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CHAPTER

4

ACTIONS OF ALCOHOL ON THE BRAIN

Introduction

A

dvances in neuroscience research have been critical to understanding alcohol abuse, tolerance (changes in the brain's sensitivity to alcohol), and physical dependence (the occurrence of physical withdrawal symptoms after abrupt cessation of alcohol intake). Neuroscience research also has provided insight into the mechanisms by which alcohol interacts with both the central and peripheral nervous systems to produce its intoxicating, neurotoxic, and behavioral effects. Such advances have been possible largely through the use of animals and animal tissue and the development of sophisticated techniques for the study of the neural function of groups of cells, single cells, and single molecules. Studies of human behavior and physiology and studies of the neurological effects of alcohol use in humans have also been of value. Following is a brief overview of scientific techniques used to generate information relevant to alcohol's neural effects.

The ability to maintain functioning, "living" tissues in culture has provided an exciting avenue of research for the neurosciences. For example, intact brain regions can be maintained in vitro for short periods of time. These preparations allow researchers to study cell communication within the brain and also to examine how alcohol affects such communication. Single cells can be isolated and the function of single molecules within these cells can be probed under normal conditions and in the presence of alcohol. One technique that is highly useful for studying the physiology of single cells is the patch-clamp recording technique, which can in

directly measure changes in electrical activity by enabling researchers to examine individual “ion channel" proteins that produce this electrical activity. Many of the observations of alcohol actions on ion channels discussed later in this chapter were made using this technique.

Neuroscience research... has provided insight into the mechanisms by which alcohol interacts with both the central and peripheral nervous systems to produce its intoxicating, neurotoxic, and behavioral effects.

Other methods also have been critical in defining the structure and function of the brain. For example, information about genetic coding of molecules found only in the nervous system has been useful in determining the normal pattern of expression of such molecules as well as the effects of alcohol on that expression. Thus, techniques that analyze various systems at the cellular and molecular levels have increased our ability to investigate brain function and to study the effects of alcohol on these functions.

To determine the effects of alcohol on the awake human brain, investigators have used such imaging techniques as positron emission tomography (PET) and magnetic resonance imaging (MRI), which examine brain structure and neural activity. Such techniques have been used to study the effects of acute alcohol intake and to examine altered brain structure and function in alcoholic subjects following prolonged abuse.

Glossary of Terms

Agonist-an agent that mimics the action or effects of an

other agent.

Antagonist-an agent that blocks or reverses the action or effects of another agent.

Anxiogenic-anxiety inducing.

Anxiolytic-anxiety reducing.

Depolarization-the process by which the electrical gradient along the cell membrane is altered (i.e., takes on a more positive charge).

Explants-living, functioning tissues that have been removed from an organism and that are maintained in culture outside that organism.

GABA (gamma-aminobutyric acid)-a neurotransmitter that inhibits the transfer of an electrical or chemical signal across the synapse of a nerve cell.

Inverse agonist-an agent whose effects are exactly the opposite of those of the agent to which it is being compared. For example, alcohol has anxiolytic or anxiety-reducing effects, whereas the partial inverse agonist of alcohol, RO 15-4513, not only blocks this effect of alcohol but also produces anxiety and stress when given alone.

Neuron (or neurone)—a nerve cell.

Neurotransmitter-a chemical messenger released by an excited or stimulated nerve cell. After being released, neurotransmitters travel across a synapse and then bind to a receptor on an adjacent nerve cell, usually triggering a series of chemical and electrical changes in the second cell.

Nucleus/nuclei (1) in neuroscience, a cluster, group, or body of nerve cells (e.g., the nucleus accumbens or the septal nuclei); (2) in biology and biochemistry, the primary structure within a cell that contains genetic material (DNA, RNA).

Receptor-a complex structure that recognizes and binds. neurotransmitters or interacts with specific enzymes.

Synapse the site of communication between neurons. Transcription-the process by which a portion of DNA that is coded for a specific protein is converted to messenger RNA (mRNA). This process takes place in the nucleus of the cell.

Translation-the process by which mRNA is converted into a protein or a smaller, protein-like substance known as a polypeptide. This process occurs outside the nucleus at a structure called the ribosome.

