Plasma physostigmine concentrations after controlled-release oral administration.
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Administration, Oral↗
Biomedical subjects
N S Sharpless
Publications and source records attributed to N S Sharpless.
Intranigral GABAergic drug effects on striatal dopamine activity.
Concentrations of striatal dopamine (DA), serotonin (5-HT) and their metabolites were measured following infusions of the GABAA receptor agonist, muscimol, or GABAA receptor antagonist, bicuculline, into the substantia nigra (SN) or areas dorsal to the SN in adult rats and 16-day-old rat pups. Results indicated that intranigral infusions of muscimol produced site-specific increases in the concentrations of striatal DA metabolites in adults, while in pups, intranigral muscimol infusions produced site-specific increases in the concentrations of striatal DA. Intranigral infusions of bicuculline had no effect on striatal DA or its metabolites in either age group. Neither GABAergic drug had any effect on striatal 5-HT or its metabolite. The data suggest that the effect of nigral GABAA agonist infusions on the activity of the nigrostriatal pathway is age-specific. The lack of opposing effects following the nigral infusion of a GABAA receptor antagonist indicates that the influences of GABAA agonists may be mediated by different mechanisms as a function of age.
3,4-Dihydroxyphenylacetic Acid↗
The effects of delta 9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study.
The effect of systemically administered delta 9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, on the potassium-evoked release of dopamine (DA) was examined in the neostriatum of the chloral hydrate anesthetized rat. Both in vivo electrochemical and in vivo microdialysis techniques were employed. A low dose of THC (0.5 mg/kg, i.p.) increased the time course of potassium-evoked in vivo electrochemical signals corresponding to released extracellular DA. In vivo microdialysis showed an increase in potassium-evoked DA release following 0.5 and 2.0 mg/kg doses of THC. Potassium-evoked electrochemical signals corresponding to released extracellular DA were augmented in time course following i.p. administration (5.0 mg/kg) of nomifensine, a recognized and potent catecholaminergic reuptake blocker. In addition, in vivo brain microdialysis studies of nomifensine (5.0 mg/kg i.p.) on neostriatal potassium-evoked DA release showed that DA levels were augmented in magnitude over the time course of the microdialysis. Taken together, these studies indicate that THC has a potent presynaptic augmenting effect on at least the neostriatal portions of the mesotelencephalic DA system in the rat, although the possibility that this effect could be mediated transsynaptically cannot be ruled out. Given the previous extensive evidence for an involvement of portions of the mesotelencephalic DA system in mediating the reinforcing and euphorigenic properties of many classes of abused drugs, and in mediating direct electrical brain stimulation reward, we suggest that the presently demonstrated effects of THC on forebrain dopamine function may be related to marijuana's euphorigenic properties and, thus, to its abuse potential.
Caudate Nucleus↗
Diminished levels of ventricular fluid norepinephrine metabolite and somatostatin in childhood-onset dystonia.
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Adolescent↗
Age-related changes in striatal dopamine activity following nigral muscimol infusions.
Microinfusions of muscimol into the substantia nigra pars reticulata produced marked increases in striatal dopamine (DA) utilization without affecting striatal DA concentration in adult rats. In contrast, muscimol increased striatal DA concentration and decreased DA utilization in 16-day-old rat pups. The striatal norepinephrine concentration was not altered in either group. Since previous studies have shown that similar infusions of muscimol are anticonvulsant in adults and proconvulsant in rat pups, our results suggest that the nigrostriatal pathway may play an important role in mediating the nigral effects on seizures.
Aging↗
Determination of total 3-methoxy-4-hydroxyphenylglycol in plasma using reversed-phase liquid chromatography with electrochemical detection.
A method is described for determination of total (free plus conjugated) 3-methoxy-4-hydroxyphenylglycol (MHPG) in plasma using high-performance liquid chromatography with electrochemical detection. After enzymatic hydrolysis of conjugates and deproteinization with zinc sulfate and sodium hydroxide, free MHPG is isolated by extraction prior to isocratic chromatographic separation. The absolute detection limit is about 30 pg which corresponds to a plasma concentration of 2-3 ng/ml when 0.5 ml of plasma is analyzed. Average within-analysis and between-analysis coefficients of variation (6.5 and 8.9%, respectively) are suitable for routine clinical analyses. Severe icterus is without effect, but even mild hemolysis causes detectable losses of MHPG from plasma. The mean +/- S.D. plasma MHPG concentration observed in sixteen healthy individuals (14.5 +/- 3.9 ng/ml) compares favorably with values reported using more complex reference methods.
Adult↗
Unilateral peri-substantia nigra catecholaminergic lesion and amygdala kindling.
