**1. Introduction**

#### **1.1 Alcohol addiction: one drink too many**

Alcoholdependenceor alcohol abuse,nowcollectivelyknownas alcoholusedisorders (AUDs), causes significant loss of productivity, health concerns, emotional instability, career‐oriented failures, and socioeconomic problems [1]. It is estimated that AUDs amount to 3.8% of global deathsand4.6%ofdisability‐adjustedlifeyears [2].*TheDiagnostic andStatisticalManual ofMental Disorders*, 4th edition (DSM‐IV‐TR), defines AUDs on the persistence of dependence symp‐ toms like tolerance, withdrawal, increased amounts of alcohol consumed over time, ineffec‐ tive efforts to reduce use, interference with personal or professional life, significant amount of time spent obtaining, using, and recovering from alcohol or continued use of alcohol despite harmful consequences [3]. The U.S. National Institute of Alcohol Abuse and Alcoholism (NIAAA) defined men who consume more than 14 drinks per week and women having more than 11 drinks per week belong to the "At Risk" category of alcohol consumers.

#### **1.2 Neurobiology of alcohol addiction: a vicious cycle**

Alcohol addiction like any other drug addiction is a chronic relapsing disorder characterized by compulsive alcohol use and alcohol‐seeking behavior [4, 5]. The neurobiology of alcohol addiction is increasingly complex; however, for the purpose of simplicity, it can be delineated in three stages. The first phase of this cycle is the *Binge and intoxication stage* [5]. During this phase, reward areas of the brain involving the mesocorticolimbic system like the dorsal striatum and nucleus accumbens (NAc) are activated, which results in pleasurable and rewarding feelings [5, 6]. Dopamine is a key neurotransmitter involved in this stage [7–9]. The positive reinforcement is triggered by the pleasurable effects of alcohol where the user wants "more" to experience the hedonic effects. This is then followed by the *Withdrawal stage* [5]. During this phase, brain regions that are associated with negative feelings and emotions are activated, such as the amygdala and bed nucleus of stria terminalis (BNST) [4, 5]. Chronic withdrawal‐induced stress blunts the activity of the stress–response system and sensitizes extrahypothalamic structures of the extended amygdala [6, 10]. This stage marks a critical phase in the addiction cycle where alcohol use is primarily motivated by the desire to avoid negative feelings of stress, dysphoria, and negative emotional states of alcohol withdrawal. The third phase is the *Preoccupation and anticipation stage* [5]. During this phase, brain regions like the frontal cortex and hippocampus [11] that respond to previously paired alcohol cues and contexts are activated, intensifying alcohol‐seeking behavior [12, 13]. Since the frontal cortex is involved in decision‐making and higher executive functions, alcohol‐induced neuroadaptations of the frontal cortex [14] impair higher cognitive and decision‐making processes, increasing the rate of relapse in alcoholics.

Over time, as this cycle is repeated, alcohol‐induced neuroadaptations in the reward circuitry, stress–response pathway, and brain regions involved in higher cognitive functions facilitate the transition from nondependent to dependent alcohol consumption. These maladaptive neuromodulations contribute to sensitization, tolerance, craving, and relapse to alcohol‐ seeking [4]. For instance, alcohol‐induced plasticity in glutamatergic signaling in the NAc may contribute to behavioral sensitization to the effects of alcohol [15], while changes in the synaptic properties of NAc‐medium spiny neurons contribute to relapse during withdrawal [16]. Furthermore, chronic alcohol modulates presynaptic and postsynaptic functions on glutamate neurons in the basolateral amygdala (BLA) [17]. Finally, alcohol impairs communication between the amygdala and prefrontal cortex to disrupt cognitive and emotional responses that lead to altered affective states that further contribute to the development of alcohol dependence [18, 19].

## **1.3. Pharmacotherapy: available treatment options for AUDS**

**1. Introduction**

**1.1 Alcohol addiction: one drink too many**

116 Recent Advances in Drug Addiction Research and Clinical Applications

Alcoholdependenceor alcohol abuse,nowcollectivelyknownas alcoholusedisorders (AUDs), causes significant loss of productivity, health concerns, emotional instability, career‐oriented failures, and socioeconomic problems [1]. It is estimated that AUDs amount to 3.8% of global deathsand4.6%ofdisability‐adjustedlifeyears [2].*TheDiagnostic andStatisticalManual ofMental Disorders*, 4th edition (DSM‐IV‐TR), defines AUDs on the persistence of dependence symp‐ toms like tolerance, withdrawal, increased amounts of alcohol consumed over time, ineffec‐ tive efforts to reduce use, interference with personal or professional life, significant amount of time spent obtaining, using, and recovering from alcohol or continued use of alcohol despite harmful consequences [3]. The U.S. National Institute of Alcohol Abuse and Alcoholism (NIAAA) defined men who consume more than 14 drinks per week and women having more