Basic Overview of

Neuroscience

Brain Structures and Regions
Involved in Alcohol's Actions

Research that has led to a better understanding of the nervous system also has enhanced our knowledge of alcohol's effects on brain function. For example, information about the function of particular brain regions has helped scientists determine the effects of abnormal function or long-term damage to these regions. In addition, identification of electrical and chemical systems involved in brain function has allowed for the assessment of the role of these systems in alcohol's effects. Further, increased knowledge of brain pathology caused by conditions such as epilepsy and stroke has provided a theoretical framework for studies of alcoholic brain damage.

Different regions in the mammalian brain have different functions. Some of these regions will be discussed briefly here and in more detail later in the chapter. The cerebral cortex surrounds the outside of the brain and controls many of the brain's functions by refining information received from other areas; one of its important functions is complex cognition. Another region, the nucleus accumbens, functions as a "reward center." The hippocampus is important for learning, especially of information that requires constant updating (e.g., spatial information). It communicates with the septal nuclei, which are involved in regulating the brain's "arousal state." The cerebellum is involved primarily in the coordination of movement. The brain stem (pons and medulla) contains discrete nuclei, or clusters of nerve cells, that communicate with the cortex and structures outside the cortex. Of particular importance and relevance are the substantia nigra and the raphe nucleus, which appear to play a role in the addictive effects of drugs of abuse, including alcohol (Samson and Harris 1992).

Neurons Transmit Information in the Brain

Acquisition and transfer of information in the brain is accomplished predominantly by nerve cells, or neurons. Although neurons in the brain and central nervous system come in many different shapes and sizes, most have the same basic structures that receive, integrate, and transmit

electrical and chemical signals. At the head of the typical neuron is the cell body, which contains a nucleus that holds the cell's genetic information. Extending out from the cell body are finger-like projections called dendrites. A long segmented fiber known as the axon also originates from the cell body; in most mammalian neurons, the axon is insulated by a protein-lipid complex known as the myelin sheath. The end of the axon branches out into a fine network of axon terminals.

Chemical and electrical signals from other cells generally are received by the dendrites and then move away from the cell body, passing along the axon to the axon terminals. When these signals reach the axon terminals, chemical messengers known as neurotransmitters are released; these neurotransmitters then cross a small synaptic gap (or cleft), the primary site of communication between neurons, to reach the synapse of an adjacent cell. The most common synaptic gaps are found between an axon and a dendrite. However, information may be transmitted across a synapse between any two parts of the neuron, e.g., between an axon and the cell body; between two dendrites or two axons; or between two cell bodies.

The signal received by the dendrites moves along the axon by inducing changes in the cell membrane. More specifically, after a neuron is activated by a change in voltage or by a neurotransmitter, the cell membrane becomes more permeable to charged atoms (ions) found both inside and outside the cell, such as sodium, chloride, potassium, and calcium. This increased permeability causes ions to cross the cell membrane through pores formed by proteins called ion channels; this process upsets the normal electrical gradient of the "resting" membrane. If the signal is strong enough, it will continue to move along the axon, triggering an increase in the permeability of the next segment of the cell membrane until it reaches the axon terminal. At this point, the signal activates channels that allow calcium ions to cross the cell membrane, causing the spherical vesicles that contain the transmitter to release the transmitter into the synapse. On the opposite side of this gap are dendrites of another neuron. These dendrites contain receptor proteins complex structures that recognize and bind neurotransmitters.

Neurotransmitter receptors influence the electrical activity of nerve cells via different mechanisms. If, for example, the ion channel is part of the receptor protein, then binding the neurotrans

mitter to the receptor directly alters the protein, causing the channel to open. Such receptor-ion channel complexes are referred to as ligandgated or ligand-dependent ion channels, in which the neurotransmitter serves as the ligand. Receptors for the neurotransmitter glutamate fall under this category: activation of glutamate receptors allows positively charged ions to enter neurons and increase the excitability of the neurons. Because of this effect, glutamate is often described as an excitatory neurotransmitter. In contrast, receptors for the neurotransmitter y aminobutyric acid (GABA) form ion channels that allow negatively charged chloride ions to enter the cell (Allan and Harris 1986; Wafford et al. 1990, 1991). This decreases the ability of other signals to excite the neuron. Thus, GABA is referred to as an inhibitory neurotransmitter. Other receptors activate the production of chemical signals and influence neuronal physiology via indirect effects on ion channels or transmitter release. In this case, the binding of a neurotransmitter to its receptor causes a separate ion channel to open or close. Most of these types of receptors are thought to be coupled to G proteins, i.e., proteins that are regulated by binding to the high-energy compound guanosine triphosphate (GTP). Thus, the neurotransmitter binds to a G protein-linked receptor, and the G protein subsequently acts either directly or indirectly, through the production of small nonprotein molecules called second messengers, on a discrete ion channel to cause the channel to open.

