Editors' ChoiceNeuroscience

From “Cheers” to Fears

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Science Translational Medicine  10 Oct 2012:
Vol. 4, Issue 155, pp. 155ec183
DOI: 10.1126/scitranslmed.3005077

The familiar call of “another round!” is a common self-medication for stress, but a vicious circle of alcoholism and anxiety develops when the bar never seems to close. Ethanol is both a short-term cure and a long-term cause of anxiety disorders, but the mechanism by which the brain becomes sensitized to such disorders is poorly understood. Recently, Holmes and colleagues used a model of chronic ethanol exposure to show changes in the prefrontal cortex of mice that correlate with behaviors related to posttraumatic stress disorder.

The investigators studied fear extinction, the process by which the brain inhibits trauma-related fear responses. As might be expected, an inability to extinguish such responses could contribute to symptoms of posttraumatic stress disorder. Holmes et al. found that chronic intermittent exposure to vaporized ethanol was associated with a decrease in the learned behavior of fear extinction compared with the behavior of control mice exposed to air. This impairment was correlated with an increased length of dendrites, the projections that receive neural signals, in a specific population of neurons. Impaired fear extinction was also correlated with a reduction of currents mediated by N-methyl-D-aspartate (NMDA) receptors, which are the receptors for the excitatory neurotransmitter glutamate. Further experiments suggested a causal role for decreased NMDA receptor function in decreased fear extinction, because blocking the receptor with an antagonist yielded the same result.

As always, data derived from animal models require careful interpretation, especially because inhibited fear extinction is not equivalent to the symptom complex of posttraumatic stress disorder. Furthermore, no strict causality was determined—further studies of chronic ethanol exposure that include concomitant modulation of the NMDA receptor will support a mechanistic role. Despite these limitations, the data have translational importance because studies in humans have identified a relationship between alcohol dependence and abnormalities of NMDA-mediated signal cascades. The development of treatments stimulating prefrontal NMDA receptors may therefore attenuate changes that impair the brain’s ability to extinguish trauma-related reactions. Of note, some studies in humans have suggested that there is a generally enhanced function of NMDA receptors associated with alcoholism. Although this may be true in a broad sense, the current experimental findings suggest that there may be regional differences in NMDA function after chronic alcohol exposure. Last, neuroimaging techniques designed to assess receptor function in humans may help screen for individuals at a particularly high risk of alcohol-related anxiety conditions such as posttraumatic stress disorder.

A. Holmes et al., Chronic alcohol remodels prefrontal neurons and disrupts NMDAR-mediated fear extinction encoding. Nat. Neurosci. 15, 1359–1363 (2012). [Abstract]

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