what happens to the brain with repeated alcohol use
Indian J Hum Genet. 2014 Jan-Mar; 20(i): 20–31.
Neurotransmitters in alcoholism: A review of neurobiological and genetic studies
Niladri Banerjee
Amity Institute of Biotechnology, Amity University, Noida, Uttar Pradesh, India
Abstract
Recent advances in the written report of alcoholism have thrown light on the interest of various neurotransmitters in the phenomenon of booze habit. Various neurotransmitters have been implicated in alcohol addiction due to their imbalance in the brain, which could exist either due to their excess activity or inhibition. This review paper aims to consolidate and to summarize some of the recent papers which take been published in this regard. The review paper will give an overview of the neurobiology of alcohol addiction, followed by detailed reviews of some of the recent papers published in the context of the genetics of alcohol addiction. Furthermore, the author hopes that the present text will be found useful to novices and experts akin in the field of neurotransmitters in alcoholism.
Keywords: γ-amino butyric acid, alcoholism, dopamine, glutamate, serotonin
Introduction
Alcohol is a multi-dimensional entity. It has been around for thousands of years and has been known for its many stimulating and mind altering effects. Alcohol is in essence, a drug, pure and simple. It is a drug which is so ordinarily bachelor in and so many dissimilar forms and guises that it is often hard to fifty-fifty await at it in that fashion.
Alcohol is truly in a course of its own. It doesn't carry the same kind of stigma or social abhorrence which other drugs of corruption such as cocaine, methamphetamines, lysergic acid diethylamide (LSD) etc., carry. Alcohol is widely accustomed in the lodge and consumed by everyone, young and the onetime alike, women and men included. In some societies, alcohol consumption is even accepted equally function of normal social etiquettes. Alcohol is thus, all pervasive and is in this way is the most dangerous drug known to flesh.
Alcohol is the first thing people go for when they are at a social gathering and are looking to have a pleasant time. Information technology is the beginning choice in the long list of things which can make a person experience intoxicated and give that feeling of loftier. Being milder in its 1st time effects when compared with other drugs such as nicotine, people falsely believe that at that place is very little chance of getting addicted to alcohol. However, the encephalon'southward reward pathways are rarely nether voluntary control. For once the brain senses a certain activity giving it pleasance; it volition rewire the brain chemical science in a way which makes the person want to have more of that activity. The action here in this case existence consumption of booze.
Slowly over a period of time, the person craves more of the drug, to achieve the same kind of high as earlier. He thus starts consuming more and more alcohol until a point comes when normal brain chemistry simply cannot function without alcohol. The brain'due south neurobiology has been permanently changed. As an example of the kind of encephalon chemistry changes which take place, the following paradigm shows the brain scan of a methamphetamine addict and a non-addict [Figure 1].
Diagram depicting the difference in the quantities of dopamine receptors in the brain of a methamphetamine aficionado (correct) and non-aficionado (left)
Thus, alcohol is a powerful drug. It affects several neurological pathways and causes meaning changes in the encephalon. Some of the neurological pathways known to be afflicted by booze consumption include the dopaminergic, serotoninergic, γ-amino butyric acrid (GABA) and glutamate pathways.
Alcohol, as a drug, like all the other drugs affects the central nervous system (CNS). The type of alcohol commonly consumed is ethanol with different alcoholic beverages containing different percentages of information technology. Ethanol acts to depress brain office, very much in the style of an anesthetic. Ethanol at depression claret concentrations releases behaviours that are otherwise inhibited and commonly produces feelings of relaxation and good mood which may facilitate socializing. Thus at depression doses, ethanol is possibly useful. Caution still, needs to be exercised as even depression quantities of alcohol bear upon the ability of hippocampus to process information, which in plow impairs retentivity formation. College doses of alcohol affect the brain farther past inducing intoxication wherein the person may experience temporary loss of coordination and judgment.[3]
It must be kept in mind, even so that the uncomplicated consumption of alcoholic beverages does not make a person booze-dependent (AD). The difference between an alcohol addict and an booze non-addict goes beyond the quantity and intensity of alcohol consumed. Long-term alcohol abuse produces physiological changes in the brain such equally tolerance and physical dependence. These changes in the encephalon chemistry maintain the alcoholic'south compulsive disability to cease alcohol consumption drinking and results in alcohol withdrawal syndrome (AWS) upon discontinuation of alcohol. An alcoholic is therefore aware of the harm caused past alcohol on his or her health but, is unable to command such compulsive drinking impulses. Diagnosis of alcoholism is performed via questionnaire based screening methodologies wherein destructive drinking patterns are ascertained. Furthermore, due to both physical and societal factors, the alcoholic woman is more susceptible, compared to the alcoholic man, at suffering the consequences of uncontrolled alcohol consumption.[one,ii]
Discussion
Neurobiology of alcoholism
Alcohol habit takes place primarily through two means. The get-go is a positive reinforcement method and the 2d is a negative reinforcement method. Positive reinforcement represents an ecology situation in which a rewarding stimulus or experience (e.one thousand., alcohol-induced euphoria) increases the chances that the individual displays a certain response (e.g., alcohol-seeking behavior). Negative reinforcement refers to an increase in behavioural patterns, such every bit alcohol ingestion, if the behavior facilitates the private to circumvent or avert an aversive stimulus. An alcoholic trying to abjure from drinking may experience a range of aversive stimuli in the class of alcohol withdrawal symptoms: irritability, anxiety and dysphoria. It is precisely such symptoms which make abstinence difficult and a relapse possible.[four]
Hence, what begins as a balmy way to seek pleasance, soon turns into a full-fledged addiction equally the alcohol begins to crusade widespread neuroadaptations in the encephalon, causing the person to convert from an alcohol non-aficionado to an alcohol addict. Such changes in the reinforcing value of alcohol during the transition from alcohol use to dependence reverberate adaptive neural changes resulting from chronic exposure to high alcohol quantities. Thus, while on one hand, the early stages of nondependent alcohol use is largely motivated past booze'due south positive reinforcing effects, the drinking behavior in the dependent state is likely driven by both the positive and negative reinforcing effects of the drug. Neuroadaptations leading to dependence are driven by a constellation of processes which heighten motivation for booze consumption. Such neuroadaptations crusade alcohol withdrawal symptoms upon cessation of drinking.[4]
Information technology has been posited past[5] that the negative-affective country induced by alcohol withdrawal and especially the increase in anxiety[6] is a major driving forcefulness in the propensity for relapse to alcohol-seeking behavior. The mechanisms involved behind booze sensitization, tolerance, withdrawal and dependence are discussed in the following sections.
