adenylate cyclase was not altered. The diminished ability to develop supersensitivity to [3H]ADTN binding could contribute to decreased [3H]ADTN binding in unlesioned rats.

Adenylyl Cyclases↗
PubMed1981

Free and conjugated dopamine in human ventricular fluid.

Free dopamine and an acid hydrolyzable conjugate of dopamine were measured in human ventricular fluid specimens with a radioenzymatic assay and by high performance liquid chromatography (HPLC) with electrochemical detection. Only trace amounts of free norepinephrine and dopamine were detected in ventricular fluid from patients with movement disorders. When the ventricular fluid was hydrolyzed by heating in HClO4 by lyophilization in dilute HClO4, however, a substantial amount of free dopamine was released. Values for free plus conjugated dopamine in ventricular fluid from patients who had never taken L-DOPA ranged from 139 to 340 pg/ml when determined by HPLC and from 223 to 428 pg/ml when measured radioenzymatically. The correlation coefficient for values obtained by the two methods in the same sample of CSF was 0.94 (P less than 0.001). Patients who had been treated with L-DOPA had higher levels of conjugated dopamine in their ventricular CSF which correlated inversely with the time between the last dose of L-DOPA and withdrawal of the ventricular fluid. Additionally, one patient with acute cerebral trauma had elevated levels of free norepinephrine and both free and conjugated dopamine in his ventricular fluid. Conjugation may be an important inactivation pathway for released dopamine in man.

Chromatography, High Pressure Liquid↗
PubMed1981

Kindling in developing rats: variability of afterdischarge thresholds with age.

In the kindling model, the occurrence of afterdischarges is necessary for the development of seizures. In this study, the afterdischarge thresholds of the amygdala were determined in rats of 4 different age groups, beginning with 15-day-old suckling rats. Afterdischarges were triggered in 75% of the suckling rats and in all of the rats in the older age groups. The afterdischarge thresholds varied with age, being highest in the suckling group, lowest in the 35-day-old group and intermediate in the older groups. This variability of the thresholds did not correlate with the alterations in the catecholamine levels in the amygdala that occur during maturation. The failure of 25% of suckling rats to develop afterdischarges may explain why some suckling rats do not kindle.

Aging↗
PubMed1981

Choline chloride fails to improve cognition of Alzheimer's disease.

Seven mildly to moderately demented patients with Alzheimer's disease were treated with either placebo or choline chloride (50, 100 and 200 mg/kg/24 hrs) in a double blind, crossover study. Detailed psychometric analysis was carried out at the end of each two-week period of drug or placebo administration. No subjects showed significant overall improvement at any dose level despite more than a doubling of the baseline plasma choline level.

Aged↗
PubMed1980

Evidence for selective loss of brain dopamine- and histamine-stimulated adenylate cyclase activities in rabbits with aging.

Dopamine-stimulated adenylate cyclase activity in striatum and both dopamine- and histamine-stimulated adenylate cyclase activity in hypothalamus, frontal cortex and anterior limbic cortex declined by about 50% as rabbits aged from 5.5 months to 5.5 years of age. These changes were primarily in maximal response to amine although an additional component involving decreased affinity in the case of dopamine may also be present. In contrast, dopamine-stimulated adenylate cyclase of retina and both basal and guanyl-5'-yl-imidodiphosphate (Gpp(NH)p)-stimulated activity in these regions were not altered with age. There was no measurable decrease in the old animals in either dopamine or norepinephrine concentration in striatum, anterior limbic cortex or retina, or in choline acetylase activity or [3H]quinuclidinylbenzilate binding in striatum, anterior limbic cortex or frontal cortex. It is proposed that selective age-dependent decreases in transmitter receptors coupled to adenylate cyclases occur in the absence of or independent from neuronal cell loss, as evidenced by the retention of the other biochemical markers.

Adenylyl Cyclases↗
PubMed1980

Treatment of myoclonus with L-5-hydroxytryptophan and carbidopa: clinical, electrophysiological, and biochemical observations.