Recent evidence suggests that the substantia nigra (SN) may be involved in the modulation of kindled seizures in adult rats. In this report we investigated the role of the dopaminergic nigrostriatal pathway in mediating the SN effect on seizures by lesioning this pathway with unilateral infusions of 6-hydroxydopamine (6-OHDA) in the vicinity of the right SN with or without desmethylimipramine pretreatment. Our data suggest that the facilitation of amygdala kindling observed following 6-OHDA lesion in the vicinity of the ipsilateral SN is due to norepinephrine depletion of the ipsilateral forebrain. Selective destruction of the nigrostriatal dopaminergic neurons neither facilitates nor inhibits the development of amygdala-kindled convulsions in adult rats.
Amygdala↗
Mechanisms of syncope in glossopharyngeal neuralgia.
Syncope is a rare presentation of glossopharyngeal neuralgia (GN). The mechanisms of the syncope were studied in a patient with recurrent episodes comprising prolonged cardiac standstill and arterial hypotension. During attacks, no supraventricular or ventricular potentials were recorded in the ECG. Atropine prevented the cardiac arrest without affecting the pain, indicating the vagus as the efferent limb of the reflex asystole. Following atropine blood pressure continued to fall during GN attacks, suggesting abolition of sympathetic tone. Indeed, serum norepinephrine levels fell during these attacks. Infiltration of either vagus above the clavicle with local anesthetics did not abolish the cardiac asystole. Carbamazepine and a dual chamber pacemaker were effective in controlling the symptoms of the patient. The results suggest that, during a neuralgic attack, the stimulation excites both vagi, causing asystole and simultaneously abolishes sympathetic tone.
Biomechanical Phenomena↗
Acute and chronic effects of oral physostigmine and lecithin in Alzheimer's disease.
Alzheimer patients were treated with lecithin and gradually increasing doses of oral physostigmine during a drug trial to determine if these compounds would improve memory. Memory was measured using a selective reminding task. Of 16 patients, 10 showed improvement in total recall, retrieval from long-term storage and a decrease in intrusions. The optimal dose was 2.0 mg or 2.5 mg of physostigmine per dose for most patients. During a replication study, all 10 patients again responded. During long-term (4 to 20 months) treatment of five patients, most demonstrated continued drug response initially but then lost responsiveness to physostigmine and their dementia progressed. Physostigmine treatment appeared to improve memory with or without concomitant lecithin therapy. However, progressive dementia ensued despite physostigmine therapy. The degree of memory improvement correlated with increasing cerebrospinal fluid cholinesterase inhibition suggesting that memory improvement is associated with entry of physostigmine into the brain.
Administration, Oral↗
Plasma physostigmine concentrations after oral administration.
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Administration, Oral↗
Ventricular fluid somatostatin concentration decreases in childhood-onset dystonia.
Somatostatin was measured in CSF from individuals with a variety of neurologic diseases. In ventricular CSF, somatostatin concentration was significantly lower in individuals with childhood-onset dystonia than in individuals with other forms of dystonia or with other disorders. Severity of childhood dystonia correlated with somatostatin concentration, suggesting a progressive dysfunction of somatostatin-containing neurons with increasing disease severity. There were no significant differences in somatostatin concentration in lumbar CSF. Multiple forms of immunoreactive somatostatin were found in a pool of lumbar CSF from normal individuals. Labeled somatostatin administered intra-arterially to rats failed to cross the blood-brain barrier.
Adolescent↗
Biogenic amine alterations in limbic brain regions of muricidal rats.
Endogenous levels of serotonin, 5-hydroxyindoleacetic acid (5-HIAA), dopamine, 3-4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in eight brain regions of muricidal (mouse killing) and non-muricidal rats. The regions studied were: the frontal cortex, caudate nucleus, septal area, hypothalamus, thalamus, amygdalae with pyriform cortex, anterior hippocampal formation, and brain stem. Serotonergic systems showed significant differences in discrete brain regions of muricidal rats as compared to those of non-muricidal rats. The differences were: significantly higher serotonin levels in the amygdalae and significantly higher 5-HIAA levels in the hippocampus of the muricidal rats. Serotonin levels were also higher in the hypothalamus of the muricidal rats, but the difference reached only borderline significance. Dopaminergic systems also showed significant differences in the septum of muricidal rats, where DOPAC levels were significantly lower than those of non-muricidal rats. The hippocampus of muricidal rats showed significantly higher dopamine levels. HVA levels in the hippocampus of muricidal rats were also higher but reached only borderline significance. These data suggest both central serotonergic and central dopaminergic involvements in rat muricidal behavior. The discrete brain regions which showed differences further suggest a limbic involvement.
3,4-Dihydroxyphenylacetic Acid↗
Striatal met-enkephalin concentration increases following nigrostriatal denervation.