The reward pathways
Underlying the encephalon changes and neuroadaptations are the reward and stress circuits of the brain. A neural circuit comprises of a series of neurons which send electro chemical signals to one another. An activated neuron sends chemic signaling molecules called neurotransmitters through the neural circuit which bind to specific molecules called the receptors. Depending upon the circuit involved, the binding of these neurotransmitters may cause excitatory or inhibitory signals to be passed farther along the circuit.
Alcohol interacts with several neurotransmitter systems in the brain's reward and stress circuits. These interactions result in booze'due south astute reinforcing effects. Following chronic exposure, these interactions in plough cause changes in neuronal function that underlie the evolution of alcoholism. The following text introduces some of the neural circuits relevant to AD, categorized by neurotransmitter systems. These neural circuits include the dopaminergic, serotoninergic, glutamatergic and GABAergic neural circuits.
Dopamine pathway
Dopamine is a neurotransmitter primarily involved in a circuit called the mesolimbic system, which projects from the brain's ventral tegmental area to the nucleus accumbens. This circuit affects incentive motivation, i.due east., how an organism reacts to incentive changes in the environment.
Studies accept shown that dopamine has a office in the incentive motivation associated with acute alcohol intoxication. This is then because alcohol consumption tin can be blocked past injecting low doses of a compound that interferes with dopamine's normal action (i.eastward., a dopamine antagonist) directly into the nucleus accumbens.[7,viii] Furthermore, the consumption of alcohol and just the apprehension of availability of alcohol results in production of dopamine in the nucleus accumbens, adamant by the increased levels of dopamine in the fluid outside neurons.[9] However, lesions of the mesolimbic dopamine system do not completely cancel alcohol-reinforced behavior, indicating that dopamine is an important, but not essential, component of alcohol-reinforcement.[10] Finally, alcohol withdrawal produces decreases in dopamine role in dependent individuals and this decreased dopamine office may contribute to withdrawal symptoms and alcohol relapse.[11]
Serotonin pathway
The neurotransmitter serotonin (as well known as 5-hydroxytryptamine or 5-HT) has been a target of interest for potential pharmacotherapy for alcoholism for a long time because of the well-established link between serotonin depletion, impulsivity and booze-drinking behavior in rats and humans.[12] According to[13] pharmacological compounds that target the serotonin organisation by inhibiting neuronal reuptake of serotonin, thereby prolonging its actions, or by blocking specific serotonin receptor subtypes have been shown to suppress alcohol-reinforced beliefs in rats. During alcohol withdrawal, serotonin release in the nucleus accumbens of rats is suppressed and this reduction is partially reversed by cocky-administration of alcohol during withdrawal.[14]
GABA pathway
GABA is the major inhibitory neurotransmitter in the brain. Information technology acts through two receptor subtypes called GABAA and GABAB. Booze acts to increment GABA activity in the brain and information technology does and so through two full general mechanisms. It can for example, human activity on the GABA-releasing (i.e., presynaptic) neuron, causing an increase in GABA release; or it tin can act on the signal-receiving (i.e., postsynaptic) neuron facilitating the activity of the GABAA receptor. The consumption of alcohol is suppressed past compounds that interfere with the actions of the GABAA receptor (i.due east., GABAA receptor antagonists) every bit well every bit compounds that stimulate the GABAB receptor (i.eastward., GABAB agonists) in the nucleus accumbens, ventral pallidum, bed nucleus of the stria terminalis and amygdala.[xv]
Amongst these regions, the fundamental nucleus of the amygdala is an important brain region involved in the regulation of emotional states. This region is specially sensitive to suppression of alcohol drinking by compounds acting on the GABA systems (i.eastward., GABAergic compounds).[16] It has been institute that astute and chronic alcohol exposure indeed results in increases in GABA transmission in this region.[17,18] In addition, compounds that target a specific component of the GABAA receptor circuitous (i.east., the α1-subunit) assistance reduce consumption of booze when injected direct into the ventral pallidum, a encephalon region which receives signals from neurons located in the extended amygdala.[xix,twenty]
The GABA systems in the brain are contradistinct in situations of chronic alcohol exposure. Every bit an example, in some regions of the brain, the expression of genes that encode components of the GABAA receptor is affected due to alcohol. This has been proven by the changes observed in the subunit composition of the receptor in those regions, the well-nigh consequent of which are decreases in α1- and increases in α4-subunits.[21] The function of GABAA receptors also is regulated by molecules known equally neuroactive steroids[22] that are produced both in the brain and in other organs (i.east., in the periphery). There is a marked increase in the levels of many neuroactive steroids following exposure to alcohol.[23] Furthermore,[24] stated that the increase in the activity of neuroactive steroids in the encephalon is not dependent on their product by peripheral organs. These findings therefore indicate that neuroactive steroids are potential central modulators of the altered GABA function which occurs during development of AD by acting direct at GABAA receptors.[24]
Glutamate pathway
Glutamate is the major excitatory neurotransmitter in the brain and it exerts its furnishings through several receptor subtypes, including one called the North-methyl-D-aspartate (NMDA) receptor. Glutamate systems take been known for a long time to be involved in the acute reinforcing actions of alcohol and the outcome of alcohol on an organism tin can be mimicked with the help of NMDA receptor antagonists.[three] Different the example with GABA, booze inhibits glutamate activity in the brain. This can be stated from the fact that astute alcohol exposure causes a drop in the extra cellular glutamate levels in a region of the brain called striatum which contains the nucleus accumbens and other structures.[25] Glutamate mediated signal transmission is suppressed in the primal nucleus of the amygdala following acute administration and it is an effect which is enhanced following chronic alcohol exposure.[26] The glutamate transmission is nearly probable affected due to alterations in the functions of both NMDA receptors[27] and some other receptor subtype known equally metabotropic glutamate subtype 5 receptors.[28] The fact that NMDA receptors are involved in alcoholism is something to take note of every bit they also play a role in neuroplasticity, a procedure characterized past neural reorganization that likely contributes to hyper excitability and craving during booze withdrawal.[29] Compounds targeting the glutamate systems have also begun to exist used for treating AD. As an instance, the agent acamprosate modulates glutamate manual past interim on NMDA and/or metabotropic glutamate receptors.[30] Therefore, past reducing excessive glutamate action, acamprosate blocks excessive alcohol consumption.
