Neurochemical mechanisms underlying alcohol withdrawal

Abstract

More than 50 years ago, C.K. Himmelsbach first suggested that physiological mechanisms responsible for maintaining a stable state of equilibrium (i.e., homeostasis) in the patient's body and brain are responsible for drug tolerance and the drug withdrawal syndrome. In the latter case, he suggested that the absence of the drug leaves these same homeostatic mechanisms exposed, leading to the withdrawal syndrome. This theory provides the framework for a majority of neurochemical investigations of the adaptations that occur in alcohol dependence and how these adaptations may precipitate withdrawal. This article examines the Himmelsbach theory and its application to alcohol withdrawal; reviews the animal models being used to study withdrawal; and looks at the postulated neuroadaptations in three systems-the gamma-aminobutyric acid (GABA) neurotransmitter system, the glutamate neurotransmitter system, and the calcium channel system that regulates various processes inside neurons. The role of these neuroadaptations in withdrawal and the clinical implications of this research also are considered.

The seesaw analogy for neuroadaptation applied to conditioning and craving. The top row shows brain neurochemistry in an alcohol-free state. At this time the environment in which alcohol is consumed (i.e., the setting) and the behavior involved in drinking are neutral stimuli; that is, they have no association with drinking and no special impact on the brain. The same is true of the initial use of alcohol (second row), in which the brain’s neurochemistry is unbalanced by alcohol’s actions. If the drug is taken repeatedly in the same setting and in the same way, however, these stimuli become capable of eliciting neuroadaptations similar to those elicited by alcohol itself (third row). Exposure to such conditioned stimuli in the absence of alcohol may thus lead to unopposed neuroadaptation, which potentially may be expressed as a craving for alcohol.

Figure 1

Pictorial representation of the Himmelsbach hypothesis as it applies to alcohol use. The balanced seesaw on the upper left side of the cycle represents brain neurochemistry in an alcohol-free state (i.e., before the brain has been exposed to alcohol). Consuming alcohol initially unbalances brain chemistry to produce the acute effects associated with alcohol use (e.g., sedation and incoordination). The brain then responds to this disruption by inducing an opposing chemical adaptation that tends to restore the neurochemical balance. At this stage, the effects of a given dose of alcohol are diminished (i.e., tolerance exists). If alcohol is removed, the adaptation is exposed, unbalancing the brain’s neurochemistry in the opposite direction. The result is a withdrawal syndrome that includes signs and symptoms (e.g., agitation and seizures) that are opposite to alcohol’s initial effects. These disturbances will continue until the adaptation can be removed from the brain (or until alcohol is consumed again), restoring equilibrium. ¹CNS = central nevous system.

Figure 2

Schematic representation of some of the major neurochemical systems affected by alcohol. Nerve cells (i.e., neurons) convert chemical messages received at the cell body (at left in this simplified neuron) into an electrical signal that is conducted along the axon to the terminal (at right). At the terminal, the electrical signal is converted back into a chemical message (i.e., a neurotransmitter) that is released from the terminal and carries the information to the next neuron in the circuit. Alcohol increases (i.e., potentiates) the effects of the major inhibitory neurotransmitter in the effects tend to inhibit electrical signaling through the neuron. Alcohol further decreases electrical activity by inhibiting the major excitatory neurotransmitter, glutamate, particularly at a glutamate-receptor protein called the N-methyl-d-aspartate (NMDA) receptor. By inhibiting glutamate at the NMDA receptor, alcohol slows the flow of calcium (Ca) into cells. Regulation of the cell’s calcium balance is essential for normal cell function. In addition to its effects at the NMDA receptor, alcohol can alter the flow of calcium through voltage-operated calcium channels (VOCC’s) at the cell body as well as at the terminal, where calcium is necessary for neurotransmitter release.

Figure 3

Effects of alcohol and possible relevance to dependence and withdrawal. (A) The major acute actions of alcohol and their possible relation to the behavioral consequences of drinking alcohol are shown in relation to the Himmelsbach glutamate at N-methyl-d-aspartate (NMDA) receptors, and inhibition of voltage-operated calcium channels (VOCC’s) may underlie the relaxation, intoxication, anesthesia, and amnesia caused by alcohol. Alcohol also increases release of the neurotransmitter dopamine (DA) in a specific area of the brain, the nucleus accumbens. This action of alcohol is not very well understood but may play an important role in the rewarding effects of drinking, such as euphoria. (B) Examples of the adaptive changes thought to oppose the acute effects of alcohol. The bottom panels show possible consequences of these adaptations during withdrawal. For example, the adaptive changes in GABA receptor proteins caused by alcohol may make benzodiazepine tranquilizers, which also act on GABA receptors, less effective (i.e., may produce tolerance). A reduction in DA release in the nucleus accumbens may accompany alcohol withdrawal and may contribute to depression, anxiety, and emotional discomfort (i.e., dysphoria), perhaps leading an alcoholic to resume his or her drinking. ¹CNS = central nevous system.