Alcohol addiction like any other drug addiction is a chronic relapsing disorder characterized by compulsive alcohol use and alcohol‐seeking behavior [4, 5]. The neurobiology of alcohol addiction is increasingly complex; however, for the purpose of simplicity, it can be delineated in three stages. The first phase of this cycle is the *Binge and intoxication stage* [5]. During this phase, reward areas of the brain involving the mesocorticolimbic system like the dorsal striatum and nucleus accumbens (NAc) are activated, which results in pleasurable and rewarding feelings [5, 6]. Dopamine is a key neurotransmitter involved in this stage [7–9]. The positive reinforcement is triggered by the pleasurable effects of alcohol where the user wants "more" to experience the hedonic effects. This is then followed by the *Withdrawal stage* [5]. During this phase, brain regions that are associated with negative feelings and emotions are activated, such as the amygdala and bed nucleus of stria terminalis (BNST) [4, 5]. Chronic withdrawal‐induced stress blunts the activity of the stress–response system and sensitizes extrahypothalamic structures of the extended amygdala [6, 10]. This stage marks a critical phase in the addiction cycle where alcohol use is primarily motivated by the desire to avoid negative feelings of stress, dysphoria, and negative emotional states of alcohol withdrawal. The third phase is the *Preoccupation and anticipation stage* [5]. During this phase, brain regions like the frontal cortex and hippocampus [11] that respond to previously paired alcohol cues and contexts are activated, intensifying alcohol‐seeking behavior [12, 13]. Since the frontal cortex is involved in decision‐making and higher executive functions, alcohol‐induced neuroadaptations of the frontal cortex [14] impair higher cognitive and decision‐making

Over time, as this cycle is repeated, alcohol‐induced neuroadaptations in the reward circuitry, stress–response pathway, and brain regions involved in higher cognitive functions facilitate the transition from nondependent to dependent alcohol consumption. These maladaptive neuromodulations contribute to sensitization, tolerance, craving, and relapse to alcohol‐ seeking [4]. For instance, alcohol‐induced plasticity in glutamatergic signaling in the NAc may

than 11 drinks per week belong to the "At Risk" category of alcohol consumers.

**1.2 Neurobiology of alcohol addiction: a vicious cycle**

processes, increasing the rate of relapse in alcoholics.

Bill Wilson and Bob Smith took early steps toward alcohol remediation in 1935 with the introduction of Alcoholic Anonymous (AA) [20, 21]. This 12‐step approach toward rehabili‐ tation was built on the premise of acceptance of individual helplessness during addiction to alcohol and other drugs of abuse [22]. This method was adopted by the "Minnesota model of addiction treatment" in a 28‐day rehabilitation setting [23]. Parallel efforts to treat alcohol‐ ism by understanding the nature and cause of alcohol dependence were gaining momentum, which led to the foundation of the National Institute of Alcohol Abuse and Alcoholism (NIAAA) in 1970 [24].

Since then, several approaches to understand and treat alcoholism were designed that took into consideration individual differences and susceptibility to AUDs. Cognitive behavioral therapy or motivational therapy was adopted as the first line of treatment to match the needs of the addict to help recuperate in a 12‐week therapy session called "Project MATCH" [25]. This project was successful in rehabilitation of patients that did not have any psychiatric conditions. The next step was to combine behavioral and pharmacotherapy in the treatment of alcoholism called "Project COMBINE" [26]. This study evaluated the efficacy of available pharmacotherapies, namely acamprosate and naltrexone, in conjunction with or without medical assistance and with or without cognitive–behavioral therapy [27].

Acamprosate (CampralTM), the calcium salt of N‐acetyl homotaurine, suppresses alcohol consumption and relapse [28, 29]. Early reports delineating the mechanism of action of acamprosate were unclear [30]; however, recent studies have shown that acamprosate works through the calcium ion in its molecular structure [31]. This was supported with improved results in patients that showed an increase in plasma calcium levels following acamprosate treatment [31]. Acamprosate has been shown to have a good safety and a tolerability profile and is highly effective in maintenance of abstinence in patients who are abstinent at treat‐ ment initiation [32].

