NIAAA Publications

Neurons, Receptors, Neurotransmitters, and Alcohol David M. Lovinger, Ph.D.

David M. Lovinger, PH.D., is chief of the Laboratory for Integrative Neuroscience at the National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.

Nerve cells (i.e., neurons) communicate via a combination of electrical and chemical signals. Within the neuron, electrical signals driven by charged particles allow rapid conduction from one end of the cell to the other. Communication between neurons occurs at tiny gaps called synapses, where specialized parts of the two cells (i.e., the presynaptic and postsynaptic neurons) come within nanometers of one another to allow for chemical transmission. The presynaptic neuron releases a chemical (i.e., a neurotransmitter) that is received by the postsynaptic neurons specialized proteins called neurotransmitter receptors. The neurotransmitter molecules bind to the receptor proteins and alter postsynaptic neuronal function. Two types of neurotransmitter receptors existligand-gated ion channels, which permit rapid ion flow directly across the outer cell membrane, and G-proteincoupled receptors, which set into motion chemical signaling events within the cell. Hundreds of molecules are known to act as neurotransmitters in the brain. Neuronal development and function also are affected by peptides known as neurotrophins and by steroid hormones. This article reviews the chemical nature, neuronal actions, receptor subtypes, and therapeutic roles of several transmitters, neurotrophins, and hormones. It focuses on neurotransmitters with important roles in acute and chronic alcohol effects on the brain, such as those that contribute to intoxication, tolerance, dependence, and neurotoxicity, as well as maintained alcohol drinking and addiction. KEY WORDS: Alcohol and other drug effects and consequences; brain; neurons; neuronal signaling; synaptic transmission; neurotransmitter receptors; neurotrophins; steroid hormones; -aminobutyric acid (GABA); glutamate; dopamine; adenosine; serotonin; opioids; endocannabinoids

The behavioral effects of alcohol are produced through its actions on the central nervous system (CNS) and, in particular, the brain. Synaptic transmissionthe process by which neurons in the CNS communicate with one anotheris a particular target for alcohol actions that alter behavior. Intoxication is thought to result from changes in neuronal communication taking place while alcohol is present in the brain. Tolerance to alcohol involves cellular and molecular adaptations that begin during alcohol exposure; the adaptations develop and diversify with repeated episodes of exposure and withdrawal and are linked to the environment present during exposure. Alcohol dependence develops after several exposure/withdrawal cycles and involves neuroadaptive changes brought about by both the exposure and withdrawal processes. Neurotoxicity produced by alcohol ingestion involves a number of cellular and molecular processes, and neurotransmitters can participate inand modulatemany of these mechanisms. The actions of alcohol on synaptic transmission also contribute to alcohol-seeking behavior, excessive drinking, and alcoholism. Thus, understanding all of these behavioral actions of alcohol requires some knowledge of neuronal signaling in the brain and, especially, the process of synaptic transmission. This article will focus on the basic processes underlying neuronal communication and review the neuronal actions of several neurotransmitters, neurotrophic factors, and hormones thought to be involved in the neural actions of alcohol. This information, although admittedly incomplete, will provide a foundation for the detailed information on alcohol actions provided in subsequent articles in this issue and in Part 2.

Neurons are the cells within the brain that are responsible for rapid communication of information. Although similar to other cells in the body, neurons are specialized in ways that set them apart from other cells and endow them with the properties that allow them to carry out their unique role in the nervous system. The neurons shape is one such unique feature. In addition to the cell body, or soma, which is much like that of other cells, neurons have specialized thin branches know as dendrites and axons. Neurons receive chemical input from other neurons through dendrites and communicate information to other cells through axons. Neurons also are excitable cells. The neuronal surface membrane contains an abundance of proteins known as ion channels that allow small charged atoms to pass through from one side of the membrane to the other. Some of these channels are opened when the voltage across the cell membrane changes. One subtype of these voltage-gated channels allows the neuron to produce a rapid signal known as the action potential, which is the fastest form of intracellular electrical signal conduction in biology (see figure 1).

Individual neurons usually are completely separated from one another by their outer cell membranes and thus cannot directly share electrical or chemical signals. The exception to this situation is the so-called electrical synapse, in which ion-conducting pores made from proteins called connexins connect the intracellular compartments of adjacent neurons, allowing direct ion flow from cell to cell (Kandel et al. 2000). This form of interneuronal communication is much less common in the mammalian CNS than chemical transmission and will not be discussed any further. Rather, the focus will be on chemical interneuronal communication involving the release of a neurotransmitter from one neuron, which alters the activity of the receiving neuron. This chemical communication usually occurs at a specialized structure called a synapse, where parts of the two cells are brought within 20 to 50 nanometers of one another (see figure 2). The neuron that releases the chemical is called the presynaptic neuron. A specialized structure at the tip of the axon of the presynaptic neuron, termed the axon terminal, contains small packets known as vesicles, which are filled with neurotransmitter molecules. When an action potential reaches the axon terminal and stimulates a rise in the concentration of calcium, this ion stimulates the vesicle to fuse with the cell membrane and release the neurotransmitter into the small synaptic gap between cells.

The neuron that is acted upon by the chemical is termed the postsynaptic neuron. The neurotransmitter molecules released from the presynaptic vesicles traverse the synaptic gap and bind to proteins, termed neurotransmitter receptors, on the surface membrane of the postsynaptic neuron.

Figure 1. Schematic drawing of a neuron showing dendrites, where neurons receive chemical input from other neurons; soma (cell body); and axon terminal, where neurons communicate information to other cells. Voltage-gated sodium channels in the membrane of the soma, axon, and axon terminal allow positively charged sodium ions to enter the neuron and produce rapid (in milliseconds) conduction of the excitatory action potential to the terminal. This signal stimulates neurotransmitter release at the axon terminal.

Neurotransmitter receptors are divided into two major classes: ligand-gated ion channel (LGIC) receptors and G-proteincoupled receptors (GPCRs). LGIC receptors are proteins specialized for rapid transduction of the neurotransmitter chemical signal directly into an electrical response (Brunton et al. 2005; Kandel et al. 2000) (see figure 3A). One part of the protein is specialized to bind the neurotransmitter molecule. This binding site is on the extracellular side of the protein. The part of the protein that is buried within the cell surface membrane forms an ion pore, which is basically a fluid-filled hole in the membrane through which the Figure 1 Schematic drawing of a neuron showing dendrites, where neurons receive chemical input from other neurons; soma (cell body); and axon terminal, where neurons communicate information to other cells. Voltage-gated sodium channels in the membrane of the soma, axon, and axon terminal allow positively charged sodium ions to enter the neuron and produce rapid (in milliseconds) conduction of the excitatory action potential to the terminal. This signal stimulates neurotransmitter release at the axon terminal. charged ions can pass (ions cannot pass through lipids or other solid membrane constituents). The time between neurotransmitter binding and opening of the ion pore is on the order of microseconds to milliseconds. Thus, at synapses using ligand-gated channels, the time between action potential depolarization1 (1For a definition of this and other technical terms, see the Glossary, pp. 279283.) of the axon terminal and the beginning of the current flowing through the postsynaptic LGIC is a matter of 1 to 2 milliseconds. This type of synaptic transmission produces a rapid and strong influence on postsynaptic neuron function.

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