This process appears to depend on the interest of genes such as Per2, which is typically involved in maintaining the normal daily rhythm (i.e. the cyclic clock) of an organism.[31] Acamprosate's capability to reduce booze consumption has been seen across different species and the drug has been approved for treatment of alcoholism in humans. This is primarily due to its perceived power to bring near a reduction in alcohol cravings in abstemious alcoholics.[xxx]
Genetics of the advantage pathways
Alcohol addiction and dependence of belatedly has been shown to exist afflicted past the influence of genes. The presence of such genes does not confirm whether a person volition turn into an booze addict, but there is a high correlation amid carriers of such genes and alcohol addiction.
Candidate genes suggested in the development of alcohol addiction are involved in the dopaminergic, serotoninergic, GABA and glutamate pathways.
Dopamine pathway
In the dopaminergic pathway, one such gene is a dopamine receptor D2 (DRD2) which codes for a receptor of dopamine.
Dopamine is an important neurotransmitter involved in advantage mechanism in the brain and thereby influences the development and relapse of Ad. The dopamine and serotonin pathways are shown every bit under [Effigy 2].
Diagram depicting the dopamine (blue) and serotonin pathways (red) in the brain along with the corresponding functions of each
It is classified as a catecholamine (a class of molecules that serve as neurotransmitters and hormones). It is a monoamine (a compound containing nitrogen formed from ammonia by replacement of one or more of the hydrogen atoms by hydrocarbon radicals). Dopamine is a precursor (forerunner) of adrenaline and a closely related molecule, noradrenalin.
The DRD2 gene on chromosome 11 (q22-q23) has been found to exist associated with increased alcohol consumption through mechanisms involving incentive salience attributions and craving in alcoholic patients.[32] The DRD2 is a G protein-coupled receptor located on postsynaptic dopaminergic neurons that is centrally involved in reward-mediating mesocorticolimbic pathways.[33] The DRD2 cistron encodes 2 molecularly distinct isoforms with distinct functions.[34] Signaling through dopamine D2 receptors governs physiologic functions related to locomotion, hormone production and drug abuse.
This DRD2 cistron shows polymorphisms of 3 kinds namely: −141c ins/del; Taq1B; Taq1A. The −141c ins/del allele and Taq1A allele have been implicated with college risks of Ad. With regards to the Taq1A allele, Advertising patients with the DRD2 A (1) allele, are characterized by greater severity of their disorder beyond a range of trouble drinking indices, when compared with patients without this allele.[35] The Taq1A polymorphism has also been implicated in conduct disorder, behavioral phenotype of impulsivity and problematic booze/drug use amongst adolescents.[36] Furthermore, this particular allelic variant has been implicated with increased mortality over a 10 twelvemonth menses in AD individuals.[37] The A1 allele of the DRD2 was significantly associated with paternal history of alcoholism (χ2 (1) = iv.66; P = 0.031) and male person, first-degree, collateral history of alcoholism (χ2 (i) = four.twoscore; P = 0.036). Age at the onset of alcohol-related problems as principal discriminator betwixt type I and type II AD does non seem to be associated by the Taq1A DRD2 polymorphism. However, the A1 allele of the DRD2 may be a marker of male familial alcoholism, which has been associated with blazon 2 Advertizement.[38]
Despite its positive correlation, some studies take produced contradictory results. A study conducted past[39] to assess the association of Taq1A polymorphism and Advertisement in south Indian population yielded negative results.[40,41] likewise did non discover any association with Taq1A polymorphism and Advert amongst Mexican-Americans. Amongst other studies which have found a negative correlation between Taq1A polymorphism and alcoholism are ones carried out by.[42,43,44] Report conducted by[43] found conflicting results regarding Taq1A allele frequency among assessed and non-assessed controls and assessed and non-assessed alcoholics in a population study comprising of Han Chinese, Caucasians and Europeans. The Taq1A allele frequency of non-assessed controls was more than that of non-assessed alcoholics. Nonetheless, the allele frequency of assessed alcoholics was found to exist 3 times that of assessed controls. The study by[42] found alien results for male and female subjects, with female person subjects showing Advert merely on the basis of alcohol disorder.[44] In their study of alcohol-dependence in Smooth population reported negative association betwixt Taq1A allele and Advertizing.
The second allele, −141c ins/del has produced much more contradictory results. For example, a study conducted by[45] on Castilian Caucasian Advertizing patients did not find whatever association with the gene and handling result of Advert patients. Even[46] did not find any association with the − 141c ins/del allele and Advertizing Caucasian men. Co-ordinate to them, evidence cannot be provided that in Advertisement Caucasian men a genetic predisposition for alcoholism along with functional variants of the DRD2 and DRD3 genes are associated with differences in dopamine receptor sensitivity. However, a written report by[40,41] in a Mexican-American population had found a significant correlation between −141c ins/del polymorphism and AD patients. The genotype frequency for the DRD2 −141C ins/del allele was significantly different between alcoholic and control subjects (P = 0.007). Furthermore, a written report conducted past[47] came upward with interesting results. Co-ordinate to them, although there were no pregnant differences in allele frequency between the entire grouping or subgroups of alcoholics and healthy controls, the − 141c del variant of DRD2 might be a protective cistron against development of withdrawal symptoms. However, it might also exist a chance factor in a highly burdened subgroup of alcoholics with a paternal and one thousand paternal history of alcoholism and it might contribute to the substantially college likelihood of suicide in alcoholics.
