Alcohol (ethanol)

Ethanol, the psychoactive compound contained in alcoholic beverages, is probably the most ancient psychoactive currently known. Its use is believed to date back to the Neolithic era, approximately 10.000 BC. Numerous archeological findings and historical records from that date on indicate that the use of alcohol was widespread throughout many cultures and regions, Babylon, China and Egypt being the oldest and most notorious examples (Gately, 2009). Furthermore, there are also records of alcohol production and consumption among pre-colonial American civilizations, which stands out, given their complete dissociation from European and Asian cultures.

The use of alcohol is entirely embedded in all developed societies, and, although some attempts have been made at illegalizing it, the most patent of which is American prohibition from 1920 to 1933, its production, distribution and use are permitted in most countries.

Ethanol is a central nervous system depressant. At low doses it causes euphoria and talkativeness; it is therefore used primarily as a socializing drug. As blood ethanol concentration rises, users exhibit increasingly dangerous symptoms associated with the depressant effects of ethanol, such as slurred speech, poor judgment, ataxia, respiratory problems, and even death.

Ethanol is highly addictive; there is particular susceptibility towards its abuse, due to its legal status and perception as an innocuous socializing drug, leading consumers to adopt use patterns which are characterized by excessive frequency and/or binge-like intake.

Mechanism of Action of Alcohol

The effects of ethanol on the brain are numerous and extremely complex, due to its ability to cross biological membranes and to interact with multiple molecular targets (i.e. ligand-gated ion channels). One of the main mechanisms implicated in the effects of ethanol is the increase in GABA function through the activation of GABAA receptors. In this sense, ethanol can increase locomotion through GABA activation in the substantia nigra pars reticulata (Arizzi-LaFrance et al., 2006). Paradoxically, ethanol decreases GABA function in the ventral tegmental area, which leads to disinhibition of dopaminergic neurons, thus increasing the firing rate of dopamine into the nucleus accumbens. This activation of the mesolimbic pathway is therefore believed to be responsible for the reinforcing properties of ethanol (Xiao et al., 2007). Additionally, it also induces endogenous opioid release in the nucleus accumbens, and directly increases dopamine release in other areas of mesocortical pathways (see Siggins et al., 2005 for a review).

Acute ethanol also acts as an inhibitor of glutamate neurotransmission in different brain areas such as the hippocampus, cerebellum, cerebral cortex, NAc, amygdala and VTA in a concentration-dependent manner (Hoffman, 2003).

Pharmacokinetics of Alcohol

Ethanol follows order zero kinetics; thus, the clearance rate remains constant, regardless of blood concentration. The metabolism of ethanol consists of 2 reactions: ethanol is firstly oxidized into acetaldehyde; this reaction can take place through 3 different routes, involving distinct enzymes:

• Alcohol dehydrogenase (cytosol)

• Multiple cytochromes (microsomes)

• Catalase (peroxisomes)

  The resulting acetaldehyde is further oxidized by acetaldehyde dehydrogenase in the mitochondria, generating acetate, which is innocuous. This metabolite is liberated into the blood circulation and subsequently excreted (Zakhari et al., 2006).

Chronic ethanol use is known to cause serious cognitive impairment, accounting for 10% of all existing dementias. Animal studies have reported that heavy ethanol consumption can cause hippocampal cell deficiencies, loss of cholinergic neurons in the basal forebrain and pathological cellular changes in other areas, such as the cerebral cortex and hypothalamus (reviewed by Brust, 2010). These effects are most prevalent after repeated binge-like use.

It is hypothesized that ethanol-induced neurotoxicity is mediated through several mechanisms, mainly glutamate excitotoxicity, oxidative stress and thiamine (vitamin B1) deficiencies (Gotz et al., 2001).