Alcohol dependence is a highly prevalent disease that consists of the need to consume alcohol at high levels consistently despite the harmful effects. Individuals with Alcohol Use Disorder (AUD) understand the addictive behavior is maladaptive and hinders normal functioning. It was previously thought that addiction to alcohol was gained the same way other addictive substances utilize the dopaminergic system. However, within the past decade, a new model of alcohol addiction has developed centering on GABA neurotransmission through the cerebellum. This model suggests that the target of sensitivity to AUD lies in the cerebellum and its associated GABA receptors. An important distinction in this research is that it shows the changes in GABA neurotransmission in the cerebellum that occurs at low, recreational levels of alcohol. This is significant because AUD acquisition is not due to initially imbibing high levels of alcohol. This fact is highlighted by a genetic difference found in the cerebellar tonic GABA receptor in the alcohol dependent phenotype. In the presence of low levels of alcohol, tonic GABAA receptors of the low-consuming phenotype will enhance the suppression of cerebellar projections. This same mechanism of action is lost in high-consuming phenotypes; thus, making them genetically sensitive to alcohol. This genetic difference is a viable therapeutic target that may make AUD an easily treatable, less prevalent disorder.
1. Background
AUD is one of the substance related disorders outlined in the Fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5).1 AUD is characterized by multiple physical and behavioral symptoms that include withdrawal, craving, and tolerance. AUD is an abnormal condition because it causes maladaptive behavioral patterns that affect multiple aspects of a person’s life.1 It was once believed that addictive behavior, like that illustrated in AUD, was reinforced by experiencing reward and pleasure activated by the mesolimbic dopaminergic pathway in the nucleus accumbens.2 However, recently there has been a shift in research to show potential neurological significance in the γ-aminobutyric acid (GABA) transmission pathway in maladaptive addictive behaviors.3 The development of this correlation exposes the GABAergic system and GABA receptors as a potential target for therapy.4–7
1.1 AUD Criteria and Epidemiology
According to the DSM-5, there are eleven criteria for diagnosing AUD that must occur within twelve months and cause personal distress.1 To be diagnosed, a patient must meet at least two criteria. The severity of the disorder is contingent on how many criteria are present. Examples of criteria for diagnosis include an intense craving for alcohol, an increased tolerance, and withdrawal symptoms typically characteristic of addiction.1 An array of factors are believed to contribute to increased risk. Genetic factors, such as single nucleotide polymorphisms, put a family member of someone diagnosed with AUD is three to four times more likely to be highly susceptible to AUD. In addition, socioeconomic and ethnicity factors may also increase the risk of AUD onset. The hallmark of AUD is consistent heavy alcohol use that hinders a person from living a normal functional life and causes personal suffering. This distinction highlights that even light alcohol use with occasional inebriation is not sufficient to make a diagnosis of AUD.1
After the DSM-5 was published, an independent epidemiological study was conducted using the revised criteria outlined in this new edition of the DSM for AUD.8 The study’s goal is to represent the twelve-month and lifetime prevalence of AUD and its associated comorbidity with other psychiatric disorders. This study used a face-to-face interview method like the previous epidemiological study on this topic when the DSM-4 was released. The study found that the prevalence for a 12-month period was 14% and the lifetime prevalence was 29%. Also, men typically have a higher prevalence than women. Notably, study respondents of low-income had the greatest prevalence for the survey’s time frames.8 The epidemiological investigation concluded that AUD is a very common disorder that is debilitating for those afflicted and is frequently left untreated.8 According to the alcohol-related disease impact reported by the Center for Disease Control, between 2006 to 2010 there were 88,129 deaths attributed to excessive alcohol use.9 These findings show that AUD poses a significant public health problem and presents a preventable cause of death that beckons researchers to find effective treatment.8,9
1.2 Current FDA Approved Treatments