Single-nucleotide polymorphism Taq1B is closer to the regulatory and structural coding regions (5' region) of the DRD2 and thus supposed to play an important part in gene function.[32] Information technology has been rarely investigated for its association with Ad. Two studies by[xl,41] carried out in Mexican-American population reported conflicting results with regard to the association of this polymorphism with Advertisement. In the study conducted by[32] no allelic or genotypic association of Taq1B polymorphism with AD in North Indians was found, concurring with the findings of[40] which besides reported negative association of Taq1B with Advertisement in Mexican-Americans. Nonetheless, in a subsequent report, the aforementioned group reported an association of Taq1B polymorphism with early on age of onset for alcohol drinking in Mexican-Americans.[41]
Serotonin pathway
Autonomously from the dopamine pathways, the addiction to alcohol has also been suggested through the serotonin pathways. Serotonin is another neurotransmitter that is affected by many of the drugs of abuse, including cocaine, amphetamines, LSD and alcohol. Serotonin is produced past neurons in the raphe nuclei. Raphe nuclei neurons extend processes to and dump serotonin onto almost the unabridged brain, as well as the spinal cord. Serotonin plays a role in many brain processes, including regulation of trunk temperature, sleep, mood, appetite and pain. Problems with the serotonin pathway tin can cause obsessive-compulsive disorder, anxiety disorders and depression. Serotonin as well modulates the behavioral response to unfairness.[48] Most of the drugs used to treat depression today work by increasing serotonin levels in the brain.[49] The image below, shows, the regions of the brain where serotonin reaches [Figure 3].
Diagram depicting the various regions of the brain under the influence of serotonin
Chemically, serotonin is a monoamine neurotransmitter, known as 5-HT. It is a derivative of tryptophan and is extensively constitute in the gastrointestinal tract, platelets and the CNS. Some of the functions of serotonin in the CNS include the regulation of mood, appetite, sleep, likewise as musculus contraction. Serotonin also has some cerebral functions, including in memory and learning. Almost of the brain serotonin is non degraded afterwards use but is collected past serotonergic neurons by serotonin transporters on their cell surfaces. Studies accept revealed nearly 10% of the total variance in anxiety-related personality depends on variations in the clarification of where, when and how many serotonin transporters the neurons should deploy[50] and the effect of this variation was found to interact with the environment in low.[51,52] Serotonin is released into the space betwixt neurons and diffuses over a relatively wide gap (>xx μm) to activate 5-HT receptors located on the dendrites, cell bodies and presynaptic terminals of adjacent neurons. Serotonergic action is terminated primarily via uptake of 5-HT from the synapse. This is accomplished through the specific monoamine transporter for 5-HT, serotonin transporter (SERT), on the presynaptic neuron.
Recently mutations in the SERT gene, commonly known equally 5'- hydroxtryptamine transporter linked polymorphic region (5'-HTTLPR), has been implicated in cases of alcoholism. This gene is constitute on chromosome 17 at 17q11.1-q12. The 5'- HTT gene has primarily two mutations. One mutation is known as the "long" allele and the other mutation is known every bit the "brusk" allele. The departure betwixt the two alleles is that the "brusk" version of the allele has a 44 bp deletion in the 5' regulatory region of the factor. This 44 bp deletion occurs 1 kb upstream from the transcription initiation site of the gene.[53] This is depicted through the following diagram [Figure iv].
Diagram depicting the difference between the 5'-hydroxtryptamine transporter (5-HTT) long allele and 5-HTT curt allele
A study by[54] aimed at looking at the differences in the allele frequency amongst non-alcoholic controls and alcohol-dependent patients in the Yunnan Han population. The study found significant differences in the allele frequency in alcohol-dependent patient and not-alcoholic controls. At (P < 0.05), the proportion of Fifty/L and L/S genotype was significantly smaller in case group than that was in the control grouping (odds ratio [OR] =0.581, P = 0.026). According to the report, 5'-HTTLPR polymorphism may be associated with AD patients and the genotype 50/L or L/S may exist a genetic factor that is responsible for decreasing susceptibility of AD in Yunnan Han population.
Another study by[55] aimed to look at the availability of the SERT in patients with AD. In the study, 11 healthy controls and 28 alcoholic patients were recruited. SERT availability was measured in vivo with single photon emission computed tomography and (123) I-labeled 2-((2-((dimethyl-amino) methyl) phenyl) thio)-five-iodophenylamine in the midbrain, thalamus and striatum. In addition to this, each subject was genotyped for the 5'-HTTLPR polymorphism. The written report found that when compared with healthy controls, patients with pure Advertizement had a significantly lower availability of SERT in the midbrain. The carriers of 1 Fifty (long) allele showed a significantly higher availability of SERT in the striatum compared with non-50 carriers. The study concludes by stating that pure alcoholics may have lower SERT availability in the midbrain and that the 5'-HTTLPR polymorphism may influence SERT availability in patients with anxiety, depression and AD.
Likewise, in a study on Estonian Children and Adolescents,[56] found a positive correlation betwixt substance abuse amongst the adolescents and the 5'-HTTLPR polymorphism. The written report involved 583 children from the Estonian Children Personality Behavior and Health Report who were enrolled at the age of 9 and recalled after at the ages of 15 and 18. According to the study, five'-HTTLPR had age-dependent effects on alcohol, tobacco and drug apply: substance use did not differ by genotype at historic period 9, only at age 15, the participants with the curt (s)/due south genotype had higher tobacco use and at historic period 18, they were more active alcohol, drug and tobacco users.
The findings of the squad led by[57] produce similar findings. In their study, 360 treatment-seeking African American male patients with single and co morbid DSM-IV lifetime diagnoses of alcohol, cocaine and heroin dependence and 187 African American male controls were genotyped for the triallelic 5'-HTTLPR functional polymorphism in the 5-HT transporter gene (SLC6A4). The report found that low 5'-HTTLPR activity (P = 0.011, OR = 2.5 [1.3-four.6]) due to the presence of the brusk allele, were more than common in men with alcohol drug dependence compared with controls.
Nonetheless, the report past[58] produced rather contradictory results. In their written report, higher students (N = 360; 192 women) cocky-reported on drinking motives and negative life events for upward to 4 years through an Internet survey. Report participants provided saliva for genotyping the triallelic (LA vs. LG or S) variants of 5-HTTLPR. The written report found that among men, individuals with two risk alleles (LG or Due south), compared with individuals with the LA/LA allele displayed lower drinking-to-cope motives. Among women, individuals with 1 risk allele (either LG or S), compared with individuals with the LA/LA allele, displayed stronger drinking-to-enhance motives. The association between yearly changes in negative life events and drinking-to-cope motives varied across 5-HTTLPR genotype and gender and was strongest in the positive direction for women with the LA/LA variant. The study concludes by stating that their findings are non consistent with prior speculation that stronger positive associations between life stress and booze use amongst individuals with the LG or South allele are the consequence of increased use of alcohol every bit a method for coping with stress. The study goes on to add that the more research is needed in understanding the gender differences in relating v'-HTTLPR polymorphism with substance corruption.
