Once acetyl-CoA is generated, it enters the normal Krebs cycle1.

 The excess of NADH also inhibits fatty acid oxidation. A fundamental metabolic result of fatty acid oxidation is the generation of NADH for ATP production through the electron transport chain, but alcohol consumers' NADH needs are met by ethanol metabolism. The excess NADH signals that conditions are appropriate for fatty acid synthesis. Therefore, triacylglycerols accumulate in the liver, leading to fatty liver, all of which is exacerbated in obese patients3. 

 The first pathway for ethanol metabolism is by the enzyme alcohol dehydrogenase which oxidizes ethanol to acetaldehyde reducing NAD+ to NADH. Then acetaldehyde is oxidized by the acetaldehyde dehydrogenase, again reducing NAD+ to NADH. 

 The second pathway for ethanol metabolism utilizes the cytochrome P450 enzymes, the microsomal ethanol-oxidizing system (MEOS) generates acetaldehyde and subsequently acetate while oxidizing biosynthetic reducing power, NADPH, to NADP+. The fact that oxygen is used in this pathway leads to the production of free radicals that damage tissue. This oxidative stress is exacerbated as NADPH is being consumed, decreasing the capacity to neutralize this oxygen reactive species by preventing the regeneration of glutathione12.

 The effects of the other metabolites of ethanol: Liver mitochondria can convert acetate into acetyl CoA in a reaction requiring ATP through a thiokinase12 .

 Additional processing of Acetyl-Co A by the Krebs cycle is blocked1

The accumulation of acetyl CoA has several consequences: First, ketone bodies will form and be released into the blood, worsening the acidic condition already resulting from the high lactic acidosis. The metabolism of lactate in the liver becomes inefficient, leading to the accumulation of acetaldehyde, which is a very reactive compound that forms covalent bonds with many essential functional groups in proteins, damaging protein function. When ethanol is persistently consumed at high levels, acetaldehyde can importantly damage the liver and eventually produce cell death1.

Ketone bodies are synthesized in the mitochondrial matrix. Acetyl-CoA formed in the liver during oxidation of fatty acids or metabolism of alcohol, can either enter the Krebs cycle or undergo conversion to the ketone bodies, D-𝞫-hydroxybutyrate, acetoacetate, and acetone, that are exported to other tissues13.

 In an extremely fine-tuned regulatory process, the pyruvate dehydrogenase complex is specifically   Inhibited by ATP, acetyl CoA, NADH, and fatty acids; the Citrate Synthase is inhibited by NADH, citrate, and ATP; the Isocitrate dehydrogenase is Inhibited by ATP; and, the 𝞪-ketoglutarate dehydrogenase complex is inhibited by NADH13.

 Then the surplus of acetyl CoA in the mitochondria enters the process of synthesis of ketone bodies that initiates from two molecules of acetyl-Co A.

 The brain which preferentially uses glucose as a fuel can, if needed, adapt to the use of acetoacetate and β-hydroxybutyrate. The brain cannot utilize fatty acids as fuel because they are unable to cross the hematoencephalic barrier13. 

Ammonia is highly toxic to animals13. The catabolic production of ammonia constitutes a serious biochemical problem because ammonia is extremely toxic. The brain is particularly vulnerable; damage from ammonia toxicity causes clinically cognitive impairment, ataxia, and epileptic seizures. In extreme cases, swelling of the brain leads to death13.

 Clearing the cytosol from ammonia requires the reductive amination of α-ketoglutarate to glutamate by the enzyme glutamate dehydrogenase and the conversion of glutamate into glutamine by the enzyme glutamine synthetase. In the brain exclusively the astrocytes express glutamine synthetase. Glutamate and its derivative γ amino butyrate (GABA) are very important neurotransmitters; some of the high sensitivity of the brain to ammonia reflects depletion of glutamate in the glutamine synthetase reaction13. 

 The Metabolic destine of the amino groups: Due to only a few microorganisms are able to convert N2 to NH3,  amino groups are sophisticatedly husbanded in biological systems.

 Four amino acids have fundamental roles in nitrogen metabolism: glutamate, glutamine, aspartate, and alanine. These amino acids are the most easily convertible into citric acid intermediates. Glutamate and glutamine are converted into α-ketoglutarate, alanine into pyruvate, and aspartic acid into oxaloacetate1. 

