Courtesy: Organic certification for Alcoholic
Alcohol addiction is termed alcohol use disorder.
Two or more consecutive alcohol-free days a week have been recommended to improve health and break dependence.
The precise mechanism of action of ethanol has proven elusive and remains not fully understood. Identifying molecular targets for ethanol has proven unusually difficult, in large part due to its unique biochemical properties. Specifically, ethanol is a very low molecular weight compound and is of exceptionally low potency in its actions, causing effects only at very high (millimolar (mM)) concentrations. For these reasons, unlike with most drugs, it has not yet been possible to employ traditional biochemical techniques to directly assess the binding of ethanol to receptors or ion channels. Instead, researchers have had to rely on functional studies to elucidate the actions of ethanol. Moreover, although it has been established that ethanol modulates ion channels to mediate its effects, ion channels are complex proteins, and their interactions and functions are complicated by diverse subunit compositions and regulation by conserved cellular signals (e.g. signaling lipids).
Much progress has been made in understanding the pharmacodynamics of ethanol over the last few decades. While no binding sites have been identified and established unambiguously for ethanol at present, it appears that it affects ion channels, in particular ligand-gated ion channels, to mediate its effects in the central nervous system. Ethanol has specifically been found in functional assays to enhance or inhibit the activity of a variety of ion channels, including the GABAA receptor, the ionotropic glutamate AMPA, kainate, and NMDA receptors, the glycine receptor, the nicotinic acetylcholine receptors, the serotonin 5-HT3 receptor, voltage-gated calcium channels, and BK channels, among others. However, many of these actions have been found to occur only at very high concentrations that may not be pharmacologically significant at recreational doses of ethanol, and it is unclear how or to what extent each of the individual actions is involved in the effects of ethanol. In any case, ethanol has long shown a similarity in its effects to positive allosteric modulators of the GABAA receptor like benzodiazepines, barbiturates, and various general anesthetics. Indeed, ethanol has been found to enhance GABAA receptor-mediated currents in functional assays. In accordance, it is theorized and widely believed that the primary mechanism of action is as a GABAA receptor positive allosteric modulator. However, the diverse actions of ethanol on other ion channels may be and indeed likely are involved in its effects as well.
Recently, a study showed the accumulation of an unnatural lipid phosphatidylethanol (PEth) competes with PIP2 agonists sites on lipid-gated ion channels. This presents a novel indirect mechanism and suggests that a metabolite, not the ethanol itself, can effect the primary targets of ethanol intoxication. Many of the primary targets of ethanol are known to bind PIP2 including GABAA receptors, but the role of PEth will need to be investigated for each of the primary targets.
In 2007, it was discovered that ethanol potentiates extrasynaptic δ subunit-containing GABAA receptors at behaviorally relevant (as low as 3 mM) concentrations. This is in contrast to previous functional assays of ethanol on γ subunit-containing GABAA receptors, which it enhances only at far higher concentrations (> 100 mM) that are in excess of recreational concentrations (up to 50 mM). Ro15-4513, a close analogue of the benzodiazepine antagonist flumazenil (Ro15-1788), has been found to bind to the same site as ethanol and to competitively displace it in a saturable manner. In addition, Ro15-4513 blocked the enhancement of δ subunit-containing GABAA receptor currents by ethanol in vitro. In accordance, the drug has been found to reverse many of the behavioral effects of low-to-moderate doses of ethanol in rodents, including its effects on anxiety, memory, motor behavior, and self-administration. Taken together, these findings suggest a binding site for ethanol on subpopulations of the GABAA receptor with specific subunit compositions via which it interacts with and potentiates the receptor.