Likewise, in the report carried out by[59] which aimed at understanding the role of v'-HTTLPR polymorphism with risky alcohol employ in adolescence, at that place was no correlation with drinking to cope motives and the 5'-HTTLPR polymorphism. The study nonetheless plant a positive correlation with drinking to cope motives and the Taq1A polymorphism of the DRD2 gene.
The results of the aforementioned study was therefore in consummate contrast to the results published by[lx] which found a positive correlation of the short (S) allele with binge-drinking beliefs, drinking more than alcohol per occasion, besides every bit drinking to get drunk more often.
The SERT gene or SERT, besides known as SLC6A4 has another polymorphism in intron 2. This polymorphism has therefore accordingly been named as serotonin intron 2 (STin2). It is a variable number of tandem repeats (VNTR) with 3 singled-out alleles. These alleles are of 9 base pair repeats, 10 base pair repeats as well every bit 12 base pair repeats. The 9 base of operations pair repeat is extremely rare and in statistical studies, frequently clubbed with the 10 base pair echo.
Recently, a report by[45] constitute an association betwixt STin2 polymorphism and treatment outcome in Advertizement patients. According to study, the SLC6A4 STin2 12/12 carriers, showed poor six-month time point treatment outcome (32.8% in the expert outcome grouping vs. 64.0% in the poor upshot grouping). On the other hand, patients having the 10/10 genotype had a better treatment outcome. The study concludes by stating that the functional polymorphism of the SLC6A4 factor may have an influence on treatment outcome in AD patients.
All the same, a subsequent study past[61] found no part of STin2 VNTR polymorphism in AD. In the written report, 165 AD patients, 113 heroin dependent patients and 420 good for you controls from a homogeneous Spanish Caucasian population were genotyped using standard methods. The report institute that genotypic frequencies of STin2 VNTR polymorphism did not differ significantly across the three groups. The written report concludes by stating that their data does non back up a role of serotonergic polymorphisms in Advert.
GABA pathway
GABA or GABA is the 3rd neurotransmitter whose functioning is critical in agreement the genetics of alcohol addiction. GABA as a neurotransmitter has been long known to be affected by alcohol consumption. Recently, two sub types of the GABAA receptor take come up into the spotlight for showing what can possibly be a genetic predisposition to booze addiction. These 2 subtypes are namely GABA A receptor α1 (GABRA1) and GABA A receptor α6 (GABRA6). The gene encoding GABRA1 is located on chromosome 5 at 5q34-35 while the gene encoding GABRA6 is located on the same chromosome at 5q34. According to a study past,[62] a significant correlation was found with the GABRA1 genotype and Collaborative Written report of the Genetics of Alcoholism (COGA) AD, history of blackouts, age at first drunkenness every bit well as the level of response to alcohol. The study concludes past stating that the efforts to characterize genetic contributions to Advertizing may benefit past examining booze-related behaviors in addition to clinical Advertizing.
Furthermore, a study on Korean population past[63] constitute a positive association between alcoholism and the GABRA1 and GABRA6 receptors. Co-ordinate to the researchers, genetic polymorphisms of the GABAA α1 and GABAA α6 receptor gene may be associated with the evolution of alcoholism and that the GG genotype of the GABAA α1 receptor gene play a vital role in the development of the early on onset and the astringent blazon of alcoholism.
Another study on Taiwanese Han population plant similar results. In the study conducted by[64] it was found that GABRA6 and GABRA1 genes account for alcohol susceptibility in Han and exert their genetic influences in a somewhat dominant and synergistic fashion.
However, non all studies have produced favorable results. In a study conducted by,[65] which looked at the data nerveless from a big number of multiplex, alcoholic families under the COGA, no association was found betwixt the GABRA1 and GABRA6 markers and AD. Similarly, some other study conducted by[66] found no clan between the genes encoding GABRA1 and GABRA6 with alcoholism.
Glutamate pathway
The 4th pathway which interests u.s. and is of note for booze addiction is the pathway of glutamate. There accept been some studies conducted into the interest of this pathway in the process of alcohol addiction. According to one study published by[67] concrete dependence, which refers to the pharmacological tolerance induced by chronic alcohol intake, results in AWS and is neurobiologically supported by the imbalance between GABA and glutamate-NMDA neurotransmission.
In improver, one of the latest studies on this pathway found an clan between a polymorphism in the promoter of a glutamate receptor subunit factor and alcoholism. The written report was conducted by[68] and the study found that short alleles were significantly less frequent amidst AD subjects. The study concludes by stating that it was the 1st time that such an association was found with the stated polymorphism and Advertizement.
Determination
The field of neurotransmitters is a highly agile field of research nowadays. Unlike alleles of the genes in the various pathways are beingness studied in different population groups across the world. However, what remains to be seen is a definitive consensus on a causative allele of alcoholism. There are conflicting reports in this regard with different population groups having dissimilar alleles as risk factors. Moreover, new alleles are also beingness discovered wherein an association exists betwixt the stated allele and alcoholism. Every bit a reviewer, I would suggest one possible way to overcome much of the conflicting reports would be to perform studies with a much larger sample size. Such efforts are hampered by inadequate funding, so collaborative efforts on a national scale, combining the skills and infrastructures of different hospitals and psychiatric intendance centers could potentially overcome this problem.
A wide consensus does exist equally to the involvement of various neurotransmitter pathways, but defining the precise causative alleles or groups of alleles in the genes of the particular neurotransmitter pathways involved in alcoholism is a challenge to be overcome in the coming years.
Limitation of the Review
The review of the papers presented does carry some inherent biases which I shall henceforth disclose:
-
Publication bias: Papers were selected by a rigorous search of PubMed. Grey literature and papers unavailable in an electronic format were not searched
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Choice bias: The pathways of dopamine, serotonin, GABA and glutamate; the specific alleles of the genes involved in the pathways were selected due to prior work performed in my graduate dissertation at a premier hospital in Republic of india
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Linguistic communication bias: Just English sources were searched. Non-English sources were non searched.
