Abstract
Alcohol use disorder (AUD) is a chronic relapsing disorder, which enforces a person to compulsively seek alcohol, restricting control over alcohol intake leads to emergence of an undesired emotional state during abstinence. There are recent advances for better understanding of neurocircuitry involved in the pathophysiology of AUD. Alcohol interaction with neuronal membrane proteins results in changes in neuronal circuits. It is also linked with the potential medication and their clinical validation concerning their pharmacological targets for alcoholic abstinence. This review covers research work from the past few decades on the therapeutic advances on treatment of alcohol dependence; further detailing the fundamental neurochemical mechanisms after alcohol administration. It also covers interaction of alcohol with GABAergic, glutaminergic, dopaminergic, serotonergic and opioid systems. This review further elaborated the neurobiology of noradrenergic, cholinergic and cannabinoid systems and their interaction with AUD. Elaborative information of potential drug targets under current exploration for AUD treatment with their mechanisms are reported here along with clinical outcomes and the associated side effects.
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Introduction
Around the world, alcoholic beverages are consumed for recreational and ceremonial activity. The moderate use of alcohol is considered to be beneficial for socialization, as a mood elevator, to reduce anxiety [1]. However, chronic consumption of alcohol leads to compulsive alcohol seeking, and when the person is not drinking, there occurs emergence of different emotional conditions [2, 3]. Alcohol use disorder (AUD) causes reward and stress, and insensitive salience, which is mediated by various neurochemical changes [4]. Modulation of neurochemicals can cause severe consequences in the functioning of various brain region of the central nervous system (CNS) [5], and associated metabolic process [6]. Chronic intake of alcohol causes brain damage, characterized by the cerebral and cerebellar atrophy, leading to impaired neuronal function within the hippocampus and frontal cortex [7, 8]. Apart from this, it causes alcohol-specific disorders, such as Wernicke-korsakoff syndrome, hepatic encephalopathy and pellagra. Heavy alcohol consumers exhibit cognitive and motor impairments, cholinergic deficits, and dementia [9]. It is known worldwide that alcohol abuse and misuse is the third-largest leading risk factor for premature death. According to the World Health Organization, about 2.5 million people die each year from alcohol-related causes, i.e., almost 4% of total death is due to AUD, which is greater in number as compared to HIV/AIDS, violence, or tuberculosis [10].
This review has an interior view on the currently available pharmacological therapies, and the major neurochemical mechanism underlying AUD. In the last few decades, researchers have come across various cellular, biochemical and molecular basis linked with AUD. The review focuses on fundamental studies of various neurochemical systems which are linked to different pathways through which any particular drug would reflect their desired pharmacological activity. There are generally two approaches used for the treatment of AUD, i.e., first to gradually reduce alcohol drinking behaviour followed by motivational approach and abstinence. However, a significant reduction in alcohol drinking behaviour improves the health and quality of life [11]. Further, the combination drug therapy and motivational approach were moderately effective for AUD [12, 13]. The review elaborately described the information of the drugs involved in the medication of AUD with a description of the changes in different neurochemical systems by a particular drug. Moreover, the review presents a table, which notifies the approved pharmacological therapies, mechanism of action, clinical reports and the adverse effects of the listed drugs. Additionally, this paper highlighted the novel biochemical and neurochemical marker and drug under trial for AUD. Based on previous pathophysiological evidence and ongoing research, it is concluded that neurochemical target-based therapy can be a better approach for the treatment of AUD.
Target-Based Therapy of AUD and Respective Neurochemical System
GABAergic System and Drugs Acting on it
Gamma-aminobutyric acid (GABA) is considered to be the principal inhibitory neurotransmitter in the brain. Alcohol seeking and drinking can be suppressed by stimulating a GABAB receptor [14]. Gabapentine mediates its action through GABAB and facilitates the chloride ions in the Nucleus Accumbens (NAc), ventral palladium (VP), bed nucleus of the stria terminals (BNST), and amygdala (AMY), thereby reducing alcohol-seeking behaviour [15]. Similarly, baclofen, a GABAB agonist, suppresses alcohol-stimulated dopamine release in the mesolimbic dopamine system and reduces alcohol drinking behaviour [16]. Further, topiramate and acamprosate antagonize the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor and act as modest GABAA agonists, acting on the calcium-dependent mechanism of alcohol reward and ultimately antagonizing alcohol-induced reward effects [17].
