The processes of alcohol tolerance and dependence - Special Focus: Alcohol and the Brain

Alcohol Health & Research World, Spring, 1990 by R. Adron Harris, Karl J. Buck

Adaptation of the neuronal membrane may reflect changes in membrane composition resulting from alcohol exposure. Changes in membrane phospholipids seen after chronic alcohol exposure are of particular interest, because phospholipids are critical to the normal functioning of cells and serve as reservoirs for substances that mediate chemical signaling between and within neurons.

Ion Channels

The excitability and function of nerve cells are controlled by ion channels embedded in the cell membrane. For example, calcium channels allow calcium to enter nerve cells; this, in turn, triggers the release of neurotransmitters, which are responsible for synaptic communication between nerve cells. High concentrations of alcohol inhibit the activity of calcium channels that open in response to neuronal electrical impulses (voltage-sensitive calcium channels, or VSCCs). Inhibition of calcium channel activity could decrease neurotransmitter release and inhibit neuronal communication. However, after chronic alcohol administration, calcium ch annels become resistant to the inhibitory actions of alcohol (Daniell and Leslie 1986; Harris and Hood 1980).

Tolerance to alcohol's effects on VSCCs may result from increases in calcium channel number and function during chronic exposure to alcohol (Dolin and Little 1989; Littleton and Lynch 1983). Treatment with calcium channel antagonists (e.g., nitrendipine) during alcohol administration prevents the number of neuronal calcium channels from increasing (Dolin and Little 1989). Calcium channel antagonists also prevent the development of tolerance to the anesthetic and incoordinating effects of alcohol and delay the acquisition of tolerance to alcohol (Wu et al. 1987).

Another important ion channel complex is the GABA receptor/chloride channel complex. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the mammalian brain. GABA is the brake that prevents the brain from racing into seizures. It acts by allowing chloride ions to enter the cell, thereby reducing neuronal excitability. Low concentrations of alcohol enhance the function of GABA-activated channels. The behavioral consequences of this can be demonstrated by motor incoordination in mice and sedation in humans. Tolerance develops very rapidly to the acute effects of alcohol on GABA action and persists following chronic alcohol exposure (Allan and Harris 1989).

Studies using drugs that affect the GABA receptor/chloride channel complex suggest that adaptation of GABA-activated channels appears to be involved in some aspects of alcohol dependence and tolerance, such as incoordination, but not in others, such as temperature regulation (Buck et al. in press; Allan and Harris 1987).

Whereas GABA is the major inhibitory neurotransmitter in the brain, the major excitatory neurotransmitter in the brain is the amino acid glutamate, which acts on several types of receptors. Of particular interest is the NMDA receptor, so called because it responds to the chemical N-methyl-D-aspartate (NMDA) in addition to glutamate. Activation of this receptor opens ion channels and excites cells by increasing intracellular calcium. Alcohol inhibits the NMDA-stimulated flow of ions through this channel (Lovinger et al. 1989). Chronic exposure to alcohol results in a compensatory increase in the number of NMDA-activated ion channels in the brain, a process known as upregulation. This results in the neuronal hyperexcitability and seizures that accompany withdrawal, a major factor in physical dependence (Grant et al. 1990).