Protein Manufacturing Within Neurons

Neuronal function is closely linked to the protein content of the cell. Proteins are manufactured within the neuron via a multistage process that begins in the nucleus of the cell. Here specific sequences of deoxyribonucleic acid (DNA) are "transcribed" into sequences of messenger ribonucleic acid (mRNA). The mRNA is then transported out of the nucleus to the ribosomes, where its sequence is "translated" into specific amino acids that make up proteins. Newly synthesized proteins are then transported to their sites of action. During the process of transport and insertion at sites of action, proteins can be modified by the addition of small molecules such as phosphate, sulfate, or sugars. Once a protein reaches its site of action, it resides there for a definite period of time and then is removed from that site. Thus, proteins in the cell are

constantly "turning over" in cycles that can last from hours to days.

Protein synthesis is regulated at several stages; this regulation, in turn, affects the content and type of protein in the cell. In the nucleus, DNA transcription can be regulated such that mRNA synthesis is altered. Further, mRNA may be spliced, or cut, at different points before exiting the nucleus to produce distinct ribonucleic acid (RNA) molecules, each encoding a different protein. This process, known as alternative RNA splicing, often produces two forms of the same protein that are necessary at different stages of development or in different cell types. Thus, the proteins translated may be functionally similar but have slightly different properties. Finally, the addition of small molecules, mentioned previously, to the synthesized protein may alter insertion of the protein into its site of action or may modify its function.

Alcohol, in turn, appears to alter membrane fluidity and disrupt important membrane-based cellular functions, such as electrical conduction and chemical transmission.

The Cell Membrane-A Lipid
Bilayer Filled With Proteins

The plasma membrane of a typical neuron consists of roughly equivalent amounts of lipids and proteins; an exception is the myelin sheath, which has a lipid:protein ratio of approximately 2:1. The lipid molecules are arranged in a double row with their charged (polar) head groups facing outward and their uncharged (nonpolar) tails facing each other. Interspersed among the lipids are proteins such as channels and receptors. These proteins often span the bilayer and interact with membrane lipids, thus giving the membrane a fluid-like character. The close physical relationship between membrane proteins and lipids suggests that normal functioning of these proteins may depend on the presence of lipids. The chemical nature and structure of the neuronal plasma membrane make it readily permeable to alcohol. Alcohol, in turn, appears to alter membrane fluidity and disrupt important membrane-based cellular functions, such as electrical conduction and chemical transmission.

Actions of Alcohol on the
Central Nervous System

Several alcohol-induced effects on the central
nervous system, many of which were discovered
very recently, are discussed in this section; most
of this discussion focuses on animal research.
Acute effects of alcohol on brain tissue are re-
viewed first; a discussion of the effects of
chronic, long-term alcohol exposure follows. Fi-
nally, alcohol effects on the human brain are con-
sidered. The section on acute actions begins
with a brief review of how alcohol levels influ-
ence behavioral changes during intoxication.
The discussion of acute alcohol effects relates to
the neural effects of alcohol on behavior; see
Chapter 5, Neurobehavioral Aspects of Alcohol
Consumption, for a more detailed analysis of the
behavioral actions of alcohol.

Effects of Alcohol During Acute Exposure

Lipids and proteins as sites for the
actions of alcohol

The molecular site or sites of alcohol's action on neurons are not yet clear. One hypothesis is that alcohol works by perturbing lipids in the cell membrane (Hunt 1985). The development of this hypothesis was based on the fact that the potency of alcohols is closely related to their ability to permeate and then alter membranes. Effects of alcohol on membranes have been demonstrated; however, these effects have not been potent at the low concentrations of alcohol that produce mild to moderate intoxication.

