Mechanism of action of alcohol in the human body

Mechanism of action

Alcohol exerts its effects on the brain by interfering with specific receptors on the macromolecular GABA complex: as occurs with benzodiazepines, barbiturates, and inhibitory amino acids, alcohol’s specific receptor binding enhances the binding capacity of the GABAergic receptor, making the neuron more permeable to the influx of chloride ions through channels controlled by the GABAergic receptor itself. Likewise, by inhibiting adenosine uptake, alcohol appears to be able to activate cyclic AMP production, with a consequent secretion of opioid peptides from neurons that produce β-endorphins. If this neuronal action is combined with ethanol’s interference with NMDA receptors—which results in inhibition of the excitatory amino-acid system—it becomes clear what underlies alcohol’s role as a central nervous system depressant. In behavioral and clinical terms, this depression follows a biphasic pattern characterized by a disinhibiting action (i.e., depression of inhibitions) at low doses and by overall central nervous system depression at higher doses. Alcohol’s effects on sociability, mood tone, and anxiety control are also influenced by interference with serotonin receptors, endogenous cannabinoids, and, more generally, catecholamines. Finally, modulation of the cholinergic system appears to be responsible for alcohol’s effects on the cardiovascular system, the gastrointestinal tract, and thermoregulation.

How alcohol is metabolized

The biotransformation of ethanol occurs predominantly in the liver. About 90% of the absorbed dose is metabolized by the liver; a negligible amount undergoes intestinal biotransformation or is excreted directly in urine and exhaled air (Morgan, 1979). Mainly at the hepatic level, ethanol is oxidized to acetaldehyde (CH3-CHO). This metabolic transformation is catalyzed by alcohol dehydrogenase (ADH) for more than 70%—an enzyme located in the cytosol of hepatocytes—and by the microsomal ethanol-oxidizing system (MEOS) for 10–15%, whose key enzyme is cytochrome P450 (CYP2E1), while a marginal role is played by catalase, accounting for no more than 10% when blood alcohol levels are very high. At low ethanol concentrations, ADH is the main oxidizing enzyme, whereas at high concentrations this role is taken on by MEOS, another oxidizing enzyme (Goldstein, 1983). Oxidation is catalyzed at the expense of NAD+ reduction for ADH and NADP+ reduction for MEOS. Three different enzymatic subclasses have been identified for ADH, called ADH I, ADH II, and ADH III: each subclass includes different isoenzymes with different metabolic capacities (Goedde and Agarwall, 1989). This variability may partly explain the corresponding inter-individual differences in the rate of ethanol elimination from plasma. MEOS, on the other hand, is characterized by an increase in its metabolic capacity after repeated ethanol administrations, a phenomenon known as “enzyme induction” and considered the basis of “metabolic tolerance” (Lieber and De Carli, 1970). It plays an important role in chronic alcoholism when liver disease coexists. Acetaldehyde, the main ethanol metabolite, does not appear to have psychoactive effects, as it is unable to cross the blood–brain barrier, also due to the presence of metabolizing enzymes in endothelial cells. Ninety percent of acetaldehyde derived from ethanol biotransformation is further oxidized to acetic acid by acetaldehyde dehydrogenase (ADLH). Acetic acid, in turn, is metabolized to CO2 and H2O in muscle tissue or converted into acetyl-CoA, which is then used in the synthesis of cholesterol and fatty acids. In addition to the metabolic pathways described above, ethanol is partly conjugated with glucuronic acid to form ethyl glucuronide, a metabolite excreted in urine (Schmitt et al., 1995).