The goal of treatment is to maintain consistent abstinence from alcohol consumption and to diminish the reinforcement of addictive behavior; however, many of the drugs historically used do not adequately accomplish this.10,11 The only three active pharmaceutical agents currently approved by the U.S. Food and Drug Administration (FDA) in the treatment of AUD are disulfiram, naltrexone, and acamprosate.2,10 Disulfiram was the first FDA-approved drug for clinical use to treat AUD.10 Disulfiram’s mechanism of action is to inhibit aldehyde dehydrogenase, an alcohol metabolism enzyme, in the liver and brain causing an accumulation of acetaldehyde which has detrimental side effects. If the drug is taken before consuming alcohol, it will cause vomiting, vertigo, a decrease in blood pressure, and blurry vision. Understandably, these noxious side effects lead to low patient compliance and also why this drug is not widely prescribed in the United States.10
Naltrexone was approved by the FDA in 1994 and works as a µ-opioid receptor inhibitor.10 The idea behind this mechanism is that some individuals who suffer from AUD have an endogenous opioid deficiency which makes them more susceptible to addictive tendencies. Unfortunately, naltrexone may reduce the amount of alcohol intake but is ineffective in promoting complete abstinence.10 Ten years after the approval of Naltrexone, the FDA released acamprosate for clinical use.10 The chemical structure of acamprosate resembles GABA, glutamate and other neurotransmitters and thus is hypothesized to help balance the chemicals in the brain that are disrupted by withdrawal. Acamprosate is not effective at alcohol abstinence. Despite these drugs, there is still an overwhelming need to find better treatment for AUD.10 The call for continued abstinence with successful treatment, along with a better understanding of genetic polymorphisms in susceptibility to AUD, has paved the way for researchers to explore the effects of GABA neurotransmission in AUD treatment.3,10,12
1.3 The Effects and Role of GABA
The main inhibitory neurotransmitter in the brain is GABA.2,13 Cumulative research has provided evidence for GABA receptors as candidates for therapeutic targeting. There are two types of receptors that are acted on by GABA: GABAA and GABAB receptors. The dynamic effects of GABA neurotransmission determined not only by the type of receptor class but also by the location of that receptor.2,13
The GABAB receptor acts as a metabotropic G-protein coupled receptor (GPCR).13 GABAB receptors have different mechanisms of actions depending on their position on either the presynaptic or postsynaptic neuron. On the presynaptic neuron, GABAB receptors limit the release of neurotransmitter by inhibiting Ca2+ channels from opening. This prevents synaptic vesicle fusion and neurotransmitter release into the synaptic cleft. Postsynaptic GABAB receptors use G proteins to regulate the opening of K+ channels.13 Research suggests this receptor may be a viable therapeutic target because positive allosteric modulators (PAMs) for GABAB receptors help decrease rodent alcohol-induced reinforcement patterns.4,6 An example of a GABAB agonist commonly used in research settings to study GABAB PAMs is baclofen.4,6,13 Baclofen is a GABAB agonist that inhibits the release of dopamine and is routinely used to determine the extent of a particular GABAB PAM’s ability.2,4,6,13
GABAA receptors (GABAAR) function as a ligand-gated chloride channel that allows the influx of Cl- ions to hyperpolarize the post-synaptic neuron.2,13 However, this type of inhibition can also act in drastically different ways depending on the location of the receptor.2 If the receptor is located outside of the synapse (extrasynaptic) it will exhibit tonic, persistent inhibition of the neuron. If the GABAAR is located on the postsynaptic neuron inside the synaptic cleft then it will function with a phasic mechanisms of action. The structure of the isotypes of the GABAAR begets their function. The varying subunits imbues the GABA receptor isotypes with different kinetic and physiological properties. The GABAAR is a heteropentamer that is made of varying combinations of an α, β, γ, δ, ε, or θ subunit. The α has six variations in order from 1-6 while β and γ both have 3 variations from 1-3. Extrasynaptic GABAAR lack the γ subunit but typically have the δ subunit.2 This distinction is of pharmacological importance because the δ subunit is more sensitive to alcohol.2,3 Tonic GABAARs with the δ subunit are typically found in the nucleus accumbens (NAc) and cerebellum, therefore these areas are a target of research.2,5,7 Although, previous research focused on the NAc, the cerebellum and it’s tonic GABAARs appears to primarily influence alcohol dependence.2,5,7 Thus, the cerebellum is the focus of current research on alcohol dependence.5,7,14,15
1.5 Emergence of the Cerebellum’s Role in Alcohol Dependence
Stimulation of dopaminergic neurons in the mesolimbic pathway, staring in the ventral tegmental area (VTA) in the midbrain leading to the nucleus accumbens (NAc) in the forebrain, has long been associated with reinforcement of addictive behaviors through reward and pleasure.2 However, this pathway seems to be indirectly stimulated when it concerns the use of alcohol.2,5,7 The mechanism of inhibiting the function of GABA, possibly in the cerebellum, seems to be the link.2 Although, the cerebellum is most commonly known to aid in coordination and motor control, it also projects through the thalamus into the pre-frontal cortex.14,16 This connection indicates that the cerebellum may influence higher cognitive thinking using distinct areas of the cerebellum to influence specialized functions.14,16