Six patients with myoclonus of varying cause were treated with L-5-hydroxytryptophan (L-5-HTP) and carbidopa. While spontaneous myoclonus decreased in three of the patients and action myoclonus in four, only two patients had marked functional improvement. Side effects included gastrointestinal and affective disturbances. L-5-HTP therapy caused a diminished frequency of paroxysmal discharges in the electroencephalograms of three patients which did not always correlate with clinical improvement. Lumbar cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) concentration after probenecid was decreased in all patients prior to therapy, but this reduction did not predict treatment response. Urinary excretion patterns for 5-HTP, serotonin, and 5-HIAA during treatment were similar in responders and nonresponders. It is concluded that while some patients with myoclonus do benefit from L-5-HTP therapy, biochemical and electrophysiological tests are not useful predictors of treatment response, and the high incidence of side effects limits the usefulness of this therapy.

5-Hydroxytryptophan↗
PubMed1979

Aging and monoamine receptors in brain.

Biochemical evidence is presented for selective decreases in biogenic amine receptor systems with age in the rabbit. Dopamine-stimulated adenylate cyclase activity in striatum, hypothalamus, frontal cortex, and anterior limbic cortex declined by about 50% as rabbits aged from less than 1 to 5 years of age. Similar decreases were found for histamine-stimulated activity in hypothalamus and the cortical regions. These changes were in maximal response rather than in affinity for amine. In contrast, dopamine-stimulated adenylate cyclase of retina and both basal and Gpp(NH)p-stimulated activity in these regions were not altered with age. In addition, with age the number of binding sites for [3H]spiroperidol, a dopamine antagonist, decreased by 30--40% without change in ligand affinity in striatum and limbic cortex. These changes in striatum and cortex occurred in the absence of decreases in either dopamine concentration or choline acetylase activity. It is proposed that selective age-dependent decreases in the functional number of biogenic amine receptors occur in the absence of, or independent from neuronal cell loss, possibly by a mechanism of desensitization. These changes occurred in brain regions that in man are thought to be of importance in the age-related loss of cerebral function.

Adenylyl Cyclases↗
PubMed1978

Juvenile parkinsonism: a patient with possible primary striatal dysfunction.

A 15-year-old boy who initially manifested dystonic features and later developed classic parkinsonism is described. Cerebrospinal fluid homovanillic acid levels were normal or slightly elevated both before and after administration of probenecid. The patient responded favorably to treatment with levodopa and carbidopa. The normal or slightly elevated cerebrospinal fluid homovanillic acid levels contrast with the low levels usually seen in adult parkinsonian patients. The data on this patient suggest direct neostriatal involvement rather than depletion of neurons of the substantia nigra. Juvenile parkinsonism may have at least two distinct pathological forms, but they have similar clinical features and a similar response to treatment.

Adolescent↗
PubMed1978

Biogenic amine-stimulated adenylate cyclase and spiroperidol-binding sites in rabbit brain: evidence for selective loss of receptors with aging.

Evidence for selective decreases in biogenic amine receptor function with age in the rabbit has been obtained. Dopamine-stimulated adenylate cyclase activity in the striatum (caudate-putamen) of rabbit brain declined by about 50 percent as rabbits aged from less than 1 to 4 to 5 years of age. Similar decreases in transmitter-stimulated adenylate cyclase activity were found for histamine as well as for dopamine and norepinephrine in hypothalamus, frontal cortex and anterior limbic cortex. Isoproterenol-stimulated activity was also decreased with age in frontal cortex. These changes appeared to represent decreases in maximal response and not alteration in affinity for amine. In contrast, dopamine-stimulated adenylate cyclase of retina and transmitter-independent (basal or Gpp(NH)p-stimulated) activity in each of the regions studied were not altered with age. Dopamine receptors in striatum directly assessed by measurement of [3H]-spiroperidol binding revealed a comparable decrease in the number of binding sites without change in ligand affinity. Preliminary data also indicated decreased spiroperidol binding sites in the cortical regions of older animals. These changes in striatum and cortex were evident in the absence of decreases in either dopamine content or choline acetylase activity, an activity presumed to be present in neurons containing dopamine receptors. It is proposed that selective age-dependent decreases in postsynaptic biogenic amine receptor content occur in the absence of, or independent from, neuronal cell loss, possibly by a mechanism involving receptor desensitization. These changes occur in the animal model in those brain regions which in man are thought to be of importance in the loss of cerebral function that is found with senscence.

Adenylyl Cyclases↗