Alcohol, Chemistry and
In particular the affiniity of ethanol for water and fat, based on its hydrogen bonding ability and alkyl group,altered the "fluidity" of the membrane. This in turn changed the ability of constituents of the membranes such as proteins to function and interact. These modifications influenced cellular function in the brain and body and led to the various manifestations of alcohol action.
The ability of ethanol to diffuse throughout the water contained in the brain suggested that there were probably multiple sites of ethanol action. Because of the chemical nature of ethanol, it was hard to believe that ethanol acted in a specific manner. For example, as late as 1983, the prominent alcohol researcher, Dr. Dora Goldstein, stated in her book that " in studying ethanol, we use many kinds of pharmacology, but receptor pharmacology, the study of specific interactions of small molecules with big ones, is hardly to be found here" (Goldstein, 1983). Thus, it was thought that ethanol acted rather globally to produce its effects rather than having specific sites of action. In particular, Drs. Goldstein, Chin, Seeman, and others tested the hypothesis that ethanol produced it effects by acting on the membranes surrounding the various cells in the body (e. g. Chin and Goldstein, 1977; Seeman, 1974).
The membranes which comprise the outer covering of all animal cells, including nerve cells, is made up of a double layer of fatty lipid molecules called a lipid bilayer. The lipid bilayer separates the inside (intracellular compartment) from the outside (extracellular compartment) of the cell, thus regulating the flow of ions and other chemicals from the outside to the inside and visa versa. In addition the cell membrane separates one cell from the next. However, because of structure and constituents of the cell membrane, chemical and electrical communication between the cells is possible.
Contained within the cell membrane are a variety of specialized proteins some of which serve to receive information in the form of chemicals or neurotransmitters from other cells. The neurotransmitters bind to specific proteins in the cell membrane (e.g. ligand-gated ion channels), which then regulate the flow of ions into and out of the neuron and/or produce an intracellular signal. These actions then produce a cascade of events within the cell, which may manifest in the generation of an electrical signal being propagated in the neuron. Other proteins, which form channels in the cell membrane and respond to the electrical impulses or electrical potential (voltage-gated ion channels), allow the flow of ions into or out of the cell. For both ligand-gated and voltage-gated ion channels the state of the membrane can influence the function of the protein and thus the cellular response. Therefore, it can be seen that chemicals, which can influence the cell membrane (lipid bilayer), can alter the function of the proteins within the membrane.
In about 1900 both E. Overton and H.H. Meyer (1937) demonstrated that the potencies of anesthetic drugs were directly proportional to their lipid solubilities. This is true for the alcohols also. Later Mullins (1954) pointed out that better correlations with potency could be had if molecular volumes were taken into account, i.e. the amount of space taken up by the compound within the membrane. If a compound were taking up space within a membrane, then it would be expected that the volume of the membrane should be greater with the compound than without. Seeman (1974) was able to demonstrate this with the effect of ethanol on blood cell membranes (erythrocytes). Higher concentrations of ethanol would be expected to occupy more space than lower concentrations and have a greater effect. Thus, one would expect a dose/response effect, which was observed.
A general membrane model for understanding the possible effects of ethanol on the cell membrane is that given by Singer and Nicolson (1972) and called the fluid mosaic model. The model generally proposes that there is a phospholipid bilayer containing cholesterol and proteins. The polar phospholipids have charged, hydrophilic head groups, which orient toward the aqueous phases, at the interface of the membrane with the intracellular fluid or at the interface with the extracellular fluid. The long acyl chains of the phospholipid fatty acids are strongly hydrophobic, thus avoid the aqueous phases and orient at the center of the membrane. Cholesterol is scattered throughout the membrane and also orients in the membrane as a function of hydrophobicity. Proteins are also distributed throughout the membrane with some loosely attached on the surface of the membrane, some embedded in the membrane, and others penetrating through to the inside of the cell.
The cell membrane can be conceptualized as a fluid structure in which proteins can move about dependent upon the fluidity of the lipids. In a fluid membrane one protein can change place with another or move to attach to another, thus facilitating function. Clearly the amount of "fluidity" of the membrane influences the function. Diminishing the fluidity decreases the ability of the proteins to move and interact, while enhancing the fluidity may lead to a disordered mess. Ethanol was shown to "fluidize" the membrane thus perhaps providing a basis for altered protein function. Interestingly, chronic exposure of mice to ethanol reduced the ability of ethanol to fluidize the membrane and therefore the data suggested a mechanism underlying tolerance (Chin and Goldstein, 1977).
It should also be recognized that at lower temperatures lipid membranes become gels rather than staying in the fluid state. The temperature at which they transition from fluid to a gel state is called the lipid phase transition temperature. Ethanol was also demonstrated to reduce the temperature of liquid phase transitions, also providing a possible basis for altered neuronal function.
These early studies, thought important and interesting, made it difficult to explain more specific behavioral effects of ethanol on the basis of altered cellular membranes. Further, ethanols effects on membranes when found were considered small and required concentrations of ethanol that were larger than those needed for behavioral manifestations. Thus, the finding of action of ethanol on specific receptor subtypes came somewhat as a surprise as well as a relief to the scientific community who was seeking for more precision in understanding the molecular basis of ethanol action.
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