Glycine
The amino acid glycine is prominent in the regulation of emotional states. It causes the suppression of alcohol drinking by acting on the GABAergic systems [18, 19]. Glycine plays a critical role as an inhibitory neurotransmitter in the spinal cord and brain stem [20], but on the other hand, it potentiates the action of glutamate via its co-agonist activity on the N-methyl-D-aspartate (NMDA) receptors. According to recent research, inhibition of glycine transporter (GlyT) in rodents may reduce alcohol consumption [6]. Alcohol causes an increase in the function of the glycine receptor (GlyR) [21].
Adenosine
Adenosine is responsible for suppressing the release of other neurotransmitters in the CNS by modulating neurotransmission. It is known that higher levels of adenosine cause glutamate increase in the brain region. Further, it is known that dimerization of postsynaptic adenosine A2A receptors with dopamine D2 receptors in the striatum influences reward-related behaviour [22, 23]. It is known that alcohol may affect the adenosine receptor coupling [24], resulting in an increase in the activation of adenosine A1 receptors, which are responsible for ataxia and the sedative effects of alcohol. Adenosine is also linked with glutamatergic neurotransmission. Thus we can say that adenosine is considered to be strongly involved in alcohol addiction [25].
Glutamatergic System and Drugs Acting on it
Glutamate is responsible for controlling signal transmission and metabolic activities in the brain. Through several research activities, it has been found that NMDA receptor has more affinity for alcohol than AMPA and kainate receptors, which are also modulated by the consumption of alcohol [26]. Chronic alcohol administration produces an adaptive up-regulation of NMDA receptor activity in rodent brains and cultured cells [27]. Thus during withdrawal or relapse, a rebound activation of these receptors occur, playing an important role in the alcohol withdrawal syndrome, including delirium tremors and especially seizures [28, 29]. According to the result of various research works, we concluded that the mechanism of action is to interfere with the phosphorylation and compartmentalization of this receptor [28, 30]. Some drugs like acamprosate (weak NMDA antagonist), zonisamide alter the concentration of γ-glutamyl-transferase, whereas memantine (newer NMDA receptor antagonist) modulates the synaptic plasticity and mitigates alcohol dependence and relapse by acting on the glutaminergic system [31, 32].
Serotonergic System and Drugs Acting on it
Serotonin (5-HT) mediates cellular communication within the brain, thus playing a crucial role in brain functioning, which includes regulation of affective states, social behaviour and addiction [33], even sharing links with alcohol abuse [33]. Alcohol potentiates the function of 5-HT3 and the somatodendritic 5-HT1a receptors, Thus increasing extracellular 5-HT levels in the NAc after the alcohol administration [34]. Acute alcohol consumption potentiates 5-HT3 receptor and these effects are antagonized by ondansetron. Similarly, chronic alcohol exposure leads to adaptive changes in 5-HT2A receptors that lead to an increase in craving and decreased abstinence behaviour [35]. Psilocybin is a classic (5HT2A agonist) hallucinogen, having clinically significant effects on alcohol and drug addiction, there is a significant decrease in the level of 5-HT1A [36].
Dopaminergic System and Drugs Acting on it
Acute administration of alcohol causes activation of mesocorticolimbic system, and upon chronic administration caused an alteration in the functions of the major reward system of the brain, i.e., dopaminergic neurons of the VTA, which projects to the NAc, AMY, prefrontal cortex (PFC) and other forebrain structures [37]. In-vivo and in vitro alcohol study revealed that alcohol causes dose-dependent excitation of dopaminergic neurons in VTA and release of dopamine in NAc [38, 39]. Owing to this fact alcohol may influence the release of dopamine from the 5-HT2 receptor, causing a flare in the firing rate of the dopaminergic neurons in the VTA and NAc, respectively, mediating indirectly alcohol-induced rewarding effects [37]. Atypical antipsychotics such as aripiprazole and olanzapine, act as antagonists to the 5-HT2 and partial antagonists to the D2 receptor, which is hence considered suitable drugs to mitigate cue-elicited alcohol craving and a related mood disorder [40].