Alteration of neurotransmitters

The neuroendocrine effects of alcohol have been extensively studied, both in response to acute administration, during chronic intoxication, and in the withdrawal period (Gavaler, 1983). One of the main difficulties in research on alcohol’s effects stems from the simultaneous presence of neuroendocrine changes connected to chronic liver alterations (Gordon et al., 1975). Brain monoamines—norepinephrine, dopamine, and serotonin—are all thought to be involved in alcohol’s pharmacological action (Nutt, 1999). Alcohol has a biphasic effect: at low doses it produces euphoric, activating, and energizing responses that would correspond to engagement of the monoaminergic system. Indeed, acute ethanol intoxication has been associated with increased adrenergic activity in the brain (Littleton, 1978; Tabakoff and Hoffman, 1980). A significant increase in catecholamine secretion has been demonstrated after acute ethanol intake (Bjorkqvist, 1975). Subsequently, an anxiolytic, sedative, and inhibitory phase occurs, which may be attributed to an inhibitory action on excitatory amino-acid (NMDA) receptors and to an increase in GABAergic activity (Kostowski and Bienkowski, 1999). Preclinical tests indicate a positive effect of NMDA receptor antagonists in alcohol dependence (self-administration, withdrawal, pain) (Danysz et al., 2002). In this second phase, there would be a reduction in catecholamines and a predominance of GABA and acetylcholine; dopamine release, together with the secretion of opioid peptides, would be responsible for ethanol’s rewarding effects and its ability to induce dependence (Eckardt et al., 1998; Koob et al., 1998). Chronic alcohol exposure would impair GABAergic transmission (Gallegos et al., 1999) and lead to a predominance of glutamatergic transmission—possibly responsible for tolerance mechanisms—along with a deficit in cholinergic activity, probably linked to memory problems (Nevo and Hamon, 1995). According to some authors, alcohol’s stimulation of dopamine secretion would be mediated through activation of opioid neurons and reduction of GABA’s inhibitory control over dopamine (Cowen and Lawrence, 1999). Acute alcohol administration also causes an increase in serotonin, but chronic abuse can lead to depletion of this neurotransmitter (Nisticò, 1990; Tollefson, 1989). The clonidine test, which evaluates alpha-adrenergic sensitivity, reveals an impaired GH response in alcoholics, indicating a possible alteration of monoaminergic pathways, which cannot be certainly attributed to the effects of ethanol intake but may preexist exposure to the substance (Vescovi et al., 1989). Alcohol can increase the production of opioid peptides and activate opioid receptors in certain brain areas. Significant alterations in the binding of opioid agonists and antagonists under the effect of alcohol have been reported in the literature in relation to its action on neuronal membrane fluidity (Morley and Krahn, 1987). Increased levels of ß-endorphins and met-enkephalins have been observed during acute intake (Gianoulakis et al., 1996; Herz, 1997). Opioid antagonists reduce ethanol’s rewarding capacity and effects, confirming the involvement of endogenous opioids in alcohol-induced euphoria and behavior (Herz, 1997; Bohn, 1992).

Alcohol and the HPA axis

Since 1966, increased corticosterone responses after ethanol administration have been observed in laboratory animals (Ellis, 1966). Circadian rhythms of corticosterone also appear to be altered in animals chronically exposed to alcohol (Kakihana and Moore, 1976). Alcohol intake in humans produces an immediate increase in plasma cortisol (Linkola et al., 1978). In alcoholic patients, increased cortisol secretion would be responsible for signs of hyperadrenalism described as pseudo-Cushing’s syndrome (Mendoza et al., 1998). Alcohol’s action on cortisol secretion is mediated by ACTH stimulation (Mendelson et al., 1966; Mendelson et al., 1971) and probably through involvement of CRF. Activation of the hypothalamic–pituitary–adrenal (HPA) axis, recognized in more recent studies, appears to be the cause of alcohol’s immunosuppressive effects (Pruett et al., 1998). Pituitary ACTH response during alcohol withdrawal is altered, suggesting reduced reserves in these patients. The naloxone test performed in alcoholic subjects who have recently stopped using the substance shows a reduced ACTH response, suggesting poor responsiveness to CRH and impairment of the entire production chain leading to ACTH starting from pro-opiomelanocortin (Inder et al., 1995). In contrast, cortisol response to ACTH stimulation reveals normal adrenal function. An inability to respond to stress with HPA axis activation in prolonged alcohol intoxication has also been described by others (Waltman et al., 1993). Catecholamines from the adrenal medulla also appear to be increased by acute alcohol ingestion (Pohorecky et al., 1974). There is also some experimental evidence indicating that individuals with an alcoholic father have higher baseline cortisol levels and a greater naloxone (opioid antagonist) response than those without a father with alcohol dependence. These studies suggest that individuals with greater vulnerability to alcoholism also have a dynamic alteration of the HPA axis and confirm a role for the opioid system in alcohol dependence (Hernandez-Avila et al., 2002).

