**2. NE and serotonin: role in alcohol dependence**

successful in reducing drinking in combination with behavioral therapy, as highlighted by the

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

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

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

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

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 drug that makes it an excellent treatment option even for cocaine addicts.

COMBINE project [37].

118 Recent Advances in Drug Addiction Research and Clinical Applications

treatment option for AUDs [44, 45].

**alternatives**

use [49].

the mu‐opioid SNP [36].

Prolonged alcohol exposure causes maladaptive changes in regions of the extended amygda‐ la that cause sensitization to negative emotional states and reinforcement of addictive behaviors during withdrawal. These neuroadaptations alter the activity of important neuro‐ transmitters particularly involved in stress. Such changes are well documented for increas‐ ing the activity of the stress neurotransmitter corticotrophin‐releasing factor (CRF) in rodent models of alcohol dependence [4]. Additionally, changes in the function and signaling of other neurotransmitters including 5‐HT [55–57] and NE [55–61] have also been implicated in the development of alcohol addiction.

NE and 5‐HT play a crucial role in regulating mood, emotions, and importantly, behavioral adaptations to stress that include addictive phenotypes [57, 60]. As these neurochemicals widely innervate the reward system [62–66] and extrahypothalamic regions involving the amygdala [67–71], these are prime candidates to influence alcohol and even other drug‐seeking behaviors.

Dysregulation of the 5‐HT pathway is implicated in AUDs and other affective states like depression and anxiety disorders [57, 72, 73]. Recent studies have demonstrated an increase in the immunoreactivity of tryptophan hydroxylase (TRH)––the rate‐limiting step in 5‐HT synthesis, in the dorsal raphe nuclei (DRN) of alcohol‐dependent victims of depression and suicide comparedto normal psychiatric controls [74]. Suchdisruptions in brain serotonin levels in these individuals have widespread implications in the role of 5‐HT to regulate emotional and behavioral vulnerability to alcohol and other drugs of abuse. Alcohol increases 5‐HT levels in the ventral tegmental area (VTA), NAc, and amygdala [75]. These brain regions play a

pivotal role in processing of information from emotional and rewarding stimuli. Chronic alcohol abuse alters the activity of these brain areas, resulting in changes in motivational and goal‐directed behaviors, which further drive alcohol‐seeking behavior [76, 77]. For instance, studies have shown that behavioral sensitization to alcohol is mediated by accumbal 5‐HT2C receptors [76], and blockade of 5‐HT3 receptors especially in the VTA attenuates alcohol consumption [77]. The 5‐HT receptors, 5‐HT1A, 5‐HT1B, 5‐HT2A, and 5‐HT2C, [78–80] have been widely implicated in alcohol consumption in animal models with new evidence also impli‐ cating 5‐HT3 and 5‐HT6 receptors in alcohol addiction [81, 82].

NE has been shown to play a significant role in negative emotional states which contribute to alcohol consumption [60, 83, 84]. Acute alcohol decreases [85], while chronic alcohol and withdrawal increases the activity of neurons in the locus coeruleus (LC), a region that provides the majority of NE in the brain [86]. Activation of the *α*2‐adrenergic autoreceptors has been shown to attenuate the overall negative effects of withdrawal [87], and blocking *α*1‐adrener‐ gic receptors (ARs) using prazosin reduced alcohol consumption in dependent rats [88] and human alcoholics [89]. Likewise, treatment with the *β*‐AR antagonist, propranolol, reduced drinking in dependent rats [60]. Evidence also suggests that *β*‐ARs may also contribute in mediating the anxiolytic effects of alcohol [58].

Furthermore, CRF is a regulating factor in the activation of the hypothalamus–pituitary– adrenal (HPA) axis to stress [90–94]. Chronic alcohol consumption affects CRF signaling in the central nucleus of amygdala (CeA) and BNST, as evidenced by alterations in CRF transmis‐ sion during withdrawal [95]. Interestingly, NE and 5‐HT have been shown to interact with the neurotransmitter CRF in neuroanatomical sites like the LC, DRN, CeA, and BNST [96–100] to influence addictive behaviors. For instance, yohimbine, a pharmacological agent used to promote stress in rats, has effects on NE, 5‐HT, and CRF signaling to potentiate alcohol drinking and reinstatement [101, 102], suggesting possible mutual regulatory roles of these neurotransmitters in alcohol dependence and relapse. This was further evidenced by CRF antagonism in the DRN to attenuate yohimbine‐induced alcohol‐seeking behaviorin rats [100]. Also, CRF and NE antagonism has been shown to be effective in reducing stress‐induced reinstatement in human alcoholics [88, 103].