Neuronal Nicotine-Acetylcholine Receptors and Drugs Acting on it
Neuronal nicotine-acetylcholine Receptor (nAChR) are ligand-gated, cation-selective ion channels, consisting of an alpha (α2–α10) and beta (β2–β4) subunits [20]. Alcohol stimulates cholinergic transmissions in the meso-corticolimbic pathway, which provides an input to the dopaminergic system. During positive inference, it causes an increase in the dopamine release, which mediates the alcohol-reward behaviour [41, 42]. Several studies have substantiated that, the ethanol raises acetylcholine-induced ion flux through the alpha-4 beta-2 nicotine-acetylcholine Receptor (α4β2nAChR) [43, 44]. The alpha-3 beta-2 nicotine-acetylcholine Receptor (α3β2nAChR) meanwhile is considered as the site at which ethanol modulates dopaminergic neurons in the VTA and NAc. α4β2nAChR partial agonist and effects on 5-Chronic Serial Reaction Time performance with a focus on correct responses (attention) and premature responding impulsivity [45, 46]. Further, the study showed that varenicline reduced cue-induced relapse to alcohol, but not nicotine seeking [46].
Opioid Receptors and Drugs Acting on it
Ethanol can modify opioid transmission at different stages, and through many studies, it is known that µ, and δ opioid receptors, as well as the enkephalins and β-endorphins, play a major role in ethanol’s actions in the brain [47]. The opioid system in alcohol addiction interferes with the mesolimbic dopamine transmission in the brain reward pathways. Therefore, there is an increase in the level of endorphins in the NAc [48]. Administration of the opioid antagonist causes a reduction in the release of dopamine in the NAc.
Acute alcohol administration stimulates the release of opioid peptides, particularly the β-endorphin, leading the µ - and δ -opioid receptors to activate the brain reward pathways and promote further alcohol consumption [49]. It is demonstrated that repeated ethanol intake causes a drop in brain levels of β-endorphin and enkephalin, and at the same time up-regulates the dynorphin/κ system. Through various studies, it is noted that there is an enhanced dynorphin/κ transmission which may link to learning and memory deficits, associated with AUD and mediate cognitive control dysfunction in subjects with AUD [50]. Nalmefene µ-opioid antagonists also reduce the craving for alcohol in response to alcohol cues. It helps to reduce beta-endorphin induced impulse in the frontal corticolimbic region that promotes alcohol drinking and other risky behaviours [51]. Naltrexone is a medication primarily used in the management of alcohol dependence and opioid dependence. It modulated the β-endorphin induced dopamine release in the mesocortical region, responsible for alcohol intake and preference behaviour [52].
Cannabinoids System and Drugs Acting on it
The endocannabinoids system is responsible for behaviours related to drug-seeking and drug administration, including alcohol dependence and drinking behaviour, and modulates reinforcing and motivational effects of alcohol [53]. Acute consumption of alcohol causes an increase in the release of dopamine in NAc and inhibition of endocannabinoid transmission; further on chronic consumption becomes hyperactive. These changes produce a great impact on the development of alcohol tolerance and dependence, which further compromises with the increased synthesis of N-Arachidonoylethanolamine (AEA) and 2-AG in the brain and the widespread down-regulation of canobinoid receptors-1 (CB-1) and their function [53, 54]. Rimonabant, CB-1 receptors blocker, significantly reduces the dopamine-mediated alcohol-seeking behaviour [55].
Miscellaneous
Apart from neurotransmitters, some neuropeptides, hormones and enzymes can be a potential target for the management of AUD.
Oxytocin
The activity of dopaminergic neurons in mesolimbic pathways determine the reward value of both natural and substance-related reinforces such as consumption of high caloric foods and drugs of abuse such as ethanol [56]. The action is accomplished by facilitating a ventral-to-dorsal shift to activation in corticostriatal loops. The neuropeptide oxytocin impacts upon the neurons in the mesolimbic pathway, thereby providing the possibility of oxytocin regulation of these behaviours [56].