The cirrhotic liver is metabolically unable to convert ammonia into urea, and blood levels of ammonia rise continuously. Ammonia is highly toxic to the nervous system and can produce coma and death1.

 Retinol (Vitamin A ) is converted into retinoic acid, which is an important signal molecule for growth and development in vertebrates, using the same dehydrogenase that metabolizes ethanol. Consequently, this activation does not take place in the presence of ethanol, because it acts as a competitive inhibitor. Furthermore, the p-450 enzymes induced by ethanol inactivate retinoic acid. These disruptions are probably responsible for fetal alcohol syndrome as well as the development of diverse types of cancers1.

Constitutes the existence of neurological symptoms caused by biochemical alterations of the central nervous system after exhaustion of B-vitamin reserves, mainly thiamine (vitamin B1). The condition forms part of a larger group of thiamine deficiency disorders, including beriberi in all its forms, and alcoholic Korsakoff syndrome. Whenever occurs simultaneously with alcoholic Korsakoff syndrome it is called Wernicke–Korsakoff syndrome.

 Classically, Wernicke encephalopathy is structured by the triad: ophthalmoplegia, ataxia, and confusion8. 

 Alcohol ingestion produces an initial inflammatory cascade because of its metabolism, resulting in steatosis produced by lipogenesis, fatty acid synthesis, and depletion of fatty acid oxidation appears as secondary to effects on the sterol regulatory transcription factor and the peroxisome proliferator-activated receptor α (PPAR-α). The intestinal derived endotoxin initiates a pathogenic cascade through toll-like receptor 4 and tumor necrosis factor α (TNF-α) that promotes hepatocyte apoptosis and necrosis. The cell damage and the endotoxin release initiated by ethanol and its metabolites also produce activation of innate and adaptive immunity pathways, thus releasing proinflammatory cytokines (TNF-α) chemokines and proliferation of T and B cells28. The net effect of chronic ethanol ingestion on intestinal permeability alters liposaccharide hepatic influx as well as microbiome dysbiosis, additionally contributing to the already existing pathogenic process3. The production of toxic protein-aldehyde adducts, the generation of reducing equivalents, and especially oxidative stress also play a definitive role. The hepatocyte injury and the regeneration following chronic alcohol ingestion are ultimately associated with the stellate cell activation and collagen production which are key events in fibrogenesis3. The resulting fibrosis from continuing alcohol consumption determines the architectural derangement of the liver and the consequent pathophysiology3. 

 The hepatic parenchyma has a limited repertoire in response to injury. Fatty liver constitutes the initial and certainly most common response to hepatotoxic stimuli, including excessive ethanol consumption. Remarkably, the accumulation of fat within the perivenular hepatocytes is coincident with the location of the enzyme alcohol dehydrogenase, the major enzyme responsible for alcohol metabolism14. Continuing alcohol consumption results in fat accumulation throughout the whole hepatic lobule14. Despite extensive fatty change and distortion of the hepatocytes with macrovascular fat, unexpectedly, the cessation of drinking results in normalization of the hepatic parenchyma architecture and diminishing of fat content. Alcoholic fatty liver has historically been regarded as entirely benign, and similarly to the spectrum of nonalcoholic liver disease, the appearance of steatohepatitis and other specific pathological features such as giant mitochondria, perivascular fibrosis, and macrovascular fat could be associated with progressive liver injury14.

 The transition between the fatty liver and the development of alcoholic hepatitis is continuous, smooth, and blurred. The significant hallmark of alcoholic hepatitis is represented by hepatocyte injury which is characterized by ballooning degeneration, spotty necrosis, polymorphonuclear infiltrate, and increasing fibrosis in perivenular and perisinusoidal space of  Disse14. Mallory Denk bodies are frequently present in florid cases but are neither considered specific nor necessary to establish the diagnosis14. Alcoholic hepatitis is considered to be a precursor of cirrhosis14. However, like fatty liver, it is potentially reversible with cessation of alcohol consumption. Cirrhosis is present in approximately 50% of the patients with biopsy-proven alcoholic hepatitis, and its regeneration is uncertain, even with absolute abstention14.