Deficits in cerebellar volume correlate to alcohol dependence or repeated high alcohol use.14,17 These deficits can render executive functioning more difficult.14 Typically, the early onset of drinking has a high correlation with an individual’s genetic predisposition to AUD. Cerebellar volume deficits may be inherently part of cerebellum genetics or merely a product of longer alcohol exposure due to the early onset.14 The current research aims to sift through the connections laid by the previous groundwork in hopes of providing viable targets in the cerebellum and its associated GABARs.2,6,7 Of particular interest is the tonic GABAA receptors located on the granule cells (GC) of the cerebellum.5,7,18 Granule cells are specialized set of interneurons that function in cerebellar neurotransmission and purkinje cells (PC) function as output projections of the cerebellum.7,18 Thus, GC tonic GABAA receptors are the targets of current preclinical research.5,7
2. Scientific Research
Historically, AUD has an observed genetic link that is a factor in an individual’s predisposition.1,2,8,14 The genetics have not been completely understood but there is evidence that differences in the cerebellar GABAA receptor genotypes may illuminate this link.2,5,7 Thus, recent research studies focus on GABA neurotransmission in the cerebellum by comparing genotypes of the GABAA receptor subunits and the effect of GABAA receptor agonists on alcohol consumption in a mouse model.2,5,7 The research attempts to find a correlation between the cerebellar GABAA receptor genotype and the alcohol dependent phenotype of high-consuming mice.7 This correlation can prove promising in the application of pharmacological agents that alter the receptor’s effects in the presence of alcohol. This may diminish the reinforcement properties of alcohol consumption in those with a predisposition.7
2.1 Tonic cerebellar GABAA receptor genotypes and their response to receptor agonists7
Mouse lines that are high alcohol consuming (B6 mice) or low alcohol consuming (D2 mice) are used as sufficient comparative test subjects.5,7 There are two goals in the recent research presented using these two distinct mice.7 The current research is designed to show if the granule cells (GCs) of the cerebellum are the primary input target of EtOH on the cerebellum instead of other possible targets in the cerebellum. The other goal is to observe the effect of modulating this pathway on the EtOH consumption. Behavioral studies are used to better understand if cerebellar transmission modulation by the GC tonic GABAA receptor influence EtOH consumption directly or not. To test these goals, two separate sets of experiments were used. One to demonstrate the impact EtOH has on cerebellar electrophysiology and the other focuses on behavior modification of mice in the presence of a GABAA receptor agonists.7
Before electrophysiology studies of cerebellar slices took place, 9mM and 31mM concentrations of EtOH were previously found experimentally to be of physiological importance in the D2 and B6 mouse lines.5,7 In previous studies, at 9 mM EtOH only the D2 mice exhibited loss of body control showing EtOH had affected the cerebellum. Only at 31 mM EtOH do B6 mice show the same cerebellar effects. It is important to note that the researchers standardize the 9 mM EtOH to the represent the typical consumption of 1-2 alcoholic drinks.5,7 The mice used for the electrophysiology experiments were not the same mice used in the behavioral experiments, however they were roughly the same age to keep that dimension uniform between subjects.7 To show the effect of EtOH on cerebellar transmission, the purkinje cells (PC) of mice were analyzed because they are the only projections out of the cerebellum. Fresh parasagittal slices of the cerebellum of each mouse lineage were prepared on each day of testing and maintained in a chamber of artificial cerebrospinal fluid (aCSF) under a standard perfusion rate. In this suspension, EtOH and drugs can be solubilized and applied to the slices and subsequently recorded for changes in post synaptic potential. The PCs of cerebrally slices were analyzed using two types of patch pipette clamps: voltage-clamped to keep the membrane potential static under variable current flow or current-clamped to keep the current flow static and manipulate the membrane potential. The PCs membrane potential and spontaneous potentials were examined using current-clamp cerebellar slices of both D2 and B6 mice. Voltage-clamp recordings were performed on PCs while being kept at a reverse potential to verify changes in the spontaneous excitatory postsynaptic potential (sEPSP) were due to the excitatory input from GC rather than a change in inhibitory input signals.7