Neurokinin-1 (NK-1)
NK-1 receptor works on hypothalamic, pituitary, adrenal (HPA) axis through G-protein-coupled corticotrophin-releasing factor receptor and nigrostriatal dopaminergic pathway, through which it potentiates synaptic changes in a different brain region involved in alcohol preference behaviour [57, 58]. NK-1 receptor regulate oxytocin secretion [59]. Further, NK-1 Receptor antagonist and oxytocin attenuates emotional challenges and anxiety-like symptoms in AUD [59]. LY686017 is a neurokinin antagonist, which obstructs the neurokinin mediated substance P and progesterone release by inhibiting the anterior pituitary hormonal modulation in reward and anti-reward system [60].
Phosphodiesterase Enzyme
Cyclic adenosine monophosphate (cAMP) signalling cascade has been implicated in mediating behavioural responses to alcohol phosphodiesterase, an enzyme that specifically catalyzes the hydrolysis of cAMP in the mesolimbic reward system and induces positive reinforcement. Ibudilast, a non-selective phosphodiesterase inhibitor, reduces alcohol drinking and relapse in alcohol-preferring rats [61].
Glucocorticoid
The main neuroendocrine stress system and consequent alterations in brain glucocorticoid receptor expression accompany compulsive-like alcohol intake in rats. The glucocorticoid receptor antagonist mifepristone reduces alcohol intake in alcohol-dependent rats but not in nondependent animals [62].
Ongoing Research for Novel Neurochemical Target and Biochemical Marker for AUD
Neurochemical and Biochemical Marker
Orexin/Hypocretin
Preclinical and clinical study suggested that, the orexinergic neurons are widely projected throughout the brain and especially in VTA and NAc and potentially involved in the development of AUC [63]. Activation of the orexinergic system contributes to the motivation of alcohol-seeking behaviour. Orexinergic system stimulates brain reward centre during the earlier stage of alcohol drinking and increases impulsivity [64]. Further, pharmacological modulation of the orexinergic system ameliorated the alcohol reward as well as abstinence which further confirms the involvement of orexinergic system in alcoholism [63]. Recently, an open pilot trial demonstrated that non-selective blockage of orexin receptor (OXR1 and OXR2) with suvorexant is efficacious for a patient with insomnia and alcoholism [65].
Ghrelin
Ghrelin hormone is involved in the regulation of food intake and energy balance. Growing evidence suggested that ghrelin modulates mesolimbic reward pathways and therefore, is directly involved in the pathophysiology of substance use disorders such as alcohol dependence. Recently Geisel et al., demonstrated that the long term effect of baclofen for the treatment of alcohol dependence could be easily accessed by measuring total plasma level of acylated ghrelin level [66]. Statistical analysis revealed that total plasma ghrelin level significantly decreased in the group of abstinent patients receiving high-dose (30–270 mg/d) of baclofen. Moreover, the plasma acylated ghrelin level increased in the group of relapsed patients under baclofen treatment. Together, these findings substantiated that the long-term response to baclofen treatment in AUD can be monitored by assessing total and acylated ghrelin plasma levels [66].
Biochemical Markers
Biochemical markers for substance and drug abuse such as alcohol dependence helps the clinician to ascertain the alcoholism or AUD. Earlier marker relied on the effect of alcohol on blood cells like mean corpuscular volume (MCV) or on body organs such as liver aspartate transaminase (AST) and alanine transaminase (ALT). However, these markers have lower specificity towards alcoholism as it could also get altered in other diseases. Further, it is hard to record baseline level with older biomarkers as it raises only after prolonged use of alcohol. Therefore, the propensity of the detection of acute alcohol intake is less. Hence, the detection of recent and acute intake of alcohol was a challenge. This has also simultaneously led to the quest for newer biomarkers that can detect recent alcohol use. The biomarkers such as 5-Hydroxytrptophol (5-HTOL), urinary Ethyl Glucuronide (EtG) and serum Fatty Acid Ethyl Esters (FAEE) are direct products of ethanol and are relatively unaffected by disease conditions [67]. They are detected soon after moderate-heavy bout of alcohol use and are present in the body fluids for a shorter period of time. However, detection of biomarkers is costly, and hence, combining different biomarkers together offers the best solution to detect alcohol use [66].