Acknowledgments
I would like to acknowledge my faculty at Amity Institute of Biotechnology, Dr. Manju Pathak for her unwavering support and encouragement in writing this review paper. She single-handedly inspired me to undertake this task and the work would not accept borne fruition without her support and guidance. Thanks are also due to my mother, Dr. Sharmila Banerjee, without whose back up and editorial help, I could non have had the will to complete this piece of work. Furthermore, I would like to state that no financial help in any form was received for undertaking this work.
Footnotes
Source of Back up: Nil
Conflict of Interest: None declared.
References
one. Walter H, Gutierrez K, Ramskogler One thousand, Hertling I, Dvorak A, Lesch OM. Gender-specific differences in alcoholism: Implications for treatment. Arch Womens Ment Wellness. 2003;vi:253–8. [PubMed] [Google Scholar]
2. Blum LN, Nielsen NH, Riggs JA. Alcoholism and alcohol abuse among women: Report of the Council on Scientific Affairs. American Medical Association. J Womens Health. 1998;7:861–71. [PubMed] [Google Scholar]
3. Gilpin NW, Koob GF. Neurobiology of alcohol dependence: Focus on motivational mechanisms. Alcohol Res Wellness. 2008;31:185–95. [PMC gratuitous article] [PubMed] [Google Scholar]
iv. Ji D, Gilpin NW, Richardson HN, Rivier CL, Koob GF. Effects of naltrexone, duloxetine, and a corticotropin-releasing factor type 1 receptor adversary on binge-like alcohol drinking in rats. Behav Pharmacol. 2008;19:i–12. [PMC gratuitous article] [PubMed] [Google Scholar]
v. Koob GF. Alcoholism: Allostasis and beyond. Booze Clin Exp Res. 2003;27:232–43. [PubMed] [Google Scholar]
six. Valdez GR, Roberts AJ, Chan K, Davis H, Brennan M, Zorrilla EP, et al. Increased ethanol self-administration and anxiety-like behavior during astute ethanol withdrawal and protracted forbearance: Regulation by corticotropin-releasing cistron. Alcohol Clin Exp Res. 2002;26:1494–501. [PubMed] [Google Scholar]
7. Hodge CW, Samson HH, Chappelle AM. Alcohol self-assistants: Further test of the office of dopamine receptors in the nucleus accumbens. Alcohol Clin Exp Res. 1997;21:1083–91. [PubMed] [Google Scholar]
8. Rassnick S, Pulvirenti L, Koob GF. Oral ethanol self-administration in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens. Psychopharmacology (Berl) 1992;109:92–8. [PubMed] [Google Scholar]
9. Weiss F, Lorang MT, Blossom Fe, Koob GF. Oral booze self-administration stimulates dopamine release in the rat nucleus accumbens: Genetic and motivational determinants. J Pharmacol Exp Ther. 1993;267:250–8. [PubMed] [Google Scholar]
10. Rassnick Southward, Stinus 50, Koob GF. The effects of six-hydroxydopamine lesions of the nucleus accumbens and the mesolimbic dopamine system on oral self-administration of ethanol in the rat. Brain Res. 1993;623:16–24. [PubMed] [Google Scholar]
11. Volkow ND, Wang GJ, Telang F, Fowler JS, Logan J, Jayne M, et al. Profound decreases in dopamine release in striatum in detoxified alcoholics: Possible orbitofrontal involvement. J Neurosci. 2007;27:12700–6. [PMC free commodity] [PubMed] [Google Scholar]
12. Virkkunen Yard, Linnoila Grand. Serotonin in early onset, male alcoholics with violent behaviour. Ann Med. 1990;22:327–31. [PubMed] [Google Scholar]
13. Johnson BA. Update on neuropharmacological treatments for alcoholism: Scientific basis and clinical findings. Biochem Pharmacol. 2008;75:34–56. [PMC free article] [PubMed] [Google Scholar]
fourteen. Weiss F, Parsons LH, Schulteis K, Hyytiä P, Lorang MT, Blossom Fe, et al. Ethanol cocky-assistants restores withdrawal-associated deficiencies in accumbal dopamine and five-hydroxytryptamine release in dependent rats. J Neurosci. 1996;xvi:3474–85. [PMC free article] [PubMed] [Google Scholar]
15. Koob GF. A role for GABA mechanisms in the motivational effects of alcohol. Biochem Pharmacol. 2004;68:1515–25. [PubMed] [Google Scholar]
16. Hyytiä P, Koob GF. GABAA receptor antagonism in the extended amygdala decreases ethanol cocky-administration in rats. Eur J Pharmacol. 1995;283:151–nine. [PubMed] [Google Scholar]
17. Roberto Thou, Madamba SG, Moore SD, Tallent MK, Siggins GR. Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat fundamental amygdala neurons. Proc Natl Acad Sci U Due south A. 2003;100:2053–8. [PMC free commodity] [PubMed] [Google Scholar]
18. Roberto M, Madamba SG, Stouffer DG, Parsons LH, Siggins GR. Increased GABA release in the key amygdala of ethanol-dependent rats. J Neurosci. 2004;24:10159–66. [PMC costless article] [PubMed] [Google Scholar]
19. Harvey SC, Foster KL, McKay PF, Carroll MR, Seyoum R, Woods JE, 2nd, et al. The GABA (A) receptor alpha1 subtype in the ventral pallidum regulates alcohol-seeking behaviors. J Neurosci. 2002;22:3765–75. [PMC free article] [PubMed] [Google Scholar]
20. June HL, Foster KL, McKay PF, Seyoum R, Woods JE, Harvey SC, et al. The reinforcing backdrop of booze are mediated by GABA (A1) receptors in the ventral pallidum. Neuropsychopharmacology. 2003;28:2124–37. [PubMed] [Google Scholar]
21. Biggio G, Concas A, Follesa P, Sanna E, Serra M. Stress, ethanol, and neuroactive steroids. Pharmacol Ther. 2007;116:140–71. [PMC gratis commodity] [PubMed] [Google Scholar]
22. Lambert JJ, Belelli D, Harney SC, Peters JA, Frenguelli BG. Modulation of native and recombinant GABA (A) receptors by endogenous and synthetic neuroactive steroids. Brain Res Brain Res Rev. 2001;37:68–80. [PubMed] [Google Scholar]