 Usually, the clinical manifestations of alcoholic fatty liver are subtle and detected during a medical visit for an apparently unrelated matter. Previously unsuspected hepatomegaly is often the only clinical finding. Occasionally patients with fatty liver could present with right upper quadrant discomfort, nausea, and rarely, jaundice8. 

Alcoholic hepatitis is manifested as a gamut of clinical features8. Fever, spider nevi, jaundice, and abdominal pain, apparently an acute abdomen, constituted the extreme end of the spectrum, while many patients will be absolutely asymptomatic8. The presence of portal hypertension, ascites, and or variceal bleeding may occur in the absence of cirrhosis. The recognition of the clinical features of alcoholic hepatitis is pivotal to the initiation of an effective and adequate diagnostic and therapeutic approach8. 

Gastric alcohol dehydrogenase initiates alcohol metabolism. There are three enzyme systems in the liver: Cytoplasmic alcohol dehydrogenase, Microsomal Ethanol oxidizing System (MEOS), and Perixosomal Catalase. Acetaldehyde is a highly reactive molecule that is metabolized, in the mitochondria, to acetate by aldehyde dehydrogenase2

The alcohol oxidation by the alcohol dehydrogenase causes the reduction of NAD+ to NADH, with a consequent decrease in NAD+ and an increase in NADH. NAD is required for fatty oxidation in the liver and also for the conversion of lactate into pyruvate. Its deficit is a main cause of the deposition of fat in the liver of alcohol consumers. The increase in NADH/NAD_ ratio in alcohol consumers also produces lactic acidosis. NAD is needed for the conversion of glyceraldehyde 3 phosphate to 1, 3 bisphosphoglycerate, by the enzyme glyceraldehyde 3 phosphate dehydrogenase8. 

ROS generation: The metabolism of ethanol in the liver by CYP2E1 produces ROS, which causes lipid peroxidation of hepatocyte membranes8. Alcohol also generates the release of the endotoxin (lipopolysaccharide) from gram-negative bacteria in the intestinal flora, which consequently stimulates the production of tumor necrosis factor (TNF) and other cytokines from macrophage and Kupffer cells, thus leading to hepatic injur8.

Ethanol consumption augments the intracellular triglyceride accumulation by increasing fatty acids' cellular intake and by suspending the fatty acid oxidation and lipoprotein secretion.

The protein synthesis, glycosylation, and secretion are altered7. The oxidative damage to the adipocyte membrane occurs as a result of the formation of reactive oxygen species7.

 Acetaldehyde is a very reactive molecule that reacts with proteins forming protein acetaldehyde molecular additions. These adducts might interfere with some specific enzyme activities, including the microtubular formation and the hepatic trafficking of proteins. With the acetaldehyde-mediated hepatocyte damage, several reactive oxygen species could result in the Kupffer cell activation with the consequent production of excess collagen and of extracellular matrix8. The connective tissue appears simultaneously in periportal and pericentral zones and eventually unites portal triads with central veins, thus forming regenerative nodules. Hepatocyte loss tends to occur, as well as collagen production and deposition, and, additionally continuing the hepatocyte destruction8. Then the liver contracts and shrinks8.  

Consists of an alternate pathway of the ethanol catabolism that occurs in the smooth endoplasmic reticulum in the process of oxidation of ethanol molecule to acetaldehyde8. Playing only a minor role in ethanol metabolism in normal individuals, the MEOS activity increases with chronic alcohol consumption. The MEOS pathway requires the CYP2E1 enzyme, ( part of the cytochrome P450 family), in order to convert the ethanol to the molecule of acetaldehyde8. The ethanol’s affinity for CYP2E1 is lower than its affinity for the enzyme alcohol dehydrogenase. Importantly, It has a delayed activity in the non-alcohol consumption states since the increase in MEOS activity is clearly correlated with an increase in the production of CYP2E1, which is seen most conclusively in the alcohol dehydrogenase negative case of the deer mice8.

The MEOS pathway metabolizes the ethanol to acetaldehyde by a redox reaction, where ethanol is oxidized (losing two hydrogens) and molecular oxygen is reduced ( accepting hydrogen) to form water8. NADPH is the donor of hydrogen, forming NADP+. The process consumes ATP and also dissipates heat, leading to the hypothesis that long-term drinkers see an increase in resting energy expenditure8.

