**1. Introduction**

Ethanol is the most licit addictive drug worldwide, and its consumption in excess is the third leading cause of death in the world [1]. Global ethanol consumption is 6.2 L of pure ethanol per person, with 15 years or older, which corresponds to 13.5 g of pure ethanol per day [2, 3]. Ethanol abuse is a health concern, which can lead to problems associated with alcoholism and increases the risk factor for other diseases such as cardiovascular disease, cirrhosis, dementia, and depression [4]. Socially, ethanol abuse can trigger other problems as well as violence, low productivity at work, traffic accidents, and crime [5].

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

Excessive ethanol use results in brain intoxication, leading to motor and behavior alterations, and eventually to death as a consequence of the depressive effects on the central nervous system (CNS) [6]. These effects result in simultaneous alterations in neuronal circuits including the prefrontal cortex, which controls behavior [7]; the cerebellum, which regulates movement and coordination [8]; the frontal lobe, which controls emotions [9]; the reticular activating system, which determines the sleep-wake cycle [10]; the hippocampus, which mediates learning and memory [8]; and the medulla, which controls vital functions [6]. Ethanol intoxication induces cellular damage and neuronal death [11]. The precise mechanism participating in ethanol toxicity in the brain is unknown. However, at the cellular level, ethanol impairs the neurotransmitters signaling [12]. Also, ethanol promotes reactive oxygen species (ROS) production [13] and activates inflammatory processes [14]. Altogether these events could be responsible for ethanol-induced damage in the brain.

**5.** Binge drinking ethanol consumption characterized by a short period of heavy ethanol consumption followed by a period of abstinence and by intermittent ethanol intake [28].

Ethanol Consumption Affects Neuronal Function: Role of the Mitochondria

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Finally, we will discuss evidence suggesting that mitochondrial dysfunction is a potential mechanism by which ethanol promotes neurotoxicity, placing ethanol intoxication as a mito-

Acute ethanol consumption refers to a high ingestion of ethanol at a rate faster than that at which the body can metabolize it. Acute ethanol intoxication leads to brain injury, resulting in significant alterations of brain structure and function, and induces neuronal apoptosis and

Although several studies have tried to explain how acute ethanol administration induces brain injury, data on pathophysiology and underlying molecular and cellular mechanisms are still insufficient [34]. One of the possible theories was shown *in vitro*. Acute ethanol exposure induces neuronal apoptosis and changes to the neuronal structure, which could be related to the development of mature synapses and lead to a deficit in brain development [35]. Another alternative is that ethanol triggers inflammatory processes by activating toll-like receptor (TLR4) signaling and down-regulating autophagy pathways that trigger cell death [36]. However, and most importantly, oxidative stress appears to be the main mechanism for explaining brain injury mediated by ethanol. Oxidative stress is significantly increased fol-

Rats exposed to ethanol through gavage administration showed an increase in inflammatory and oxidative stress markers in the brain 1 h post ethanol exposure [38]. Also, pre-treatment for 3 days with 150 mg/kg of antioxidant vitamin E decreased inflammation, an effect that is not observed with other antioxidants such as *N*-acetylcysteine (NAC) or selenium [38]. Similarly, ethanol-related increases in ROS generation are a prime factor in ethanol neurotoxicity. Primary cortical neurons treated with 2.5 mg/mL ethanol for 24 h elicit a rapid onset of oxidative stress, which resulted in mitochondria-dependent apoptotic cell death both in cultured fetal rat cortical neurons and during embryonic development [32, 39]. Also, ethanol downregulates protective cellular antioxidant content in this neuronal model, thus seriously disturbing the cellular redox state [32]. Indeed, pretreatment with NAC increased cellular glutathione and prevented apoptosis, suggesting that oxidative stress precedes a cascade of events mediated by mitochondria. Prevention of apoptosis with NAC antioxidant supports

The mitochondria appear to be a major target of ethanol toxicity in the brain. Some studies suggest that disturbances of the integrity of the mitochondrial membrane are essential for ethanol-induced cell death in mitochondria isolated from ethanol-exposed fetal brains [40].

lowing ethanol administration in several animal and cellular models [32, 37–39].

**2. Patterns of ethanol consumption: mitochondrial alterations**

neurodegeneration in mouse, rat, and cellular models [11, 29–33].

the role of oxidative stress in neuronal death [32].

chondrial disease.

**2.1. Acute ethanol consumption**

Mitochondria are dynamic organelles, which regulate the production of ATP, redox balance, and calcium homeostasis in the neuron [15]. Interestingly, many effectors described in ethanol toxicity are directly or indirectly related to mitochondria. Mitochondria are the main source of ROS in the brain, and they are mainly affected by the oxidative damage induced by ethanol intoxication [16]. Likewise, dysfunctional mitochondria play a role in inducing proinflammatory events [17]. Finally, during synaptic process, ATP production and calcium buffering capacity produced by mitochondria are critical [18, 19]; therefore, mitochondrial injury may have severe consequences on neuronal communication.

In fact, evidence suggests that ethanol produces catastrophic changes in the mitochondria of organs such as liver [20] and heart [21], and over the last decade, many studies have reported the toxicity of ethanol to the brain's mitochondria [22, 23]. Briefly, ethanol increases ROS production [23], alters mitochondrial respiration [23, 24], impairs ATP production [22, 25], and eventually induces cell death by opening the mitochondrial permeability transition pore (mPTP) [26], observed both *in vitro* and *in vivo* [27].

In this chapter, we will discuss the effects of ethanol toxicity in the brain, focusing on the mitochondria. We will describe the specific ethanol-induced alterations to mitochondrial integrity, dynamics, and bioenergetics in different scenarios of ethanol exposure including:


**5.** Binge drinking ethanol consumption characterized by a short period of heavy ethanol consumption followed by a period of abstinence and by intermittent ethanol intake [28].

Finally, we will discuss evidence suggesting that mitochondrial dysfunction is a potential mechanism by which ethanol promotes neurotoxicity, placing ethanol intoxication as a mitochondrial disease.