23. VanDoren MJ, Matthews DB, Janis GC, Grobin Air-conditioning, Devaud LL, Morrow AL. Neuroactive steroid 3alpha-hydroxy-5alpha-pregnan-twenty-one modulates electrophysiological and behavioral actions of ethanol. J Neurosci. 2000;20:1982–9. [PMC costless commodity] [PubMed] [Google Scholar]
24. Sanna E, Talani G, Busonero F, Pisu MG, Purdy RH, Serra K, et al. Brain steroidogenesis mediates ethanol modulation of GABAA receptor activity in rat hippocampus. J Neurosci. 2004;24:6521–thirty. [PMC free article] [PubMed] [Google Scholar]
25. Carboni S, Isola R, Gessa GL, Rossetti ZL. Ethanol prevents the glutamate release induced past N-methyl-D-aspartate in the rat striatum. Neurosci Lett. 1993;152:133–half dozen. [PubMed] [Google Scholar]
26. Roberto Chiliad, Schweitzer P, Madamba SG, Stouffer DG, Parsons LH, Siggins GR. Acute and chronic ethanol alter glutamatergic manual in rat central amygdala: An in vitro and in vivo analysis. J Neurosci. 2004;24:1594–603. [PMC gratis article] [PubMed] [Google Scholar]
27. Lovinger DM, White G, Weight FF. Ethanol inhibits NMDA-activated ion electric current in hippocampal neurons. Science. 1989;243:1721–4. [PubMed] [Google Scholar]
28. Blednov YA, Harris RA. Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption: Relationship to acamprosate deportment. Int J Neuropsychopharmacol. 2008;11:775–93. [PMC free article] [PubMed] [Google Scholar]
29. Pulvirenti L, Diana Chiliad. Drug dependence every bit a disorder of neural plasticity: Focus on dopamine and glutamate. Rev Neurosci. 2001;12:141–58. [PubMed] [Google Scholar]
30. Littleton JM. Acamprosate in booze dependence: Implications of a unique mechanism of action. J Aficionado Med. 2007;ane:115–25. [PubMed] [Google Scholar]
31. Spanagel R, Pendyala Chiliad, Abarca C, Zghoul T, Sanchis-Segura C, Magnone MC, et al. The clock factor Per2 influences the glutamatergic system and modulates booze consumption. Nat Med. 2005;11:35–42. [PubMed] [Google Scholar]
32. Prasad P, Ambekar A, Vaswani M. Dopamine D2 receptor polymorphisms and susceptibility to alcohol dependence in Indian males: A preliminary written report. BMC Med Genet. 2010;eleven:24. [PMC free article] [PubMed] [Google Scholar]
33. Neville MJ, Johnstone EC, Walton RT. Identification and label of ANKK1: A novel kinase gene closely linked to DRD2 on chromosome ring 11q23.1. Hum Mutat. 2004;23:540–5. [PubMed] [Google Scholar]
34. Usiello A, Baik JH, Rougé-Pont F, Picetti R, Dierich A, LeMeur M, et al. Singled-out functions of the 2 isoforms of dopamine D2 receptors. Nature. 2000;408:199–203. [PubMed] [Google Scholar]
35. Connor JP, Young RM, Lawford BR, Ritchie TL, Noble EP. D (two) dopamine receptor (DRD2) polymorphism is associated with severity of booze dependence. Eur Psychiatry. 2002;17:17–23. [PubMed] [Google Scholar]
36. Esposito-Smythers C, Spirito A, Rizzo C, McGeary JE, Knopik VS. Associations of the DRD2 TaqIA polymorphism with impulsivity and substance use: Preliminary results from a clinical sample of adolescents. Pharmacol Biochem Behav. 2009;93:306–12. [PMC gratis article] [PubMed] [Google Scholar]
37. Berggren U, Fahlke C, Berglund KJ, Wadell Yard, Zetterberg H, Blennow K, et al. Dopamine D2 receptor genotype is associated with increased mortality at a 10-year follow-upwards of alcohol-dependent individuals. Alcohol Alcohol. 2010;45:ane–5. [PubMed] [Google Scholar]
38. Pinto Eastward, Reggers J, Gorwood P, Boni C, Scantamburlo G, Pitchot W, et al. The TaqI A DRD2 polymorphism in type II alcohol dependence: A marker of age at onset or of a familial affliction? Alcohol. 2009;43:271–5. [PubMed] [Google Scholar]
39. Shaikh KJ, Naveen D, Sherrin T, Murthy A, Thennarasu K, Anand A, et al. Polymorphisms at the DRD2 locus in early-onset alcohol dependence in the Indian population. Addict Biol. 2001;6:331–five. [PubMed] [Google Scholar]
twoscore. Konishi T, Calvillo M, Leng AS, Lin KM, Wan YJ. Polymorphisms of the dopamine D2 receptor, serotonin transporter, and GABA (A) receptor beta (three) subunit genes and alcoholism in Mexican-Americans. Alcohol. 2004;32:45–52. [PubMed] [Google Scholar]
41. Konishi T, Luo HR, Calvillo G, Mayo MS, Lin KM, Wan YJ. ADH1B*1, ADH1C*ii, DRD2 (-141C Ins), and 5-HTTLPR are associated with alcoholism in Mexican American men living in Los Angeles. Alcohol Clin Exp Res. 2004;28:1145–52. [PubMed] [Google Scholar]
42. Lucht M, Barnow S, Schroeder W, Grabe HJ, Rosskopf D, Brummer C, et al. Booze consumption is associated with an interaction between DRD2 exon 8 A/A genotype and self-directedness in males. Neuropsychobiology. 2007;56:24–31. [PubMed] [Google Scholar]
43. Noble EP. The D2 dopamine receptor gene: A review of association studies in alcoholism and phenotypes. Booze. 1998;16:33–45. [PubMed] [Google Scholar]
44. Samochowiec J, Kucharska-Mazur J, Grzywacz A, Jabłoński M, Rommelspacher H, Samochowiec A, et al. Family-based and case-control study of DRD2, DAT, 5HTT, COMT genes polymorphisms in alcohol dependence. Neurosci Lett. 2006;410:1–5. [PubMed] [Google Scholar]
45. Florez G, Saiz P, Garcia-Portilla P, Alvarez Southward, Nogueíras L, Morales B, et al. Association between the Stin2 VNTR polymorphism of the serotonin transporter gene and handling outcome in alcohol-dependent patients. Alcohol Booze. 2008;43:516–22. [PubMed] [Google Scholar]