The current-clamp readings from both D2 and B6 mice were found to have similar basal membrane potentials with frequent sEPSP.7 It was found that 9 mM EtOH decreased the frequency of sEPSP in D2 mice but had no significant effect on B6 mice PCs (Figure 1A). The percent change of sEPSP frequency was analyzed in solely 9mM and with both 9 mM and GABAzine (GBz). GBz is used as a GABAA receptor antagonist to show the specificity of EtOH and rule out conflicting factors. It is shown that D2 mice have a statistically significant change in frequency of sEPSP but little change is observed in B6 mice (Figure 1B). Under 31 mM EtOH, cerebellar PCs from both mice show reduced sEPSPs (Figure 1C). The mean change under 31 mM EtOH perfusion shows a net decrease for both mouse lines. The differences between the mouse lines observed at 9 mM EtOH were lost at 31 mM EtOH. Importantly, even under GBz, the mean reduction in sEPSP is still present (Figure 1D). High levels of EtOH may possibly be equally competing with the GABAA receptor antagonist. These findings show at low levels of EtOH, only D2 mice have decreased sEPSP and specifically by strengthening the inhibitory action of GC tonic GABAA receptors.7
In another electrophysiology experiment, voltage-clamps of PCs were recorded being helped at a reversed membrane potential.7 Another variable introduced during the reverse PC potential experiment is perfusion of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol hydrochloride (THIP) instead of EtOH. THIP acts as a specific GABA receptor agonist that targets the δ subunit. The findings were similar to the previous experiment were the membrane potential was not kept in reversed polarity. 9 mM EtOH selectively decreased spontaneous excitatory post synaptic current (sEPSC) in only the PC of D2 mice (Figure 2A). Under THIP perfusion, there is a decrease in sEPSCs in both mouse lines (Figure 2B). This shows that absence of an effect of 9 mM EtOH on B6 sEPSCs is not to from an intrinsic factor of the inhibitory currents to change PC excitation. Mean changes in the frequency of EPSC in the presence of 9 mM EtOH, 31 mM EtOH, and 300 mM THIP were analyzed using PC voltage clamps.7
Mean changes in the inhibitory postsynaptic currents (IPSCs) and action potentials (APs) were also obtained in 9 mM EtOH perfusion (Figure 3).7 Also under THIP perfusion, inhibition of PC EPSC was seen in both mouse line. Notably, just as with sEPSP, the inhibitory preference of EtOH on D2 mice was lost at 31 mM EtOH. Also by pharmacologically isolating sIPSC they showed that showed EtOH does not contribute to any significant inhibitory input on the cerebellum. The findings also verify that genotypic specific mechanism of EtOH on PCs are specifically mediated by GC GABAA currents because EtOH at low levels did not notably change AP frequency in either mouse line.7
Various behavioral experiments were carried out to demonstrate what effect pharmacological modulation has on the GC tonic GABAA receptors and consumption.7 To observe behavior as a function of cerebellar transmission, the mice underwent surgery to install the cannulas in the cerebellum. Cannulas gave access for researchers to implement various infusions directly on the cerebral area in question. The mice were implanted with a unilateral cannula aimed at different lobes of the cerebellum depending what portion of the experiment the mice were part of. The first four experiments had mice with cannula aimed at lobes IV, V, and VI (Figure 4). These lobes seem to influence dopamine release in the forebrain by inhibition. Mice slated for the fifth experiment had their cannula focused on lobe II and III (Figure 4). Before being subjected to experimental manipulation, the mice were given at least a week to recover post-op.7
The protocol used to give access to EtOH to certain mice, as well as sucrose and water access, to reinforce alcohol dependence is strictly outlined and followed for each subsequent trial.7 The experiments were conducted in the dark phase during a reversed 12-hour light-dark cycle, the lights were turned off at 8:00 AM, for all the experiments except for experiment four which is designed to observe locomotor activity. That experiment was run in the light phase on a normal 12-hour light-dark cycle where the lights were turned on at 6:00 AM. It took 3 weeks to adapt the mice to this light-dark cycle due to their nocturnal nature of activity. The experiments performed in the dark phase were constructed so to observe high levels of EtOH consumption because of mice nocturnal nature. After 3 hours into the dark phase, the mice were given access to a “25 ml bottle of EtOH (10% volume per volume) or sucrose (2% weight per volume) for 2 hours.”7 They were also give access to water during both EtOH and sucrose access. After 2 hours, the access to the bottles was discontinued and measured for consumption levels over the allotted access period.7 The experiments that utilized drug infusions were also conducted in a precise manner.7 Before given a drug, the researchers simulated the infusion using an injector that was inserted into the cannula but with no fluid. Consecutively, 200 nl chemical infusions were given over the span of one minute, with an additional 30 seconds of diffusion time after complete injection. Mice were given access to either EtOH or sucrose five minutes later.7 To allow the mice to return to baseline measures of EtOH consumption, the mice were not given infusions for 3 days. The same stabilization of sucrose consumption occurred for at least 2 days until another chemical infusion was performed.7
