Deficiency hypothesis

The transmethylation hypothesis depended on the psychosis of mescaline as an example of how methylated compounds similar in structure to the monoamine neurotransmitters could be psychotogenic, and demonstrated how methionine, the precursor of the methyl donor S-adenosylmethionine, could exacerbate the psychotic symptoms of schizophrenia in patients. This theory was fed by studies of the now notorious pink spot, an amine found in paper chromatography of urine extracts from schizophrenics and thought to be 3,4-dimethoxyphenylethylamine (i.e., O-methylated dopamine). Subsequent studies eventually identified this as another compound or compounds, primarily of dietary origin. Another methylated derivative erroneously proposed to be found in higher quantities in schizophrenia was dimethyltryptamine. This compound is similar in structure to LSD, the hallucinogenic nature of which was the key to the serotonin deficiency hypothesis, which proposed that the known antagonism of serotonin (5-HT) by LSD indicated that psychotic disorders such as schizophrenia may result from a hypofunction of 5-HT. 

The 1960 s and 1970 s saw several other hypotheses proposed and dis-proven. The monoamine oxidase (MAO) deficiency hypothesis was based on the observation of diminished activity of platelet MAO-B in schizophrenia, although this was likely to be an artifact of drug treatment and the small deficits could not, in any case, account for changes in monoamine transmitters. Other hypotheses relating to, among other transmitter molecules, noradrenaline and enkephalin/endorphin have also been proposed. Each of these have had propo-... 

Borbely AA The S-deficiency hypothesis of depression and the two-process model of sleep regulation. Pharmacopsychiatry 20 23-29, 1987 Borbely AA, Wirz-Justice A Sleep, sleep deprivation and depression. Human Neurobiology 1 205-210, 1982... 

In keeping with the S deficiency hypothesis of depression, different manipulations of adenosine transmission in the basal forebrain show that favoring A i adenosiner-gic transmission promotes SWS, while decreasing it, for instance with agents that block Ai receptors such as caffeine, inhibits SWS and increases wakefulness [88], However, straight indications of a decrease adenosine transmission in depressive disorders are not found in the literature. A blunted platelet A2A receptor function was described in depressed patients [105], as well as a decreased serum activity of adenosine deaminase [106],... 

With respect to the correlation between liver disorders and the functions of the brain, discussion currently focuses on five hypotheses concerning the development of hepatic encephalopathy (7.) intoxication hypothesis, (2.) neurotransmitter hypothesis, (2.) deficiency hypothesis, (4.) synergistic neurotoxicity, and (J.) hypothesis of primary gliopathy. 

Deficiency hypothesis Substances which are essential to the smooth functioning of the central nervous system are not provided, or are only inadequately provided, by a seriously damaged liver. This hypothesis relates to the branched-chain amino acids as well as cellular deficits of zinc, potassium, magnesium and unsaturated fatty acids. 

It was appreciated later that zinc might be fundamental to the pathogenesis of this rare inherited disorder and that the clinical improvement reflected improvement in zinc status. Support for zinc deficiency hypothesis came from the observation that a close resemblance between the symptoms of zinc deficiency in animals and man as reported earlier (85) and... 

The dopamine deficiency hypothesis of Parkinson s disease led to new treatment approaches involving the administration of L-dopa, a precursor of dopamine. L-dopa was administered to patients in hopes of correcting the dopamine deficiency and proved to be dramatically effective in relieving the symptoms of this disease. Dopamine itself is not effective because it does not enter the brain from the bloodstream. The brain is protected from toxic compounds that might enter... 

Bin QH, Garfinkel D. The cadmium toxicity hypothesis of aging A possible explanation for the zinc deficiency hypothesis of aging. Med Hypotheses 1994 42 380-4. 

Ferguson, FI. B., Pappas, B. A., Trites, R. L., Peters, D. A., and Taub, FI., Plasma free and total tryptophan, blood serotonin, and the hyperactivity syndrome No evidence for the serotonin deficiency hypothesis, Biol. Psychiatr., 16(3), 231, 1981. 

The 5-HT precursors Trp and 5-HTP have been explored most extensively by proponents of the 5-HT deficiency hypothesis, in efforts to increase brain 5-HT levels.65 The earliest trials of Trp in depression found it to potentiate the beneficial effects of MAO inhibitors.66,67 Ensuing reports have claimed that D,L-Trp is as effective as electroconvulsive shock ther-apy68 or imipramine69 and it has been successfully used "as a last resort". In other studies, however, L-Trp has been less impressive.71... 

Since equatorial attack is roughly antiperiplanar to two C-C bonds of the cyclic ketone, an extended hypothesis of antiperiplanar attack was proposed39. Since the incipient bond is intrinsically electron deficient, the attack of a nucleophile occurs anti to the best electron-donor bond, with the electron-donor order C—S > C —H > C —C > C—N > C—O. The transition state-stabilizing donor- acceptor interactions are assumed to be more important for the stereochemical outcome of nucleophilic addition reactions than the torsional and steric effects suggested by Felkin. 

The original monoamine hypothesis of depression states that depressions are associated with a deficiency of catecholamines, particularly norepinephrine, at functionally important adrenergic receptor sites in the brain. Elation conversely may be associated with an excess of such amines. The hypothesis was articulated in 1966 only after the mechanism of action of the tricyclic antidepressant desipramine and of the psychostimulants... 

One deficiency in both hypotheses is a mechanistic explanation of injury. With respect to Pegg and Diaper s hypothesis, why should cells that start at a given... 

Our results do not support the protein stress model. However, this model may apply in cases where stress is intermittent and results in tissue loss, as observed in the study of crows (Hobson and Clark 1992). Low protein levels throughout life after weaning may have produced overall slow and reduced rate of growth rather than tissue loss. Adult rats fed protein-deficient diets after maturation show systematic losses of nitrogen from most tissues that are in proportion to their turnover rates and masses (Uezu et al. 1983). Perhaps tissue nitrogen isotope enrichment may occur under these conditions. New experiments are needed to evaluate this hypothesis. 

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