Neurotransmitter hypothesis

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. 

The major controversy in nutritional support of the patient with liver failure has centered around the use of protein products. Modified amino acid solutions for PN (HepatAmine, others) are marketed for patients with liver failure and hepatic encephalopathy. They are enriched with BCAAs and have reduced amounts of AAAs and methionine. The products are formulated on the basis of the false neurotransmitter hypothesis, which concludes that hepatic encephalopathy may be due to increased AAA concentrations in the central nervous system. 

For a large number of dmgs, including neurotransmitters, peptide and protein hormones (qv), and thein analogues and antagonists, the ceU membrane is the principal locus of action. Concepts of ceU membrane stmcture are derived from the original Davson-DanieUi Hpid bilayer hypothesis. 

Sihra, TS and Nichols, RA (1993) Mechanisms in the regulation of neurotransmitter release from brain nerve terminals current hypothesis. Neurochem. Res. 18 37-58. 

In view of the apparent pleasurable effects of MDMA, it becomes of considerable interest to understand the mechanism of action of substances with a similar effect. Major efforts have been directed toward the study of agents that have an effect on serotonin pathways, since that is the neurotransmitter system that seems most implicated in the mechanism of action of MDMA. This hypothesis is further reinforced by the observation that MDMA substitutes for fenfluramine (Schechter 1986). and fenfluramine substitutes for MBDB (Oberlender and Nichols, unpublished). The substitution data for (+)-amphetamine and cocaine in (-t-)-MBDB-trained rats are also similar to the data for substitution of these agents in fenfluramine-trained rats (White and Appel 1981). 

The neurotransmitter receptor hypothesis suggests that depression is related to abnormal functioning of neurotransmitter receptors. In this model, antidepressants presumably exert therapeutic effects by altering receptor sensitivity. In fact,... 

After neurotransmitter molecules have influenced the firing of a receiving neuron (more technically called a postsynaptic neuron), some of them are destroyed by enzymes in the synaptic cleft (the synapse), some are reabsorbed by the sending presynaptic neuron in a process that is called reuptake , and the rest remain in the space between the two neurons. The chemical-imbalance hypothesis is that there is not enough serotonin, norepinephrine and/or dopamine in the synapses of the brain. This is more specifically termed the monoamine theory of depression, because both serotonin and norepinephrine belong to the class of neurotransmitters called monoamines. 

When the chemical-imbalance theory was introduced more than 40 years ago, the main evidence in favour of it was the contention that antidepressants, which were thought to increase the availability of serotonin and/or other neurotransmitters in the brain, seemed to be effective in the treatment of depression. As Alec Coppen wrote in 1967, one of the most cogent reasons for believing that there is a biochemical basis for depression or mania is the astonishing success of physical methods of treatment of these conditions. 26 The situation has not changed very much since then. People still cite the supposed effectiveness of antidepressants as fundamental support for the chemical-imbalance hypothesis. This theory, they say, is supported by the indisputable therapeutic efficacy of these drugs .27... 

The astrocyte-neuron lactate shuttle hypothesis is controversial. In recent years the possibility that lactate, formed within the brain and released by astrocytes, is an important neuronal substrate both for energy and incorporation into neurotransmitters has been the subject of many studies and considerable controversy. There is evidence that suggests transient release of lactate in human brain on stimulation [48,8,88], Little is known about the highly active metabolism that takes place in the many elaborate, lamellar distal processes of astrocytes dispersed through the neuropil and interacting with an estimated >100,000 synapses [82, and references therein]. However, it is well established that astrocytes do respond to neuronal activity [89], For example, in the isolated mouse optic nerve preparation, upon stimulation, astrocytic glycogen... 

Biogenic amine hypothesis. Depression may be caused by decreased brain levels of the neurotransmitters norepinephrine (NE), serotonin (5-HT), and dopamine (DA). 

Dysregulation hypothesis. This theory emphasizes a failure of homeostatic regulation of neurotransmitter systems, rather than absolute increases or decreases in their activities. Effective antidepressants are theorized to restore efficient regulation to these systems. 

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