Mice in behavior experiment one were given access to EtOH on a Monday to Friday schedule for three weeks before they underwent the cannula surgery.7 After post-op recovery, the behavioral drinking patterns were returned after seven days of access to alcohol. The mice were given an infusion of aCSF to act as a vehicle. Vehicle infusions serve as a control to show that the act of administering fluid has little effect on the results of the experiment and that the cannulas are functional. Three days after the infusion of aCSF, the mice were given an infusion of 500 ng THIP. has been found to suppress EtOH consumption by augmenting GC tonic GABAA receptor output.3,7 Blood was taken from the mice immediately following the allotted two hours of access to measure the blood EtOH content on the days any type of infusion was performed. Mice EtOH access was continued to allow consumption to return to baseline after finishing the THIP trial. After returning to baseline, the mice were given water during the 2 hours of access instead of EtOH. Five days after the switch to the water regiment the water intake, the mice were given infusions of aCSF and THIP as before. This portion was done to serve as a control to assess if the infusion itself had any effect on fluid consumption. This initial study showed that THIP infusion notably decreased EtOH consumption and that blood EtOH content has a strong positive
correlation with the EtOH consumed over 2 hours (Figure 5).7 To show that the EtOH reduction was from the pharmacologic origins of THIP and not from the mechanical or physiological impact of infusions, a separate examination of EtOH consumption must be performed utilizing different parameters.7
In experiment two, EtOH consumption was also observed but with a quantitative change in variables and the frequency.7 A set of mice were not exposed to EtOH before undergoing cannula surgery. Once recovered from the cannula surgery, the mice were given access for 7 days a week under the same standard procedure. Once the mice established a baseline of EtOH consumption the infusions proceeded in a specific order: “vehicle, 500 ng THIP, 50 ng THIP, 100 ng THIP, 250 ng THIP, and lastly vehicle again.”7 The purpose of vehicle infusion at the beginning and end of the set of infusions is to demonstrate to the stress of repeated infusions is not a significant factor in diminishing EtOH consumption. The decrease in EtOH consumption is shown to be induced pharmacologically by THIP (Figure 6). The variation in THIP shows the effective dose of THIP to be between 100-250 ng.7 To analyze cerebellar GC excitation from pleasurable substances independent to that substance’s identity, another experiment was conducted using sucrose instead of EtOH.7
Experiment three is carried out in a similar manner as experiment one except sucrose is used instead of EtOH.7 The mice were not given access to sucrose until after the cannula surgery. The sucrose access and consumption measurements occurred on the 5-day schedule. Once the sucrose intake baseline had been achieved, the mice underwent the same protocol of false injection and THIP infusion as in experiment one. However, the blood was not analyzed for EtOH like in experiment one. The results showed a marked decrease in sucrose consumption upon infusion of THIP. This shows that THIP has an impact on the function of reward-processing regardless if the reward is alcohol. Once the infusions were complete, the mice were given only water access for three weeks and transitioned to the light-dark cycle for experiment four, observation of mice movement.7
Once accommodated to the light-dark cycle, mice were tested in the light cycle instead of the dark cycle which is different than previous behavioral experiments they performed.7 This difference allowed discrimination between the effect of drugs on activity separate form normal nocturnal movement. Testing observed activity as a function of 500 ng THIP or vehicle infusions. The results show there was no statistically significant effect of THIP or vehicle infusion on locomotion. The fifth behavior experiment followed the same protocol as experiment one but the cannulas were surgically located at the cerebellar lobes II and III. The THIP infusions on these lobes showed similar results as experiment one.
