The neurobiology of alcohol consumption and alcoholism: an integrative history

Abstract

Studies of the neurobiological predisposition to consume alcohol (ethanol) and to transition to uncontrolled drinking behavior (alcoholism), as well as studies of the effects of alcohol on brain function, started a logarithmic growth phase after the repeal of the 18th Amendment to the United States Constitution. Although the early studies were primitive by current technological standards, they clearly demonstrated the effects of alcohol on brain structure and function, and by the end of the 20th century left little doubt that alcoholism is a "disease" of the brain. This review traces the history of developments in the understanding of ethanol's effects on the most prominent inhibitory and excitatory systems of brain (GABA and glutamate neurotransmission). This neurobiological information is integrated with knowledge of ethanol's actions on other neurotransmitter systems to produce an anatomical and functional map of ethanol's properties. Our intent is limited in scope, but is meant to provide context and integration of the actions of ethanol on the major neurobiologic systems which produce reinforcement for alcohol consumption and changes in brain chemistry that lead to addiction. The developmental history of neurobehavioral theories of the transition from alcohol drinking to alcohol addiction is presented and juxtaposed to the neurobiological findings. Depending on one's point of view, we may, at this point in history, know more, or less, than we think we know about the neurobiology of alcoholism.

Keywords: Addiction; Alcohol research history; GABA; Glutamate; Mesolimbic dopamine system; Reward.

Figure 1. Dopaminergic Neurons as Signalers of Reward

A. The dopaminergic projections from the ventral tegmentum (ventral tegmental area, VTA) to the NAc, i.e., the mesolimbic pathway, represent a central component of the “reward” pathway. The dopaminergic neurons in the VTA project to the NAc, amygdala, prefrontal cortex and other limbic areas. Opiate peptides (β-endorphin, β-END) released from the hypothalamus inhibit the activity of VTA GABAergic interneurons, the cell bodies of which reside in the rostromedial tegmentum, and increase VTA dopaminergic neuron activity. B. Ethanol increases the release of hypothalamic opiate peptides, further inhibiting the GABAergic interneurons, and leading to enhanced dopamine release through this disinhibition mechanism. At the same time, ethanol can inhibit NMDA receptor function, decreasing excitatory input to the VTA GABAergic interneurons, which further disinhibits VTA dopamine neuron activity.

Figure 2. Ethanol’s Action on Glutamatergic Activation of Nucleus Accumbens Medium Spiny Neurons (MSN)

Left Panel. Phosphorylation of NMDA receptors controls the strength of excitatory input to the MSN. When dopaminergic activity at the D1 dopamine receptor is low, protein phosphatase-1 (PP1) activity is relatively high, leading to dephosphorylation of the NMDA receptor, and reduced excitatory input to the MSN. Ethanol also inhibits NMDA receptor function in the presence of low dopaminergic input, and these factors both reduce the output of the MSN. Right Panel When dopamine release is high, stimulation of D1 receptors increases cAMP levels in the MSN, which promotes phosphorylation of DARPP-32 on threonine-34 (T34), converting DARPP-32 into a form that inhibits PP-1. This results in maintained phosphorylation of the NMDA receptor, which in turn produces resistance to ethanol inhibition of NMDA receptor function. Overall, ethanol, by activating DA release in the VTA (see Figure 1), leads to an inhibition of its actions on NMDA receptor function in the NAc, resulting in increased excitatory input to the MSN.

Figure 3. Stages of Addiction

The three panels illustrate a composite of the theoretical frameworks discussed in the text on the progression from the initial drinking experience to addiction in susceptible individuals. A. Initial Experience. During the initial experience with ethanol, interoceptive and exteroceptive cues become associated with a pleasurable result (positive reinforcement). Ethanol directly activates the “pleasure signals” at the level of the hypothalamus and the VTA to initiate the attention to and processing of the ethanol-related events. The salience and valence of the ethanol-related events as processed through the prefrontal cortex, hippocampus and amygdala, determine the motivation for further ethanol ingestion. A stronger motivation can be interpreted as a greater level of “liking”. B. Habituation. During the stage of habituation, learning and expectation lead to the strengthening of certain sensory cues which drive and respond to ethanol ingestion. Activation of “pleasure signals” from the hypothalamus and VTA become strongly associated with the particular sensory cue (relief of stress, anxiety, or maybe even the taste of a good wine). The intake of the alcoholic beverage at this stage can result in either positive or negative reinforcement to drive further drinking. The drinking becomes more automated with diminished influence of the prefrontal cortex and the strengthening of activity of sub-cortical regions: nucleus accumbens and dorsal striatal connections to the pallidum, and input from the amygdala to the nucleus accumbens strengthening the sub-cortical initiation of motor action to obtain more ethanol. C. Dependence. In the alcohol-addicted state, the sensory cues become the untoward effects of not having ethanol in the body. The ethanol intake alleviates these negative sensory states (negative reinforcement) and the system learns that pleasure can be derived from alleviation of these negative states. The salience of this experience, modulated through the amygdala, drives motivation and drinking is at this point a repetitive act to prevent exposure to negative states (“wanting”).