 The increment in the rest energy expenditure has been hypothesized as if the MEOS would expend 9 Cal/gram of ethanol to catabolize versus 7 Cal/ per gram of the ingested ethanol2. Therefore this would produce a net loss of 2 Cal/gram of the ethanol that has been ingested. So ethanol unexpectedly would make lose weight3.

 Ethanol (CH3CH2OH) in a direct manner affects different types of neurochemical systems and many signaling cascades and, especially has powerful rewarding and addictive properties. It is without any doubt the oldest recreational drug and probably contributes to more morbidity, mortality, and public health cost than all the rest of illicit drugs combined11. The last Diagnostic and Statistical Manual of mental disorders (DSM-5) has integrated alcohol abuse and alcohol dependence into a single disorder: alcohol use disorder (AUD), with subclassifications as mild, moderate, and severe12.

The mechanisms of the ethanol effects in the central nervous system constitute the basis for understanding the rewards, disease processes, and treatment for ethanol-related conditions12. 

Aspirin use inhibits gastric alcohol dehydrogenase and increases the bioavailability of ethanol12.

The main enzymes involved in ethanol metabolism are Alcohol dehydrogenase and aldehyde dehydrogenase, followed by catalase and CYP2E1, CYPs 1A2, and 3A4 in some metabolic instances12.

Each step of metabolism requires two molecules of NAD+ stoichiometrically to oxidize it, reducing them to NADH. Oxidation of one mole of ethanol (46 gr), the equivalent to three glasses of wine, requires 1.3 Kg of NAD+. This highly exceeds the availability of NAD+ in the liver. Thus, the bioavailability of the NAD+ limits the metabolism of ethanol to approximately  8 grams per hour, maintaining it in zero-order kinetics12. 

The results of the oxidation of ethanol are increase NADH; increase lactate by lactate dehydrogenase; reducing pyruvate into lactate and converting NADH into NAD+.

The conversion of glyceraldehyde 3-phosphate into 1,3 Bisphophoglycerate by the glyceraldehyde 3 phosphate dehydrogenase requires  NAD+ to convert into NADH 

Increase Acetyl CoA from ethanol derived acetic acid decrease Krebs cycle  activity and increase of fatty acid synthesis is a cytosolic process12.

In the synthesis of fatty acids, each step of two carbon additions comes from the molecule of malonyl-CoA, which is produced by the enzyme Acetyl-CoA carboxylase12.

 NADH, acetyl-CoA, and ATP are expected to be increased13.

As explained, cytoplasmic ADH and mitochondrial ALDH, stoichiometrically convert 2 NAD+ to 2 NADH for each molecule of ethanol. Ethanol is eventually converted to acetic acid13.

 Two thiokinases are associated with the conversion of acetic acid to acetyl-CoA1). acyl-CoA synthetase short-chain family member 2 ACSS2 (EC 6.2.1.1) and acetyl-CoA synthase 2 (confusingly also called ACSS1) which is localized in mitochondria13.

 The Complete Reaction with all the Substrates and Products Included is13

ATP + Acetate + CoA <=> AMP + Pyrophosphate + Acetyl-CoA

Ethanol has many diverse and widespread effects on the whole body and impacts directly or indirectly almost on every neurochemical system in the CNS16.

 Even at relatively low doses, alcohol can exacerbate most clinical problems and perturbates the medications metabolized in the liver, and at higher doses can, per se,  transitively mimic many medical (diabetes)  and also psychiatric (depression) diagnoses16.

Alcohol use disorders, as a such,  decrease the lifespan by approximately ten years17.

 Congeners could include other alcohols like methanol and butanol, acetaldehyde, histamine, tannins, and the metals iron, and lead16. Ethanol decreases neuronal activity and has similar behavioral effects and also cross-tolerance with several other depressants, like benzodiazepines and barbiturates16.

 Alcohol also interferes with the absorption of diverse vitamins in the small intestine and decreases their amount stored in the liver, with some effects on vitamin A, folate, thiamine, pyridoxine, and nicotinic acid16.

Fasting heavy drinking in a healthy individual may produce transient hypoglycemia within six to thirty-six hours, secondary to the acute actions of ethanol which decreases gluconeogenesis. All this could result in temporary abnormal glucose tolerance tests (diabetes mellitus16). 