The cumulative findings from the electrophysiology and behavioral experiments cultivate into significant correlations and applications.7 Electrophysiology analysis of PC output shows that EtOH primarily affects the GC tonic GABAA receptors current and only affects D2 mice at low 9 mM EtOH. The results point also to the connection of the GABAA receptor agonist mediating EtOH and sucrose consumption. Which implies the cerebellar neurotransmission plays a role in reward processing and reinforcement of substances other than EtOH. Suppression a low EtOH concentrations through the cerebellar projections seems to serve as a protective function for D2 mice to deter alcohol dependence. These findings advance scientific understanding that EtOH specifically affects the magnitude and polarity of GC tonic GABAA receptors current and the role its resistance to EtOH contributes to the high-consuming phenotype. This study is also the first that modulates cerebellar output using THIP with no significant impact to coordination of movements, another important function of the cerebellum. The findings show that genetic differences in the GC tonic GABAA receptor serve to restrict consuming high amounts of EtOH in the low consuming phenotype. This is accomplished by GC tonic GABAA receptors to response to low amounts of EtOH with an augmentation of inhibitory GABA neurotransmission through the cerebellum. This protective function is lost in the high-consuming phenotype, giving that individual a predisposition to developing alcohol dependence. The data has strong evidence for the use of THIP, or another comparable GC tonic GABAA receptor agonist, in treating an individual with a predisposition for AUD. If physicians know what definitively predisposes a person to AUD, a targeted intervention can save them from AUD and psychological distress.7
3. Medical Application
Diagnosing and treating individuals with AUD can be difficult due different barrier that exacerbate compliance.1,10 Exposure to alcohol early in life is a factor that further increases the risk of AUD.1 However, at a young age the criteria to be diagnosed do not usually manifest till later when disruptions to functionality are observed. Very few people with AUD initially seek medical assistance because of the stigma and not believing treatment can help.10 Remission and then subsequent relapse is typical in individuals with AUD.1 This can be a deterrent to seeking additional medical assistance and lead to diminishing compliance. Like treating any disease, there are a multitude of complex factors that influence prognosis with AUD such as comorbidity with dependence on another drug.19 This can cause someone to have a more severe form of AUD.19 Also, the risk of suicide risk is increased among those with AUD.1,10,19 Individuals with AUD have significant increase in risk of accidents, harm to others, work-life problems, and a diminished ability to function. These compounding consequences highlight the severe nature of AUD and demand more effective treatment.1,10,19
Acamprosate, naltrexone, and disulfiram are three drugs the FDA allows in the treatment of AUD; their inefficacy calls for effective targeted treatment.2,10 These drugs show little sustained improvement with alcohol abstinence and relapse is high. There are a few drugs that were studied in pre-clinical experiments and phase II clinical trials.10 Ondansetron underwent a randomized controlled trial which found it to be effective for AUD, however it seems to compensate for serotonin malfunction.20 Topiramate, a drug that activates GABAA receptors, recently went through clinical trials.10,21 Topiramate was effective at reducing drink amounts however It did not promote alcohol abstinence and adverse side effects. The specific mechanism of action of Topiramate seems to be inadequate at producing desired outcomes.10,21 The current research points researchers to a path to sufficient treatment.7
3.1 Significance of GABA research results and Implications for Treatment3,4,6,7
Research shows that both the GABAA and GABAB receptors have a correlation in alcohol dependence.6,7 The findings show that there are many avenues for clinical trials that target GABA receptors. As in the GABABR, it was shown a GABA agonist can elicit a significant reduction in alcohol-induced reinforcement and behavior.4,6 However, it was important to note the relapse in addictive behavior post treatment. Perhaps longer treatment schedules in trials could have lowered the incidence of relapse.4,6 A more promising route to effective treatment seems to be with the GABAAR.5,7,18