Medications Involved in the Treatment of AUD
The approved drugs with pharmacotherapy, mechanism of action (MOA), clinical report and adverse effects are enlisted detail in Table 1.
Drugs Under Phase-II Trial
Ghrelin Receptor Inverse Agonist PF-5190457
Clinical study demonstrated that, when PF-5190457 is co-administered (100 mg twice in a day) with alcohol. PF-5190457 reduced alcohol craving during the cue-reactivity procedure [68]. This finding provides the first translational evidence of safety and tolerability of the PF-5190457 when co-administered with alcohol. The mechanism involved is the facilitation of GABAergic system which reduces the plasticity of alcohol reward [69]. Further, the pharmacokinetics, pharmacodynamics and behavioural data supported the continued research of PF-5190457 as a potential pharmacological agent to treat AUD [69].
NK-1 Antagonist LY686017
NK-1R antagonist mitigated the conditional place preference by reducing extracellular dopamine content in the NAc [70]. LY686017 obstructs the neurokinin mediated substance P and progesterone release by inhibiting the anterior pituitary hormonal modulation in reward and anti-reward system [60]. GlaxoSmithKline has a dual NK1R/NK3R antagonist, GSK1144814, in the pipeline for future clinical trials for psychiatric patients suffering from AUD [71].
Nociceptin (NOP) Receptor Antagonist BTRX-246040
BTRX-246040 reduced depression symptoms in a second trial with heavy alcohol drinkers. Clinical study demonstrated the efficacy of BTRX-246040 in major depressive disorder (MDD) patients. In this study, administration of BTRX-246040 (40 mg, p.o.) reduced alcohol drinking behaviour in depressed patients. In addition, plasma levels of gamma-glutamyl transferase were decreased by BTRX-246040 compared to placebo control thus implying an improvement in liver function. Collectively, the clinical data reviewed within this review suggest that BTRX-264040 normalize the dysfunction in reward circuits [72].
Non-selective OXR1 and OXR2 Antagonist SB 334867
SB 334867 significantly reduced compulsive-like consumption at doses lower than those reported to reduce quinine-free alcohol intake. The dose of 3-mg/kg SB 334867, in particular, suppressed only compulsive-like drinking [73]. Furthermore, SB 334867 did not alter saccharin and quinine consumption. In addition, the OX2R antagonist TCS-OX2-29 (3 or 10 mg/kg) did not alter intake of alcohol with or without quinine. Together, these results suggest that OX1R signalling is particularly important for promoting compulsive-like alcohol drinking and that OX1Rs antagonist might represent a novel therapy to counteract compulsive aspects of human AUD [74].
Discussion and Conclusion
Targeting the neurochemical system is an important strategy for the treatment of AUD. As per the present evidences, the alcohol interacts with various inhibitory and excitatory neurotransmitters. The drugs presently used are effective for the alcoholism but for a shorter period of time. Targeting of opioid, glutaminergic and serotonergic system depletes dopamine in NAc and reduces alcohol preference tendency in clinical patients. However, cannabinoid drugs and GABA mimetic are most effective for reward circuitry in NAc. As per preclinical and clinical study reports, the targeting of adenosine receptor would be a more effective treatment strategy because it forms a communication between both excitatory and inhibitory neurotransmitters. Recent preclinical and clinical evidence also suggested that, targeting of orexin and ghrelin would also be a novel approach as it directly controls food reward and energy homeostasis. Apart from that, the present review also addressed the recently used or under trial biomarker for AUD.