46. Wiesbeck GA, Dürsteler-MacFarland KM, Wurst FM, Walter 1000, Petitjean S, Müller S, et al. No association of dopamine receptor sensitivity in vivo with genetic predisposition for alcoholism and DRD2/DRD3 gene polymorphisms in alcohol dependence. Aficionado Biol. 2006;eleven:72–v. [PubMed] [Google Scholar]
47. Johann M, Putzhammer A, Eichhammer P, Wodarz Northward. Clan of the -141C Del variant of the dopamine D2 receptor (DRD2) with positive family history and suicidality in German alcoholics. Am J Med Genet B Neuropsychiatr Genet. 2005;132B:46–ix. [PubMed] [Google Scholar]
48. Crockett MJ, Clark Fifty, Tabibnia G, Lieberman Doctor, Robbins TW. Serotonin modulates behavioral reactions to unfairness. Science. 2008;320:1739. [PMC complimentary article] [PubMed] [Google Scholar]
49. Benmansour Southward, Cecchi Grand, Morilak DA, Gerhardt GA, Javors MA, Gould GG, et al. Furnishings of chronic antidepressant treatments on serotonin transporter part, density, and mRNA level. J Neurosci. 1999;xix:10494–501. [PMC free article] [PubMed] [Google Scholar]
l. Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter cistron regulatory region. Science. 1996;274:1527–31. [PubMed] [Google Scholar]
51. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT cistron. Science. 2003;301:386–9. [PubMed] [Google Scholar]
52. Levinson DF. The genetics of low: A review. Biol Psychiatry. 2006;60:84–92. [PubMed] [Google Scholar]
53. Heils A, Teufel A, Petri S, Stöber G, Riederer P, Bengel D, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem. 1996;66:2621–4. [PubMed] [Google Scholar]
54. Wang XJ, Zhong SR, Bao JJ, Dou SJ, Wu WY, Jing Q. Association of polymorphism in the serotonin transporter gene promote with the susceptibility to alcohol dependence in Yunnan Han Population. Yi Chuan. 2011;33:48–53. [PubMed] [Google Scholar]
55. Ho PS, Shih MC, Ma KH, Huang WS, Ho KK, Yen CH, et al. Availability of the serotonin transporter in patients with alcohol dependence. World J Biol Psychiatry. 2011;12:134–42. [PubMed] [Google Scholar]
56. Merenäkk Fifty, Mäestu J, Nordquist N, Parik J, Oreland L, Loit HM, et al. Effects of the serotonin transporter (five-HTTLPR) and α2A-adrenoceptor (C-1291G) genotypes on substance use in children and adolescents: A longitudinal report. Psychopharmacology (Berl) 2011;215:13–22. [PubMed] [Google Scholar]
57. Enoch MA, Gorodetsky E, Hodgkinson C, Roy A, Goldman D. Functional genetic variants that increase synaptic serotonin and 5-HT3 receptor sensitivity predict alcohol and drug dependence. Mol Psychiatry. 2011;xvi:1139–46. [PMC complimentary article] [PubMed] [Google Scholar]
58. Armeli South, Conner TS, Covault J, Tennen H, Kranzler 60 minutes. A serotonin transporter gene polymorphism (v-HTTLPR), drinking-to-cope motivation, and negative life events among college students. J Stud Booze Drugs. 2008;69:814–23. [PMC free article] [PubMed] [Google Scholar]
59. van der Zwaluw CS, Kuntsche E, Engels RC. Risky alcohol apply in adolescence: The role of genetics (DRD2, SLC6A4) and coping motives. Alcohol Clin Exp Res. 2011;35:756–64. [PubMed] [Google Scholar]
60. Herman AI, Philbeck JW, Vasilopoulos NL, Depetrillo PB. Serotonin transporter promoter polymorphism and differences in alcohol consumption behaviour in a college student population. Alcohol Alcohol. 2003;38:446–9. [PubMed] [Google Scholar]
61. Saiz PA, Garcia-Portilla MP, Florez G, Arango C, Corcoran P, Morales B, et al. Differential function of serotonergic polymorphisms in booze and heroin dependence. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:695–700. [PubMed] [Google Scholar]
62. Dick DM, Plunkett J, Wetherill LF, Xuei Ten, Goate A, Hesselbrock V, et al. Association between GABRA1 and drinking behaviors in the collaborative study on the genetics of alcoholism sample. Alcohol Clin Exp Res. 2006;30:1101–10. [PubMed] [Google Scholar]
63. Park CS, Park SY, Lee CS, Sohn JW, Hahn GH, Kim BJ. Association betwixt alcoholism and the genetic polymorphisms of the GABAA receptor genes on chromosome 5q33-34 in Korean population. J Korean Med Sci. 2006;21:533–eight. [PMC free article] [PubMed] [Google Scholar]
64. Chang YT, Sunday HS, Fann CS, Chang CJ, Liao ZH, Huang JL, et al. Association of the gamma-aminobutyric acid A receptor gene cluster with booze dependence in Taiwanese Han. Mol Psychiatry. 2002;vii:828–nine. [PubMed] [Google Scholar]
65. Dick DM, Edenberg HJ, Xuei X, Goate A, Hesselbrock V, Schuckit K, et al. No association of the GABAA receptor genes on chromosome 5 with alcoholism in the collaborative study on the genetics of alcoholism sample. Am J Med Genet B Neuropsychiatr Genet. 2005;132B:24–viii. [PubMed] [Google Scholar]
66. Vocal J, Koller DL, Foroud T, Carr K, Zhao J, Rice J, et al. Clan of GABA (A) receptors and alcohol dependence and the effects of genetic imprinting. Am J Med Genet B Neuropsychiatr Genet. 2003;117B:39–45. [PubMed] [Google Scholar]
67. Rolland B, Karila L, Guardia D, Cottencin O. Pharmaceutical approaches of binge drinking. Curr Pharm Des. 2011;17:1333–42. [PubMed] [Google Scholar]
68. Domart MC, Benyamina A, Lemoine A, Bourgain C, Blecha L, Debuire B, et al. Association between a polymorphism in the promoter of a glutamate receptor subunit gene (GRIN2A) and alcoholism. Addict Biol. 2012;17:783–5. [PubMed] [Google Scholar]
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