Alternatively, effects of alcohol may be explained by a direct alcohol-protein interaction. For example, it is now known that many proteins contain long regions of uncharged amino acid residues. These "hydrophobic” regions are especially rich in proteins such as neurotransmitter receptors that span the cell membrane. Thus, the relationship between alcohol potency and ability to enter membranes could also result from the interaction between alcohol and the hydrophobic portion of membrane proteins. Another hypothesis is supported by the observation that alcohol interacts directly with a lipid-free enzyme protein and that the potency of this reaction is related to alcohol concentration (Franks and Lieb 1984). The alcohol-specific nature of these reactions is suggested by evidence that other manipulations that disrupt lipid and pro

tein components of the membrane, such as increases in temperature, do not faithfully reproduce the effects of alcohol.

Thus, although it is not clear whether alcohol acts on lipids or on proteins, it is clear that it alters the function of neuron-specific proteins, as discussed below. These proteins may provide target sites for therapies designed to counter alcohol's neural effects.

The behavioral sequelae of alcohol ingestion commonly known as intoxication can be subdivided into different behavioral changes (Kissin 1988; Schuckit 1979). For example, inexperienced drinkers at low blood alcohol concentrations (BACs) (.02 to .05 g/dL, or 1 to 2 drinks containing 1/2 ounce of ethyl alcohol1) generally experience euphoria and have a perceived reduction in anxiety. As the BAC climbs (.06 to .10 g/dL, or 3 to 5 drinks), judgment and motor coordination become impaired; these signs become more severe and may be accompanied by aggressive behavior as the BAC rises. At the upper end of the intermediate range of BACS (i.e., approximately .20 to 25 g/dL, or 10 to 13 drinks), signs of sedation appear. General anesthetic effects and loss of consciousness are observed at approximately .30 g/dL; the ability to learn and remember information becomes severely impaired at this level as well. Respiration is depressed at higher concentrations of blood alcohol (.40 to .50 g/dL), and one can slip into a coma or die from loss of adequate respiration. Thus, acute ethanol ingestion has effects on motivation and emotion, cognition, movement, and, ultimately, respiration and consciousness. To a great extent these behavioral consequences are separable, and perhaps they are attributable to different neural actions of alcohol. The following discussion of the acute actions of alcohol concentrates on the actions of alcohol on identified molecules in the brain and the contribution of these effects to changes in brain physiology. See chapter 5 for further discussion of the influence of alcohol on behavior.

Alcohol potentiation of GABAA receptor function

GABA is the major inhibitory neurotransmitter in the mammalian brain. Several studies suggest that the activity of the neuronal chloride ion channel linked to the A-type GABA receptor

(GABAA) (figure 1) is increased during acute exposure to intoxicating concentrations of alcohol (Aguayo 1990; Allan and Harris 1986; Celentano et al. 1988; Mehta and Ticku 1988; Nakahiro et al. 1991; Nestoros 1980; Suzdak et al. 1986). This receptor is the site of action of sedative/ anesthetic drugs including barbiturates (e.g., pentobarbital) and sedative/anxiolytic benzodiazepines (e.g., diazepam). Alcohol's effects on the GABAA receptor may contribute to alcohol's anxiolytic, sedative, and motor impairment actions (Givens and Breese 1990; Suzdak and Paul 1987). A compound called RO 15-4513, which acts at the same site as benzodiazepines on the GABAA receptor, can counteract alcohol-induced potentiation of GABAA receptor function while having little effect by itself.

Alcohol's effects on the GABA receptor may contribute to alcohol's anxiolytic, sedative, and motor impairment actions.

The action of alcohol at the GABAA receptor differs from that of the benzodiazepines or the barbiturates in that alcohol is less effective at potentiating receptor function (Wafford et al. 1990, 1991). Furthermore, alcohol appears to act only on select subtypes of the receptor, whereas the other drugs are less selective. Recent work suggests that certain portions of the proteins that make up the receptor may be involved in alcohol's actions. The amino acid makeup of the GABAA receptor and the DNA sequence coding for it were discovered in the late 1980s (Schofield et al. 1987). The whole receptor protein complex is formed by a complex of five individual subunit proteins. Each of these proteins is large and appears to span the plasma membrane of the neuron. Several types of GABAA receptor subunits have been identified; they are designated alpha, beta, gamma, or delta subunits (Olsen and Tobin 1990). Each subunit type may exist in one to six forms, and a receptor may be made from any combination of five of these subunits; thus, the number of possible subtypes of the GABAA receptor is large. However, it has been shown that receptors made

1 One-half to six-tenths of an ounce of ethyl alcohol is approximately the equivalent of one 12-ounce beer, one 4-ounce glass of wine, or one shot of 80 proof spirits.

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