The current data outlined in this paper shows promise in finding adequate treatment for AUD using GABAAR agonists.7 Targeting GC tonic GABAAR current with THIP was shown not only to curb consumption but showed little effect on water consumption or locomotion.7 This is an important finding because it shows a lack of impairment to the functioning of the cerebellum and basic primitive drives. However, this data only is not definitive to prove a lack of adverse effects so further testing is needed.7 Perhaps, THIP and other agonist specific to the GC tonic GABAA receptor whose genotype predispose an individual will be tested in the use of human clinical trials in treating AUD. The goal of treating AUD is to increase prevalence of alcohol abstinence, improve overall patient well-being, increase societal contribution, and decrease relapse potential.1,2,10
4. Future Directions of the Research
The research outlined is poised to create better understanding as to why certain individuals react to small doses of alcohol with dependence and others do not.7 If this direction is expanded on it should focus on assessing the specificity of THIP’s action. Researchers could make comparative observations by using other GABA agonists or using THIP in the presence of competitive inhibitors. The research showed that coordinated body movements and water consumption were not affected so cerebellar function remained intact in concert with the desired reduction of EtOH consumption.7 However, this reduction was not a cessation of EtOH consumption which is the goal of treating AUD.1,7,10
It may be viable if researchers study the epigenetic factors that enable the alcohol sensitive δ subunit of the GC tonic GABAAR to be more prevalent in individuals with AUD.2,3,7,22 If research shows the factors that influence the δ subunit gene expression in a mouse model, it may be possible to manipulate these factors to change the phenotype more consistently. This may lead to ways to either down regulate the δ subunit gene or upregulate the γ subunit to lead to a low risk phenotype.2,22 Typically when treating AUD, synergy of more than one treatment will produce more lasting results.1,10 The usage of THIP in concert with a drug that changes the genotype may lead to sustained abstinence or even the ability to intake low amounts of alcohol safely.1,10,2
There is a call for a better way to inspect the genetic means of alcohol sensitivity.10 There needs to be a more comprehensive study of genetic polymorphisms and their variability across low socioeconomic status, race, and gender. Analyzing the difference in AUD predisposition with one of these factors as an independent variable may illuminate any unforeseen confounding variables between subjects. However, the genetic markers that predispose a person to AUD may be more dynamic than any of the current research can yield for appreciation.10 Further research should reach to expand the knowledge of how specifically low amounts of EtOH seems to have no little change to currents from GABAAR in the high consuming phenotype.7 AUD is a complex and detrimental disorder that will continue to elude effective treatment until the analysis of genetic and molecular markers show holistic pharmacogenetic targets. GC tonic GABAAR as a pharmacogenetic target seems the next logical advancement of more comprehensive research.7
Bibliography
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. American Psychiatric Association; 2013. doi:10.1176/appi.books.9780890425596.
2. Tabakoff B, Hoffman PL. The neurobiology of alcohol consumption and alcoholism: An integrative history. Pharmacol Biochem Behav. 2013;113:20-37. doi:10.1016/j.pbb.2013.10.009.
3. Sundstrom-Poromaa I, Smith DH, Gong QH, et al. Hormonally regulated alpha(4)beta(2)delta GABA(A) receptors are a target for alcohol. Nat Neurosci. 2002;5(8):721-722. doi:10.1038/nn888.
4. Maccioni P, Zaru A, Loi B, et al. Comparison of the Effect of the GABAB Receptor Agonist, Baclofen, and the Positive Allosteric Modulator of the GABAB Receptor, GS39783, on Alcohol Self-Administration in 3 Different Lines of Alcohol-Preferring Rats. Alcohol Clin Exp Res. 2012;36(10):1748-1766. doi:10.1111/j.1530-0277.2012.01782.x.
5. Kaplan JS, Mohr C, Rossi DJ. Opposite actions of alcohol on tonic GABAA receptor currents mediated by nNOS and PKC activity. Nat Neurosci. 2013;16(12):1783-1793. doi:10.1038/nn.3559.
6. Maccioni P, Vargiolu D, Thomas AW, et al. Inhibition of alcohol self-administration by positive allosteric modulators of the GABAB receptor in rats: Lack of tolerance and potentiation of baclofen. Psychopharmacology (Berl). 2015;232(10):1831-1841. doi:10.1007/s00213-014-3815-8.