Alcohol and control of gonadal function

It has already been well documented that alcohol and its metabolite acetaldehyde influence gonadal function in males (Cobb et al., 1978), but the interaction pathways between alcohol and the gonads are not entirely clear. Altered metabolism of redox factors and vitamin A due to alcohol may explain ethanol-induced damage to spermatogenesis and testosterone biosynthesis (Gavaler et al., 1980; Chiao et al., 1981). Despite reduced gonadal function, alcoholic subjects show, according to some, non-elevated gonadotropin levels and impaired LH responses to clomiphene and hypothalamic LHRH (Gavaler, 1983). Adrenal overproduction of sex steroid precursors, with an inability of the body to aromatize estrogens and convert them into androgens, has been found in some chronic alcoholics (Martinez-Riera et al., 1995), helping to explain feminizing traits sometimes observed in alcoholics. In females, acute alcohol exposure would cause a reduction in progesterone and a transient rise in prolactin (Sarkola et al., 1999). Gonadal hypofunction has also been described in alcoholic women in association with oligomenorrhea and in some cases infertility (Mello et al., 1983; Bo et al., 1982). Decreases in plasma estradiol and progesterone levels during alcohol abuse manifest through a disruption in ovarian rhythmicity (Ellingboe, 1987). This estrogen deficiency has also been measured in alcohol-exposed subjects with unchanged LH levels and preserved LH response to LHRH, suggesting that the steroid deficit is not linked to alteration of the HPG axis but rather to changes in hepatic, gonadal, and adrenal metabolism (Ellingboe, 1987). Other studies attribute menstrual dysfunctions in women with alcoholism to reduced or absent LH peaks with the characteristic monthly pattern (Bo et al., 1982). In women who abuse alcohol in the premenopausal period, increased conversion of androstenedione to testosterone has been observed, with signs of hyperandrogenism (Sarkola et al., 2000).

Alcohol, GH and PRL

Alcohol administration in normal subjects and alcoholics decreases or blocks growth hormone (GH) release (Gavaler, 1983), and exposure to high doses of ethanol in laboratory animals affects spontaneous GH secretion. Chronic liver disease in alcoholics may be associated with elevated baseline GH levels but reduced GH responses to alpha-2 adrenergic receptor stimulation with the clonidine test (Vescovi et al., 1989). Abnormal GH responses have also been observed in response to nonspecific stimuli such as TRH, which in normal subjects are unable to increase hormone secretion (Van Thiel et al., 1975). Data regarding ethanol-induced changes in PRL are conflicting. A transient rise in prolactin, as mentioned earlier, has been reported during acute alcohol exposure (Sarkola et al., 1999). According to older studies, prolactin does not appear to be influenced by acute ethanol administration (Earll et al., 1976). Loosen and Prange, in contrast, reported evidence of reduced baseline PRL levels and diminished PRL responses to TRH in alcoholics (Garbutt et al., 1995). Patients with cirrhosis have elevated baseline PRL levels and reduced PRL responses to TRH; in contrast, alcoholic subjects with normal liver function show reduced baseline PRL levels and increased TRH responses (Van Thiel et al., 1979). More recently, PRL has been found unchanged during alcohol exposure (Ekman et al., 1996). According to other authors, alcoholic subjects would present hyperprolactinemia (Seilcovich et al., 1991; Seki et al., 1997; Mello et al., 1988): if this PRL rise does not normalize during abstinence, it would be a negative prognostic sign.

Alcohol and thyroid function

It is not easy to interpret data obtained from studies of thyroid metabolism in relation to ethanol’s effects; indeed, endocrine research results in alcoholics are influenced by metabolic changes due to liver disease, which have already been considered significant interferences for other hormones. Reduced serum levels of thyroxine (T4) and triiodothyronine (T3) have been reported after experimental alcohol administration (Israel et al., 1979). Despite data suggesting reduced thyroid function in alcoholics, ethanol has been shown to increase iodine uptake by the thyroid (Mello et al., 1988). Altered function of the hypothalamic–pituitary–thyroid axis has been reported by other studies in alcoholics, showing a diminished TSH response to TRH (Van Thiel et al., 1979). More recent studies confirm a suppressive action of alcohol on TSH peaks, particularly the nocturnal rise of the hormone (Wright et al., 1975; Ekman et al., 1996).

