Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

"Dale's Principle" states that each neuron releases one and only one synaptic transmitter. Mental disorders and behavioral drug effects are attributed to activation or blockade of one or more of these specific transmitters. A series of biochemical, electrophysiological, and behavioral studies suggests the alternative view that at each monoaminergic synapse the action of the transmitter is modulated by several metabolically related substances: amine analogs (2-phenylethylamine [PEA], p-tyramine, etc.), deaminated products (aldehydes, acids, and alcohols), and possibly also amino acid precursors. In support of this view, the authors present evidence for the presence, synthesis, metabolism, and biological activity (at the cellular level, using microelectrode techniques) of amino acid, amines, and deaminated compounds metabolically related to catecholamines and sorotonin. That neuroamino acids exert direct effects (not mediated via their amine metabolites) is illustrated by the rapid effects of microiontophoretic dopa upon cortical unit activity, and by the observation that neither the lethargic effect of 5-hydroxytryptophan (considered to support Jouvet's serotonergic theory of sleep) nor the behavioral stimulant effects of dopa (considered to support the catecholamine theory of affective behavior) are significantly prevented by L-aromatic amino acid decarboxylase inhibitors. The biological activity of the deaminated metabolites of catecholamines and serotonin is illustrated by the effects of their microiontophoretic administration upon cortical units. Further, probenecid (an inhibitor of acid transport across the blood-brain barrier) is shown to qualitatively alter the effects of intraventricularly administered PEA and of its metabolite phenylacetic acid upon visual evoked potentials. Rabbit brain is shown to synthesize a series of pharmacologically active noncatecholic phenylethylamines as by-products of catecholamine metabolism. Amine modulators such as PEA differ from typical transmitters by their ability to cross biological barriers; inhibition of decarboxylase in peripheral tissues only (using alpha-methyldopa hydrazine) markedly depletes brain PEA (but not catecholamines). Because of the homeostatic control of the rate of transmitter synthesis and disposition, physiological, pharmacological, and pathological changes may be expected to affect more the tissue levels of related modulators. This modulator theory of drug action is illustrated by the effect of several psychotropic drugs upon the brain levels of PEA and of norepinephrine. For instance, amphetamine initially decreases and then increases brain PEA levels, without altering brain norepinephrine levels. The authors propose an expanded "Dale's Principle": each neuron is specific in that it releases at all its endings the same pool of chemical messengers, composed of one transmitter and metabolically related modulators, the relative proportion of which is determined by the physiological state of the cell (biochemical plasticity)...
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PMID:Biochemical plasticity of synaptic transmission: a critical review of Dale's Principle. 0 60

To better assess the role of hyperammonemia versus hypoosmolarity versus hyponatremia in the TUR syndrome, we developed a rat model. Sprague-Dawley female rats received an intraperitoneal injection (250 cc/kg body weight) of either 1.5% glycine, 2.0% glycine, 2.0% glycine plus 1.5% mannitol, 3.0% mannitol, 5.0% mannitol, or 2.0% glycine plus 0.25% saline. Arterial blood samples were obtained prior to injection, at 2, 8, 16, and 24 hr and analyzed for osmolarity, sodium, and ammonia. Those animals receiving 2.0% glycine, 2.0% glycine plus 1.5% mannitol, and 5.0% mannitol all died within 24 hr with lethargy, convulsions, and coma. Hyponatremia developed in all animals; death, however, occurred only when the sodium concentration declined to 90-95 meq/dl. Mannitol maintained serum osmolarity but did not prevent coma and death. Including 0.25% saline in the initial injection, or an iv injection of 5.0% saline delayed 8 hr achieved 100% survival. Ammonia concentrations increased 15-fold by 8 hr in groups receiving 2.0% glycine; it rapidly decreased to near normal by 24 hr. Decreasing the rise in ammonia by 50% with iv arginine had no effect on survival. Our results suggest that hyponatremia rather than hyperammonemia or hypoosmolarity accounts for the major morbidity and mortality secondary to the TUR syndrome.
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PMID:The physiologic basis of the TUR syndrome. 291 15