7. Kaplan JS, Nipper MA, Richardson BD, et al. Pharmacologically Counteracting a Phenotypic Difference in Cerebellar GABAA Receptor Response to Alcohol Prevents Excessive Alcohol Consumption in a High Alcohol-Consuming Rodent Genotype. J Neurosci. 2016;36(35):9019-9025. doi:10.1523/JNEUROSCI.0042-16.2016.
8. Grant BF, Goldstein RB, Saha TD, et al. Epidemiology of DSM-5 Alcohol Use Disorder: Results From the National Epidemiologic Survey on Alcohol and Related Conditions III. JAMA Psychiatry. 2015;72(8):757-766. doi:10.1001/jamapsychiatry.2015.0584.
9. Alcohol Related Disease Impact (ARDI) application. Prevention, Centers for Disease Control and. www.cdc.gov/ARDI. Published 2013.
10. Seneviratne C, Johnson BA. Advances in Medications and Tailoring Treatment for Alcohol Use Disorder. Alcohol Res. 2015;37(1):15-28. http://www.ncbi.nlm.nih.gov/pubmed/26259086%5Cnhttp://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC4476601.
11. Gelernter J, Gueorguieva R, Kranzler HR, et al. Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: results from the VA Cooperative Study. Alcohol Clin Exp Res. 2007;31(4):555-563. doi:10.1111/j.1530-0277.2007.00339.x.
12. Ooteman W, Naassila M, Koeter MWJ, et al. Predicting the effect of naltrexone and acamprosate in alcohol-dependent patients using genetic indicators. Addict Biol. 2009;14(3):328-337. http://10.0.4.87/j.1369-1600.2009.00159.x.
13. Pin J-P, Prézeau L. Allosteric Modulators of GABA(B) Receptors: Mechanism of Action and Therapeutic Perspective. Curr Neuropharmacol. 2007;5(3):195-201. doi:10.2174/157015907781695919.
14. Hill SY, Lichenstein SD, Wang S, O’Brien J. Volumetric Differences in Cerebellar Lobes in Individuals from Multiplex Alcohol Dependence Families and Controls: Their Relationship to Externalizing and Internalizing Disorders and Working Memory. Cerebellum. 2015:1-11. doi:10.1007/s12311-015-0747-8.
15. Herting MM, Fair D, Nagel BJ. Altered fronto-cerebellar connectivity in alcohol-naïve youth with a family history of alcoholism. Neuroimage. 2011;54(4):2582-2589. doi:10.1016/j.neuroimage.2010.10.030.
16. Middleton FA, Strick PL. Cerebellar projections to the prefrontal cortex of the primate. J Neurosci Off J Soc Neurosci. 2001;21(2):700-712. http://medlib-proxy.mercer.edu/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=cmedm&AN=11160449&site=eds-live&scope=site.
17. Gozzi A, Agosta F, Massi M, Ciccocioppo R, Bifone A. Reduced limbic metabolism and fronto-cortical volume in rats vulnerable to alcohol addiction. Neuroimage. 2013;69:112-119. doi:10.1016/j.neuroimage.2012.12.015.
18. Fritschy J-M, Panzanelli P. Molecular and synaptic organization of GABAA receptors in the cerebellum: Effects of targeted subunit gene deletions. The Cerebellum. 2006;5(4):275-285. doi:10.1080/14734220600962805.
19. Dick DM, Agrawal A, JC W, et al. Alcohol dependence with comorbid drug dependence: genetic and phenotypic associations suggest a more severe form of the disorder with stronger genetic contribution to risk. Addiction. 2007;102(7):1131-1139. http://medlib-proxy.mercer.edu/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=c8h&AN=106143424&site=eds-live&scope=site.
20. Johnson BA, Roache JD, Javors MA, et al. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients – A randomized controlled trial. JAMA-JOURNAL Am Med Assoc. 284(8):963-971. http://medlib-proxy.mercer.edu/login?url=https://search.ebscohost.com/login.aspx?direct=true&db=edswsc&AN=000088769000022&site=eds-live&scope=site.
21. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: A randomised controlled trial. Lancet. 2003;361(9370):1677-1685. doi:10.1016/S0140-6736(03)13370-3.
22. Crabbe JC, Phillips TJ, Harris RA, Arends MA, Koob GF. Alcohol-related genes: contributions from studies with genetically engineered mice. Addict Biol. 2006;11(3-4):195-269. doi:10.1111/j.1369-1600.2006.00038.x.