Following specific lesion of the nigrostriatal dopaminergic pathways in rat brain, striatal met-enkephalin on the lesioned side increased to 245% of that on the non-lesioned side. This increase was evident only after a lag period of 7 days and the increase was maintained for at least 2 months after lesion. By contrast, there was no change in striatal somatostatin or vasoactive intestinal polypeptide concentration, indicating that the effect was not a generalised one. Levels of all three of these neuropeptides were unchanged in frontal cortex. These findings support the concept of a dopaminergic-enkephalinergic functional interrelationship in the striatum. In addition, the findings provide evidence that, following destruction of nigrostriatal dopaminergic neurons, not only is there a gradually developing postsynaptic dopamine receptor supersensitivity but also a compensatory alteration in the enkephalinergic system.
Animals↗
Classical conditioning, decay and extinction of cocaine-induced hyperactivity and stereotypy.
Following 10 daily pairings of multiple conditioned stimuli with injection of cocaine (15 mg/kg), the presentation of the stimuli alone elicited behaviors in rats similar to those induced by cocaine. The behaviors included increased duration or frequency of rearing, sniffing, head bobbing, and horizontal locomotor activity (crossing). The level of the conditioned response for several of these behaviors approximated that induced by the drug itself. The conditioned drug effect showed decay over 15 days but little extinction during 4 daily trials. Brain concentrations of the dopamine metabolites, homovanillic acid and dihydroxyphenylacetic acid, were similar in the conditioned and pseudoconditioned control groups in both the caudate and mesolimbic areas. The behavioral results demonstrate that, in a classical conditioning paradigm, previously neutral stimuli can elicit behaviors similar to those induced by cocaine and that certain conditioned responses show time related decline. This agrees with the reported conditioning of amphetamine's behavioral effects but differs in terms of the action on brain dopamine turnover.
3,4-Dihydroxyphenylacetic Acid↗
Oral physostigmine and lecithin improve memory in Alzheimer disease.
Eight patients with early Alzheimer disease were treated with gradually increasing multiple daily doses of oral physostigmine and supplemental lecithin. Six individuals showed improvement in total recall and retrieval from long-term storage (LTR), with a decrease in intrusions (a measure of inaccurate recall). The optimal individual dose was either 2.0 or 2.5 mg of physostigmine for each responding patient. Results of this open trial were subsequently replicated during a double-blind crossover trial comparing physostigmine treatment to placebo. All six patients again demonstrated improvement in total recall and LTR, with a decrease in intrusions. The decrease in intrusions was strongly correlated with increasing inhibition of cholinesterase activity in cerebrospinal fluid, suggesting that the degree of improvement in the patient's memory was related to the amount of physostigmine that reached the brain. Other neurotransmitters and metabolites in cerebrospinal fluid were unaffected by the physostigmine therapy, suggesting a specific effect of physostigmine on the cholinergic system. The results suggest that small oral doses of physostigmine combined with lecithin ingestion have therapeutic benefit for some patients with Alzheimer disease.
Aged↗
Excretion of amines and their metabolites by two patients in hepatic coma treated with L-dopa.
Two patients in hepatic coma were treated with L-dopa. The first patient showed clear clinical improvement, but the second patient did not. Analyses of urinary metabolites indicated that L-dopa was not absorbed by the second patient. There was evidence that L-dopa had the following beneficial effects in the first patient: (1) increased production of urine, which could have been accompanied by increased excretion of toxins; (2) displacement of tyramine from transmitter sites (because increased excretion of p-hydroxyphenylacetic acid, a major metabolite of tyramine, occurred during L-dopa treatment in patient 1); (3) replenishment of dopamine, and to a much lesser extent, norepinephrine, at central or peripheral neuroeffector junctions; and (4) scavenging of methyl groups by L-dopa, because ratio of methylated amines to catecholamines was higher than normal in both comatose patients before L-dopa treatment, and this ratio decreased during L-dopa treatment in patient 1.
Dopamine↗
Narcolepsy and hypersomnia.
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Disorders of Excessive Somnolence↗
Decreased ventricular fluid norepinephrine metabolite in childhood-onset dystonia.
3-methoxy-4-hydroxyphenylglycol (MHPG), the primary brain metabolite of norepinephrine (NE), was measured in ventricular fluid from 51 patients with dystonia, other movement disorders, or hydrocephalus. The dystonic patients were divided into three categories: childhood-onset form with early limb dystonia and rapid progression to generalized symptoms, more localized and benign adult-onset dystonia, and symptomatic dystonia. Patients with the childhood form had significantly lower ventricular fluid MHPG levels (8.7 +/- 0.6 ng per milliliter) than other dystonic patients (11.4 +/- 1 ng per milliliter), age-matched controls with neurologic disease (11.7 +/- 1.1 ng per milliliter), or other movement disorders (11.8 +/- 0.7 ng per milliliter). Decreased ventricular fluid MHPG levels suggest a possible abnormality of brain NE function in childhood dystonia.
Adolescent↗