Ozone, a lower-airway irritant, produces fatigue, lethargy, and increased respiratory rates in several species, including man. Ammonia, an upper-airway irritant, produces burning of the eyes, nose, and throat, and a decrease in respiratory rate. The effects of exposure to these two prototypical irritants were examined to see if behavioral changes during and after exposure occurred at concentrations comparable to those that produce symptoms in humans. Long-Evans rats and Swiss mice, individually housed in running wheels, were exposed either to ozone (0.08, 0.12, 0.25, or 0.5 ppm) or to ammonia (100 or 300 ppm) for 6 hr. Each animal's behavior was compared with its own control performance. Running in both species decreased in a concentration-related manner during exposure to either irritant. The decrease in running activity produced by high concentrations of ozone persisted for several hours after exposure. Concentrations of ammonia that eliminated running during exposure led to an increase in activity following exposure. At comparable concentrations of both compounds, activity in rats decreased more than in mice.
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PMID:Alterations in behavior produced by inhaled ozone or ammonia. 409 73

Stuporous states induced by sodium valproate (VPA) are accompanied by an isolated marked hyperammonemia. In reality, hyperammonemia occurs after administration of VPA even in the absence of neurological complications. The hyperammonemia is of purely renal origin and results from modifications in glutamine metabolism, this compound being the main precursor of amino acid neurotransmitters. Combined administration of VPA and phenobarbitone increases the level of hyperammonemia due to lack of detoxification by the liver of the excess of ammonia produced by the kidneys. The anatomical site of origin of the ammoniogenesis, and its intensity, were studied in two patients with a history of stuporous states during combined VPA-phenobarbitone treatment. A single injection of VPA at a later date when they were being treated by combined phenobarbitone-carbamazepine therapy, induced disturbances in ammonia metabolism which did not differ qualitatively from those observed when intolerance to VPA is lacking. It is therefore not possible to rely on simple biological tests to detect patients at risk. Correlation is also lacking between the degree of hyperammonemia and disorders of vigilance. Ammonia does not therefore appear to be the only factor responsible for neurological complications and the role of other factors must be investigated. These include: disturbances of metabolism of inhibitory and excitatory aminoacid neurotransmitters, the condition of the cerebral parenchyma, and the excitatory effect of sodium valproate which could act to varying degrees in synergy with the hyperammonemia to provoke a stuporous state.
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PMID:[Role of hyperammonemia in stuporous states induced by sodium valproate]. 642 Aug 66

Ammonia, normally produced from catabolism of amino acids, is a deadly neurotoxin. As such, the concentration of free ammonia in the blood is very tightly regulated and is exceeded by two orders of magnitude by its physiologic derivative, urea. The normal capacity for urea production far exceeds the rate of free ammonia production by protein catabolism under normal circumstances, such that any increase in free blood ammonia concentration is a reflection of either biochemical or pharmacologic impairment of urea cycle function or fairly extensive hepatic damage. Clinical signs of hyperammonemia occur at concentrations > 60 micromol/L and include anorexia, irritability, lethargy, vomiting, somnolence, disorientation, asterixis, cerebral edema, coma, and death; appearance of these findings is generally proportional to free ammonia concentration, is progressive, and is independent of the primary etiology. Causes of hyperammonemia include genetic defects in the urea cycle ("primary") or organic acidemias ("secondary"), as well as genetic or acquired disorders resulting in significant hepatic dysfunction. Thus, because of the neurotoxic implications of hyperammonemia and the typical absence of other specific laboratory abnormalities, appearance of the clinical signs should trigger an emergent search for elevated blood ammonia concentration.
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PMID:Hyperammonemia, bane of the brain. 1549 74

The urea cycle is the major metabolic pathway for excretion of waste nitrogen. Ornithine transcarbamylase deficiency is the most frequent urea cycle disorder. It is a hereditary-X-linked disease with over 150 mutations described. Ornithine transcarbamylase deficiency causes vomiting, lethargy, hyperventilation, and even death, mainly in the neonatal period. Ammonia, an extremely toxic molecule for the organism, is generated during protein catabolism and is accumulated in patients with this deficiency. Part of the treatment consists of a low-protein diet, to avoid hyperammonemia episodes, which can even have a fatal outcome. Patients can become deficient in several amino acids, either through the low-protein diet or directly through the primary enzyme deficiency; this in turn can cause an acrodermatitis enteropathica-like dermatosis.
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PMID:Acrodermatitis enteropathica-like dermatosis associated with ornithine transcarbamylase deficiency. 1784 64