Dynamics 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. Rewarding and reinforcing actions The reinforcing effects of<unk> consumption are mediated by acetaldehyde generated by catalase and other oxidizing enzymes such as cytochrome P-4502E1 in the brain. Although acetaldehyde has been associated with some of the adverse and toxic effects of ethanol, it appears to play a central role in the activation of the mesolimbic dopamine system. Ethanol's rewarding and reinforcing (i.e., addictive) properties are mediated through its effects on dopamine neurons in the mesolimbic reward pathway, which connects the ventral tegmental area to the nucleus accumbens (NAcc). One of ethanol's primary effects is the allosteric inhibition of NMDA receptors and facilitation of GABAA receptors (e.g., enhanced GABAA receptor-mediated chloride flux through allosteric regulation of the receptor). At high doses, ethanol inhibits most ligand-gated ion channels and voltage-gated ion channels in neurons as well. With acute<unk> consumption, dopamine is released in the synapses of the mesolimbic pathway, in turn heightening activation of postsynaptic D1 receptors. The activation of these receptors triggers postsynaptic internal signaling events through protein kinase A, which ultimately phosphorylate cAMP response element binding protein (CREB), inducing CREB-mediated changes in gene expression. With chronic<unk> intake, consumption of ethanol similarly induces CREB phosphorylation through the D1 receptor pathway, but it also alters NMDA receptor function through phosphorylation mechanisms; an adaptive downregulation of the D1 receptor pathway and CREB function occurs as well. Chronic consumption is also associated with an effect on CREB phosphorylation and function via postsynaptic NMDA receptor signaling cascades through a MAPK/ERK pathway and CAMK-mediated pathway. These modifications to CREB function in the mesolimbic pathway induce expression (i.e., increase gene expression) of ΔFosB in the , where ΔFosB is the "master control protein" that, when overexpressed in the NAcc, is necessary and sufficient for the development and maintenance of an addictive state (i.e., its overexpression in the nucleus accumbens produces and then directly modulates compulsive<unk> consumption). Relationship between concentrations and effects + Blood<unk> levels and effects mg/dL mM % v/v Effects 50 11 0.05% Euphoria, talkativeness, relaxation, happiness, gladness, pleasure, joyfulness. 100 22 0.1% Central nervous system depression, anxiety suppression, stress suppression, sedation, nausea, possible vomiting, impaired motor and sensory function,impaired memory impaired cognition >140 30 >0.14% Decreased blood flow to brain, slurred speech, double or blurry vision. 300 65 0.3% Stupefaction, confusion, numbness, dizzyness, loss of consciousness. 400 87 0.4% Ethylic intoxication, drunkeness, inebriation,<unk> poisoning or possible death. 500 109 >0.55% Unconsciousness, coma and death. Recreational concentrations of ethanol are typically in the range of 1 to 50 mM. Very low concentrations of 1 to 2 mM ethanol produce zero or undetectable effects except in<unk> naive individuals. Slightly higher levels of 5 to 10 mM, which are associated with light social drinking, produce measurable effects including changes in visual acuity, decreased anxiety, and modest behavioral disinhibition. Further higher levels of 15 to 20 mM result in a degree of sedation and motor incoordination that is contraindicated with the operation of motor vehicles. In jurisdictions in the United States, maximum blood<unk> levels for legal driving are about 17 to 22 mM. In the upper range of recreational ethanol concentrations of 20 to 50 mM, depression of the central nervous system is more marked, with effects including complete drunkenness, profound sedation, amnesia, emesis, hypnosis, and eventually unconsciousness. Levels of ethanol above 50 mM are not typically experienced by normal individuals and hence are not usually physiologically relevant; however, such levels – ranging from 50 to 100 mM – may be experienced by<unk> cs with high tolerance to ethanol. Concentrations above this range, specifically in the range of 100 to 200 mM, would cause death in all people except<unk> cs. List of known actions in the central nervous system Ethanol has been reported to possess the following actions in functional assays at varying concentrations: * GABAA receptor positive allosteric modulator (primarily of δ subunit-containing receptors) * NMDA receptor negative allosteric modulator * Decreased levels of Nitric Oxide in brain medulla * Increased levels of dopamine and endogenous opioids in the mesolimbic pathway, secondary to other actions * AMPA receptor negative allosteric modulator * Kainate receptor negative allosteric modulator * Glycine receptor positive allosteric modulator * Serotonin receptor positive allosteric modulator * Opioid receptor endogenous positive allosteric modulator * Muscarinic acetylcholine receptor positive allosteric modulator. * Nicotinic acetylcholine receptor positive allosteric modulator * 5-HT3 receptor positive allosteric modulator * Glycine reuptake inhibitor * Adenosine reuptake inhibitor * Dopamine reuptake inhibitor * L-type calcium channel blocker * GIRK channel opener Some of the actions of ethanol on ligand-gated ion channels, specifically the nicotinic acetylcholine receptors and the glycine receptor, are dose-dependent, with potentiation or inhibition occurring dependent on ethanol concentration. This seems to be because the effects of ethanol on these channels are a summation of positive and negative allosteric modulatory actions. Kinetics Absorption Ethanol can be taken orally, by inhalation, rectally, or by injection (e.g., intravenous), though it is typically ingested simply via oral administration. The oral bioavailability of ethanol is around 80% or more. In fasting volunteers, blood levels of ethanol increase proportionally with the dose of ethanol administered. Blood<unk> concentrations may be estimated by dividing the amount of ethanol ingested by the body weight of the individual and correcting for water dilution. Peak circulating levels of ethanol are usually reached within
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