 A glucose load can not be totally catabolized into pyruvate, through glycolysis, because there are no enough NAD+ available, which is required in order to convert glyceraldehyde 3 phosphoglycerate into 1,3 bisphosphoglycerate by the enzyme glyceraldehyde 3 phosphate dehydrogenase, which incorporates inorganic phosphate and is considered the substrate-level phosphorylation for antonomasia, stopping glycolysis, because NAD+ is being used in the metabolism of alcohol, depleting the cell of NAD+ and giving a high level of glucose evidenced in the glucose tolerance test16. 

 The alcohol ketoacidosis, probably as a result of diminished fatty acid oxidation coupled with inadequate diet and/or persistent vomiting can be wrongly diagnosed as diabetic ketosis16. With alcohol-related ketoacidosis, patients could show an increment in serum ketones along with a mild increase in the level of glucose but with a large anion gap, a mild to moderate increase in lactate in serum, and a β-hydroxybutyrate/lactate ratio of between 2:1 and 9:1 instead the normal of 1:116.

The incidence of acute pancreatitis is roughly  25 per 1,000/year and is almost three times higher in patients with alcohol use disorders than in the non-ethanol consuming population15. Alcohol disturbs gluconeogenesis in the liver, producing a fall in the glucose produced from glycogen,  an increase in lactate production, and an elevation in fatty acids oxidation15. These participate in an increase in fat hepatic accumulation. In healthy individuals, these changes are thoroughly reversible, however, with repeated consumption of ethanol, mainly daily heavy drinking, more severe changes in the liver would appear, including alcohol-produced hepatitis, perivenular sclerosis, and eventually cirrhosis, which is observed in 15% of individuals categorized as alcohol use disorder patients15. Probably,  through an increased susceptibility to infections, subjects with alcohol use disorders have an increased rate of hepatitis C16.

 Ethanol consumption causes an increase in red cells´ mean corpuscular volume, which might reflect its effects on the stem cells. If heavy drinking is coincident with folic acid deficiency, there can additionally be hypersegmented neutrophils, reticulopenia, and hyperplastic bone marrow; if additionally malnutrition is present, sideroblastic changes could appear16. With chronic heavy ethanol drinking, a decrease in the production of blood cells, decrease granulocyte mobility and adherence and impair delayed hypersensitivity responses to novel antigens and a possible false-negative tuberculin skin test may result16. Associated immune deficiencies could contribute to the vulnerability to infections, such as hepatitis and HIV, and also interfere with their appropriate treatment16. Finally, many patients with alcohol use disorders might have mild thrombocytopenia, which may resolve within weeks of abstinence unless there is already hepatic cirrhosis or congestive splenomegaly.

 In the acute case, ethanol diminishes myocardial contractility and produces peripheral vasodilation, thus resulting in a mild decrease in blood pressure and a compensatory increase in cardiac output. Exercise-induced increases in the consumption of cardiac oxygen are higher after alcohol consumption16. These acute effects do not have important clinical significance for the average healthy drinker but can become very problematic when there is concomitant cardiac disease16.

 The consumption of three or more drinks per day produces in a dose-dependent fashion an increase in blood pressure, which tends to return to normal after weeks of abstinence. Therefore, heavy drinking is a main factor in mild to moderate hypertension16. Chronic heavy drinkers may also have a sixfold increased risk of coronary artery disease, partially related, to an increase in low-density lipoprotein cholesterol, and also carry an increased risk for cardiomyopathy through the direct effects of ethanol on heart myocytes16. Symptoms could include arrhythmias in the presence of left ventricular impairment, heart failure, hypercontractility of myocardial cells, and dilation of the four heart chambers, also with an associated potential mural thrombus and probable mitral valve regurgitation. Atrial or ventricular arrhythmias, especially paroxysmal tachycardia, can also occur temporarily after events of heavy ethanol consumption in individuals with no other evidence of heart pathology, which constitutes a syndrome known as “holiday heart”16.