In addition to acamprosate, the mu‐opioid receptor antagonist, naltrexone (Re ViaTM), was found effective as a treatmentfor alcohol consumption and relapse [33]. However, studies have shown that naltrexone is ineffective in achieving abstinence in alcoholic subjects; instead it is more effective to reduce consumption [34, 35]. Also, recent research demonstrated that it acts more specifically for a cohort with single nucleotide polymorphism (SNP) in exon 1 of the mu‐ opioid receptor gene (*OPRM1*) [36] limiting broader efficacy. Nevertheless, naltrexone reduces alcohol consumption through a dopaminergic/opioidergic reinforcement system, causing increased sedation and less arousal in patients consuming alcohol [35]. Both these drugs were

successful in reducing drinking in combination with behavioral therapy, as highlighted by the COMBINE project [37].

In addition to acamprosate and naltrexone, disulfiram (Antabuse®) was approved as a therapeutic treatment for alcoholism. The anti‐alcohol addiction properties of disulfiram were serendipitously discovered, when a Danish physician Jacobsen accidentally ingested alcohol over disulfiram and experienced its unpleasant and nauseous effects [38, 39]. Disulfiram inhibits the enzyme aldehyde dehydrogenase (ALDH), which results in the accumulation of acetaldehyde on alcohol ingestion [40]. This toxic metabolite produces aversive symptoms, such as flushing, nausea, and vomiting, and a desire to avoid this reaction encourages abstinence [41]. Disulfiram also inhibits dopamine‐*β*‐hydroxylase (DBH), the enzyme required to synthesize noradrenaline (NE). It reduces NE concentrations and elevates dopamine (DA) concentrations to facilitate normal DA functioning [40, 41], a pharmacotherapeutic feature of the drug that makes it an excellent treatment option even for cocaine addicts.

In addition to this, our lab has investigated the role of neuronal nicotinic acetylcholine receptors in alcohol addiction and came up with varenicline (ChampixTM) as a treatment option for AUDs [42, 43]. Varenicline was found to be more efficacious in heavy‐drinking smokers because of the comorbid nature of both the types of addiction involving the recruitment of nicotinic acetylcholine receptors. Varenicline is now in its third stage of clinical trial as a treatment option for AUDs [44, 45].

#### **1.4. Shortcomings of available treatment options for AUDs: need for better pharmaceutical alternatives**

Acamprosate, naltrexone, and disulfiram are the only available medications for alcoholism approved by the Food and Drug Administration (FDA), while nalmefene (SelincroTM), an opioidreceptor antagonist having a similar mechanism of action to naltrexone [46], is approved as a medication for alcohol abstinence in Europe [47]. Most of these drugs treat one aspect of alcoholism at best without significantly altering other parameters of alcohol addiction.

Drugs like acamprosate reduce consumption and are effective in motivating abstinence for a certain period of time. However, acamprosate does not significantly affect abstinence‐induced rebound consumption of alcohol [48]. Also, despite achieving an aversion for alcohol, the likelihood of the addict returning to drinking with increased tolerance cannot be assured. A case study also indicated the development of Parkinson's‐like syndrome with acamprosate use [49].

Although naltrexone was shown to be very effective with and without cognitive behavioral therapy, noncompliance with maintenance of drug regimen was shown to limit efficacy [50]. About 37% patients were reported to discontinue naltrexone therapy by 12 weeks and 80% by 6 months [50]. It is possible that some of the severe complications involved with naltrex‐ one use, that is, renal failure and hepatitis, may have contributed to its early discontinuation [51]. Furthermore, the efficacy of naltrexone appears to be related to alcohol abusers having the mu‐opioid SNP [36].

All the above drugs work best when combined with an individual's motivation to quit drinking. Disulfiram works on this principle as it deters the positive reinforcing effects of alcohol and masks them with aversive and negative feelings stimulated by the action of the drug post‐alcohol consumption [52]. As a result, this drug is effective for alcoholics with a goal to achieve complete abstinence, but has limited efficacy for alcoholics without these goals. Noncompliance is one of the biggest challenges in the use of disulfiram, illustrated by the 20% compliance measure in the largest controlled trial to date [53]. Also, disulfiram is contraindi‐ cated in patients with cardiac disease and on rare occasions may cause severe liver damage [54].

Despite the availability of these pharmacotherapies and behavioral therapy, AUDs are widely prevalent. As illustrated by COMBINE, no single medication or treatment strategy is effec‐ tive in every case or in every person [37]. A detailed investigation of other neurobiological factors that play a role in alcohol dependence is needed as are further strategies to treat alcoholism.

The remainder of this chapter highlights the role of serotonin (5‐hydroxytryptamine, 5‐HT), NE, and BLA in alcohol addiction with a view to improve current treatment strategies for AUDs.