Half a century has passed since the discovery of AUD as a disease, but still, we have only managed to discover a few drugs, with some of them proving to be controversial in the later run. So, as the situation demands, there is an immediate need to find a proper mechanism to treat AUD, as the exact mechanism by which ethanol exerts its effects on the brain is still unknown. Significant complexity occurs because alcohol is, directly and indirectly, linked with the function of almost every neurotransmitter. It is very well known that neurochemical approach favours the pharmacotherapy of AUD as the alcohol interacts with specific neuronal membrane proteins, thus involved in the signal transmission, which results in a change in neuronal activity [75]. Alcohol interacts with two membranes receptor: GABAA and NMDA ion channel receptors, which indeed causes the enhancement of the inhibitory effect of GABAA and antagonizes the excitatory effect of glutamate. In the case of the brain reward system, the dopaminergic, serotonergic and opioid system is also well affected by the drugs [2]. As mentioned in the review, noradrenergic, neuronal nicotine acetylcholine receptors and cannabinoid systems also plays a significant role in the neurobiology of alcohol interactions.
The curiosity of research scientists, with their organized study, will gather the needs for the pharmacological treatment for AUD. The heterogeneity of AUD patients and the complex aetiology of the disease and even different patterns of consumption, onset of drinking and drinking behaviour have involved in the pharmacotherapy [2]. For example, acamprosate shows greater efficiency in promoting naltrexone efficacy, and even showed a more significant effect in a patients who had already undergone detoxification [76]. Naltrexone is more efficacious in reducing heavy drinking and showed more considerable medication effects than acamprosate for the treatment of AUD yield mixed finding. Other medications like nalmefene, gabapentin, varenicline, topiramate, and zonisamide showed good efficacy, with side effects that were mild to moderate in intensity. However, baclofen, ondansetron had a mixed preliminary results but is awaiting for finding of additional studies. A final group (levetiracetam, quetiapine, aripiprazole, and SSRIs) had promising preliminary results but has not demonstrated efficacy in larger trials [77]. Through various studies, we concluded that rather than single-agent treatment, there should be a multi-drug treatment; for example, disulfiram may cause potentially fatal hepatotoxicity. Taking into consideration the alcohol drinking is frequently related to liver disease [78]. Thus it would be more beneficial to go for combination therapy including disulfiram and other agents such as acamprosate or naltrexone [20]. Thus, further studies in the following area are vital to arrive at meaningful answers, which will help to optimize pharmacotherapy for AUD.
In conclusion, the development of AUD mainly involves the modulation of biomarkers which are regulated by neurotransmitter or other neurochemical systems. The FDA approved drugs target limited neurochemical systems and mainly opioid and glutaminergic systems. However, these systems are also modulated by various other neurotransmitters like dopamine, seorotonin, GABA, adenosine, acetylcholine and adrenaline. In recent, an ongoing preclinical and clinical study suggested that, newer neurochemical marker such as orexin, ghrelin, neurokinin and nociceptin could also alter dopaminergic, serotonergic, cholinergic and noradrenergic systems. Therefore, targeting these markers would be a better treatment approach for AUC due to established role in the modulation of major neurochemical contributing in the development of AUD. These findings are under phase-II trial and based on their overall efficacy and safety it can be used as a newer treatment strategy for AUD.
Future Perspective and Social Relevance
The development of the neurochemical and combination based therapy which targets multiple neurotransmitters involved in the positive reinforcement and development of withdrawal symptoms is essential to treat group of symptoms of AUD. In our society, AUD mostly leads to cognitive impairment so that inclusion of cognitive or motivational therapy can further improve the quality of life of the patients affected by AUD. Moreover, testing of biochemical and neurochemical markers can increase the understanding of heritable factors involved in AUD. In future, these may serve as a guidance to clinicians in identifying and prescribing the most suitable pharmaceutical interventions to AUD patients.
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The authors would like to thank Department of Pharmaceutical Engineering and Technology, IIT (BHU) Varanasi.
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Prajapati, S.K., Bhaseen, S., Krishnamurthy, S. et al. Neurochemical Evidence of Preclinical and Clinical Reports on Target-Based Therapy in Alcohol Used Disorder. Neurochem Res 45, 491–507 (2020). https://doi.org/10.1007/s11064-019-02944-9
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DOI: https://doi.org/10.1007/s11064-019-02944-9