 As effects in other systems, between 50%-75%  of individuals with ethanol use disorders, develop progressive skeletal muscle weakness produced by acute alcoholic myopathy, which is a condition that improves but might not fully remit with abstinence16. Among the effects of repeat, heavy ethanol consumption on the skeletal system changes in calcium metabolism diminished bone density, and a decreased growth in the epiphysis, therefore leading to an increased risk for fractures and also osteonecrosis of the femoral head. Among hormonal changes, an increase in the cortisol levels, which could remain elevated during heavy ethanol drinking; an inhibition of vasopressin secretion at high plasma alcohol concentrations and increased secretion during falling blood alcohol consumption and falling blood alcohol concentrations (with the final result that the majority of the patients with alcohol use disorders are lightly overhydrated); also minor and reversible decrease in serum thyroxine with a more marked decrease in the serum triiodothyronine16. These hormone abnormalities usually disappear after several weeks of total ethanol consumption abstinence.

The reinforcer is constituted by the drug and sometimes could be more powerful than any other natural reinforce9. This is especially the case in binge and Intoxication. The neuroanatomical substrate is constituted of the mesolimbic dopaminergic circuit, from the ventral tegmental area to the nucleus accumbens. Additionally, endorphins are liberated in these instances of addiction9.

 The globus pallidus is also activated and it is associated with the formation of the habit; The prefrontal cortex, corresponding to the Freudian superego, normally regulates the activity from the nucleus accumbens, but not during the drug's effects4.

 The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia24.

 During this first stage, alcohol and the drugs of abuse, make the globus pallidus encode drug-related behaviors as habits. The globus pallidus is associated with the formation of habits and automatic behaviors4.

 The prefrontal cortex is a region responsible for the executive functions as are planning and decision making4910. Normally, the prefrontal cortex inhibits the lower brain regions such as the nucleus accumbens; however, alcohol and drugs of abuse weaken this control, thus disinhibiting the nucleus accumbens423. This is thought to underlie the impulsivity that is characteristic of the binge and intoxication stage4.

 A completely different subset of neuronal structures is involved in the withdrawal, and negative affect, which is considered the second stage in the addiction cycle4.

 Because drug use increases dopamine levels beyond what is normal, the chronic consumption of ethanol and other drugs leads to a number of compensatory responses4. The result is that when the consumer is not intoxicated the dopamine signal is lower than normal, leaving the user feeling awful and unhappy and much less able to be reinforced by natural reinforcers423.

 The neural systems that underlie this negative affective state include a group of midbrain structures conceptualized as the extended amygdala3.

 Learning which environmental conditioned stimuli predict danger is essential for survival through Pavlovian fear conditioning. In both, humans and rodents, fear conditioning is amygdala-dependent and rests on analogous neurocircuitry28. Rodent research has epagogically inferred a causative role for dopamine in the amygdala in fear memory formation; however, the participation of dopamine in aversive conditioned stimulus learning in humans is less clear28. It has been discovered that dopamine is released in the amygdala and the striatum during the process of fear learning in humans2829. By using simultaneously positron emission tomography and functional magnetic resonance imaging, it has been recently demonstrated that the amount of dopamine release is directly linked to the magnitude of conditioned fear responses and linearly coupled to learning-induced activity in the amygdala30. Thus, like in rodents, the formation of amygdala-dependent fear memories in humans appears to be supported by the endogenous dopamine release, consistent with an evolutionary conserved neurochemical mechanism responsible for aversive memory formation28.

 The behavior has become compulsive rather than the original pleasurable desire. Thus, the behavioral changes from impulsive to compulsive. The bed nucleus of the stria terminalis constitutes the anatomical substrate of this condition31.

 The activations of these systems tend to increase the production of stress hormones323. Eventually, consuming ethanol or the drug no longer produces pleasure but instead is now used in an effort to escape or evade the highly unpleasant psychological and physiological symptoms of the withdrawal 316.

 Skinnerian escape and avoidance responses characterize this stage. Therefore alcohol and drug consumption has become a highly compulsive need rather than the pleasurable impulsive desire of the beginning.

 Therefore the last stage of the ethanol and drug addiction cycle is the anticipation and craving stage, which frequently means the level whereby an individual`s chronic ethanol or drug consumption may lead to the development of a substance abuse disorder7. While this phase is conceptualized commonly as craving,  it does not, by itself, lead to relapse and another cycle826. This final stage is characterized by a significant loss of prefrontal control and continued ethanol and drug use compromises frontal lobe structures that are critical for evaluation, judgment, and decision making8926. This stage is characterized by altered glutamatergic signaling82631. Glutamate plays a principal role in memory formation and consolidation as well as in the initiation of behavior82631.