Alcohol, vasopressin and oxytocin

Reduced vasopressin levels have been demonstrated after alcohol intake; the immediate diuretic effect of ethanol, presumably connected with vasopressin suppression, has been well known for several years (Linkola et al., 1977). Chronic alcohol abuse decreases vasopressin secretion, affecting its hypothalamic control (Marquis et al., 1975). Experimental data show ethanol’s ability to acutely inhibit oxytocin release as well, but few clinical results are available (Wagner and Fuchs, 1968).

Alcohol and the endocrine pancreas

Since 1963, alcohol’s ability to produce severe hypoglycemia has been described (Piccardo et al., 1979). Alcohol increases basal insulin secretion and increases insulin responses to glucose intake and tolbutamide stimulation (Metz et al., 1969). In contrast, glucose intolerance observed in liver failure may be due to the concurrent increase in glucagon levels (Thoma et al., 1996).

Alcohol and the immune system

Acute exposure to high doses of alcohol interferes with responses to interleukin-8 and tumor necrosis factor-alpha stimuli: this could explain reduced neutrophil migration and activation capacity, with a consequent lowered defense threshold against infections during acute alcohol intoxication (Arbabi et al., 1999). Interferences of alcohol—both acutely and chronically consumed—on T and B lymphocytes, natural killer activity, and monocyte-macrophage function have been reported in the literature, with associated alterations in inflammatory response, cytokine secretion, and responses to antigenic stimuli (Szabo, 1999).

Behavioral effects and expected effects

The effects of alcohol on the psychological sphere of people who consume it in moderate quantities were studied by Peele and Brodsky (2000). The authors emphasize that moderate consumers use it to address various problems: health-related (cough, colds…), mood-related (depression), to reduce stress, to facilitate social integration, and to enhance socialization skills; alcohol may also be consumed to improve cognitive functioning and increase work performance. In general, both individuals with problematic alcohol use and alcoholics proper expect alcohol use to improve mood and provide psychological help in social relationships. Heavy alcohol consumption, documented among college student populations, seems to correlate positively with high social expectations and high desirability: drinking alcohol would therefore be both an expected behavior and one accepted and shared among students (Jackson and Matthews, 1988). It has also been shown that high alcohol consumption is positively correlated with the “extroversion” dimension of the EPI, whose subfactors suggest that impulsivity and sociability may independently predict alcohol abuse. Some studies (Rosenwasser, 2001) suggest that alcohol exerts direct influences on the circadian rhythm of sleep and wakefulness. Alcohol’s effects would be similar to those of antidepressant drugs and would be mediated, at least in part, by an alteration of the serotonergic system, which plays an important role in regulating the sleep–wake rhythm. It is well known that alcohol has anxiolytic and disinhibiting effects on behavior through its action on subcortical structures involved in regulating anger and aggression (Lyvers, 2000). Data from a recent study appear to support the existence of comorbidity between bipolar disorder and alcohol abuse in patients with social phobia. The socializing and disinhibiting effects that many people with social phobia report may be mediated by an alcohol-induced elevation in mood. The presence of a “bipolar diathesis” in patients with social anxiety may explain their increased susceptibility to alcohol, and alcohol abuse can also be interpreted as an attempt to overcome social difficulties connected to their disorder (Perugi et al., 2002). In a study conducted by Soderpalm and De Wit (2002), it was shown that in a group of subjects who had consumed alcohol, stress increased sedative effects and decreased stimulating effects. This led to the conclusion that at relatively high doses of alcohol (ethanol), stress increases alcohol’s sedative effects without increasing the desire to consume further quantities of alcohol.

Stages of intoxication

The effects induced by alcohol intake depend largely on the amount of alcohol consumed. The following table summarizes the main effects produced by this substance in relation to quantity.