 During the anticipation and craving stage, the large amount of dopamine received by the prefrontal cortex during drug and ethanol consumption promotes the reciprocal release of glutamate in the midbrain, thus committing the alcohol or the drug, and the experience to memory3.

 As the plasticity of the brain is continuously shaped and reshaped by the consumption of ethanol and drugs, new paths become consolidated as alcohol-related contextual information is stored by the hippocampus, through the establishment of operant behavior and activation of the basolateral amygdala leads to conditioned responses to a  highly specific, ethanol-related cues (reinforced conditioned stimulus)331. In this manner, chronic alcohol consumption can be considered as a dysfunctional adaptive form of learning whereby alcohol capitalizes on the highly plastic nature of the brain3.

 Extended ethanol consumption then leads to the exploitation and the restructure of the neural circuitry consolidating memories, habits, and goals that place much greater importance on alcohol and drug consumption behavior rather than on the natural rewards3826.

 The total amount of satisfaction diminishes with the drug. However, all the satisfaction is drug-related. The drug becomes a powerful negative reinforcer. The reinforcement is remembered as produced by the consumption of the drug. The consumption of the drug prevents withdrawal. When the withdrawal is already present the response of drug consumption constitutes the behavior of escape. In one situation the subject escapes from the withdrawal syndrome and in the other avoid the withdrawal to appear!

 In the brain, ethanol affects almost all neurotransmitters systems, with acute effects that are frequently the opposite of those following desistance after a period of heavy consumption. The most profound acute actions relate to boosting 𝞬-aminobutyric acid (GABA) activity, especially at the GABAA  receptors3. Enhancement of this very complex chloride channel system significantly contributes to anticonvulsant, sleep-inducing, anti-anxiety, and the muscle-relaxing effects of all GABA-boosting drugs8. The Acute administration of ethanol produces a release of GABA, and the continued consumption increases the density of GABAA  receptors, whereas alcohol withdrawal states, are clearly characterized by a decrease in GABA-related activity38. Of Equal  importance is the ability of acute ethanol consumption to inhibit the post-synaptic N-acetyl-D-aspartate (NMDA) excitatory glutamate receptors, whereas chronic alcohol consumption and desistance are associated with an upregulation of the excitatory receptors' subunits described8. The relationships between greater GABA and diminished NMDA receptor activity during the acute ethanol intoxication and diminished GABA with enhanced NMDA actions during ethanol withdrawal let us understand much of the ethanol intoxication and the withdrawal phenomena8.

 As happens with all pleasurable activities, ethanol consumption acutely increases the dopamine levels in the ventral tegmentum and in the related brain regions, also this effect plays a major role in continued ethanol consumption, craving, and relapse8. The changes in dopamine pathways are also related to increases in cortisol and adrenocorticotropic hormone (ACTH) during acute ethanol intoxication and in the context of withdrawal8. Such alterations are probably to contribute to both the feelings of reward during acute intoxication and the depression during falling blood alcohol concentrations8. Also very close linked to alteration in the dopamine in the nucleus accumbens are ethanol-induced changes in the opioid receptors, with acute ethanol consumption causing the release of β-endorphins38.

 Several additional neurochemical alterations include an increase in the synaptic levels of the neurotransmitter serotonin during acute ethanol consumption and subsequent upregulation of serotonin receptors38. The acute increases in the nicotinic acetylcholine systems contribute to the impact of ethanol in the ventral tegmental region, which occurs in concomitant with enhancing dopamine activity; in the same regions, ethanol impacts on the cannabinoid receptors, which results in the release of dopamine, glutamate, and  GABA as well as consequent impacts on the brain reward circuits38.

The subject with acute ethanol intoxication may experience a blackout which is an episode of anterograde amnesia, even though the person was awake but has forgotten all of what occurred during the acute drinking period8.

Another very common problem that is seen after as few as one or two drinks before bedtime is a state of disturbed sleep8. Even though ethanol could initially help a subject to fall asleep, it alters sleep through for the rest of the night. The stages of sleep are disturbed, and the periods spent in rapid eye movements (REM) and deep sleep initially in the night are diminished7. Ethanol produces relaxation in the muscles of the pharynx which may produce snoring and also exacerbate sleep apnea. The Symptoms of this apnea occur in 75% of men with ethanol use disorders that are older than 60 years. The patients can experience very prominent and sometimes highly disturbing dreams later in the night8. All these sleep perturbations could contribute to relapse to ethanol consumption8.

 Another common very significant adverse consequence of ethanol consumption even at relatively low concentration is impaired mathematical and logical judgment, as well as coordination, which increases the risk of injuries and other personal adverse consequences8. 

 Heavy ethanol consumption could also be associated with headache, thirst, nausea, vomiting, and fatigue the next day, also, the hangover syndrome that is responsible for much-missed time in work and l time, and much more important, with temporary cognitive deficits8.

 The chronic high ethanol doses produce peripheral neuropathy in around 10% of patients with alcohol use disorders which is similar to diabetes, experiencing bilateral limb numbness, tingling, and paresthesias, all being more pronounced distally8. Close to 1% of individuals with alcohol use disorder can develop cerebellar degeneration or atrophy thus producing a syndrome consisting of progressive unsteady stance and gait frequently accompanied by mild nystagmus, neuroimaging studies would demonstrate atrophy of the cerebellar vermis7. Probably as few as 1 in 500 patients with alcohol use disorders would develop total Wernicke´s (ophthalmoparesis, ataxia, and encephalopathy) and Korsakoff`s (severe retrograde and anterograde amnesia) syndromes, but a higher proportion would manifest has one or more neuropathological altered states related to these conditions8. These are produced from low levels of thiamine, especially in those predisposed individuals with transketolase deficiencies8. The repeated heavy ethanol consumption could significantly contribute to progressive cognitive problems and the temporary memory impairment that can last for weeks to months after abstinence8. Brain atrophy, as evidenced by the ventricular system enlargement and widened of the cortical sulci on magnetic resonance scans appears in half of the patients with long-term alcohol use disorders; these derangements tend to be typically reversible if abstinence is strictly maintained8. The adolescents are especially vulnerable to ethanol-related brain derangements8. Thus there is no unique so called syndrome of “alcohol dementia”; rather, this general label describes patients who have reached irreversible cognitive derangements from several causes in the frame of chronic alcohol use disorders8.

Humans inadvertently have produced an artificial selection of organisms that are producers of substances that release dopamine in the nucleus accumbens.

 Humans have artificially selected organisms that produce substances that activate the mesocortical-limbic dopamine reward pathway. The ability to produce these substances has been selected. It is the evolutionary historical origin of all-natural drugs.

 Furthermore, synthetic or artificial drugs are specifically designed to activate the mesocortical-limbic Dopamine reward pathway.

 The human digestive system produces approximately 3 g of ethanol daily through fermentation. Catabolism of ethanol is thus essential, not only of humans but of all organisms. Several amino acid sequences in the enzymes used to oxidize ethanol are evolutionary, going back to the last common ancestor more than 3.5 billion years ago. This function is necessary since all organisms produce small amounts of alcohol by several pathways, mainly through fatty acid synthesis, the metabolism of glycerolipids , the biosynthesis of bile acid pathways. Without this mechanism for catabolizing the alcohols, the body would build up alcohol and become toxic. This is evidence of evolutionary advantage for alcohol catabolism and by sulfotransferase too 13.

 Survival by augmenting the capacity for fructose present in dwindling fruit to be stored as triglycerides, as a consequence of increased uric acid production during the fructose metabolism that emulated lipogenesis and also blocked the fatty acid oxidation32. Furthermore, a mutation in class IV alcohol dehydrogenase ~10 MYA produced a  40-fold increase in the ability to oxidize ethanol, which helped our ancestors to ingest fermenting fruit from the ground. The ethanol ingested would have activated aldose reductase that consequently stimulates the conversion of glucose to fructose, while uric acid produced during ethanol metabolism could further enhance the fructose production and its metabolism32. Aiding survival, and in turn evolutionary reproductive advantage of their genes,  these mutations would have allowed our ancestors to produce more fat, mainly from fructose, to survive and to reproduce the very same mutated advantageous genes32. Sadly, the augmented ability to metabolize and utilize ethanol may now be increasing our risk for alcoholism,  another consequence of the once-adaptive successfully reproduced thrifty genes32.