**4. Neuropharmacological aspects of chronic alcoholism**

The neuropharmacological actions of alcohol such as cognitive impairment and other behavioral changes are mediated via their interaction with brain neurotransmitters. Neurotransmitters are the chemicals involved in communication of neurons in brain and may be inhibitory or excitatory depending upon their mechanism of action. Although alcohol does not have any specific target neurotransmitter, it acts on multiple neurotransmitter systems (Deitrich and Erwin, 1996; Tabakoff and Hoffman, 1992).

Chronic alcohol consumption may cause cognitive impairment, tolerance and physical dependence due to changes in neurotransmitter system in brain. The neuropharmacological changes caused by chronic alcoholism involve monoamine oxidase, neurotransmitter amino acids and calcium ion channels and some other pathways leading to neuroadaptations and development of tolerance (Zaleski et al., 2004). The complex mechanism of action involving neurochemical changes explains why even moderate doses of alcohol may lead the subject to develop psychiatric complications and alcohol dependence. The addictive and alcohol seeking behavior can be explained by understanding the neurotransmitter involved in the processes (Vengeliene et al., 2006).

Few of the neurotransmitters involved in alcohol dependence are as follows:

Pharmacogenetics – A Treatment Strategy for Alcoholism 239

VSCC are of L-type (dihydropyridine-sensitive), N-type (neuronal), P-type (Purkinje), Rtype (Resistant), and T type (transient) channels. It has been found that alcohol (ethanol) blocks L-type channels. The L-type VSCC antagonists show some ethanol, like effects in rats. Evidence suggested that chronic administration of alcohol in mice up-regulates the number and function of N-type calcium channels. Ethanol actions at VSCCs may modulate its behavioral effects in humans (Zaleski et al., 2004). It has been reported that there is an increase in the inflow of Calcium ions through these channels, contributing to the

Studies assessing cognitive functions have associated the chronic ingestion of ethanol with the reduction in concentration of acetylcholine in humans as well as mice, caused by the degeneration of brain tissues which seems to be related to the development of tolerance of alcohol. Chronic consumption of alcohol may affect opioid receptor system thus exerting neurobehavioral effects such as reinforcement. The three major classes of opioid system are µ, δ and κ. Alcohol may stimulate the release of certain opioid peptides such as endorphins and enkephalins, which in turn, could interact with the centers (mesolimbic dopamine pathway) of the brain, associated with reward and positive reinforcement and may lead to further alcohol consumption (Vengeliene et al., 2008). Human and animal studies have suggested that µ opioid receptor is mainly involved in initial sensitivity and response to alcohol. The increased activity of brain opioid peptide systems, in response to ethanol exposure, may be important for initiating and maintaining high alcohol consumption and

for mediating the positive reinforcing effects of alcohol (Gianoulakis et al., 1996).

Alcohol exerts its effects such as reward and reinforcement by acting on a number of neurotransmitter in the brain. Studies have revealed that polymorphisms in genes encoding for neurotransmitter may increase the risk of developing alcoholism (Radel & Goldman, 2001; Foley et al., 2006). The knowledge of gene variants affecting neurotransmitters is very important as it serves the basis for developing novel and targeted therapeutic agents in treatment of alcoholism. A few of the genetic variants of neurotransmitters associated with

Candidate gene studies have shown that individuals bearing G603A polymorphism of glial glutamate transporter gene (EAAT2) are at increased risk of alcoholism (Sander et al., 2000). The individuals with genetic variants of NMDA (subunit NR2A) and glutamate receptor metabotropic gene (mGLUR5) have been studied in a hospital based study in Germany (Schumann et al., 2008). It was found that carriers of the NR2A risk genotypes for rs2072450 CC and rs9924016 Del/Del had higher risk of developing alcohol dependence as compared to the individuals with protective genotypes rs2072450 AC and rs9924016 Del/Ins (Schuman et al., 2008). In the case of mGLUR5 gene, individuals of the risk genotypes rs3824927 C/C and rs 3462 G/G have been found to be at higher risk of developing alcohol dependence when compared with individuals bearing the protective genotypes rs3824927 CA and rs3462 GA.

development of withdrawal symptoms such as seizures and craving.

**4.4 Alcohol and other mechanisms of actions** 

**5. Genetic variants of neurotransmitters** 

alcohol dependence are as:

**5.1 Glutamate** 

#### **4.1 Alcohol and monoamines**

Ethanol affects the release of the main neurotransmitters present in central nervous system, such as dopamine, gamma amino butyric acid (GABA), serotonin, noradrenaline and opioid peptides (Kianmaa &Tabakoff, 1983; Tabakoff, 1977, 1983). Alcohol activates the firing of dopaminergic neurons in the ventral tegmental area and nucleus accumbens structures which together are a part of mesolimbic pathway and play an important role for the rewarding effect of ethanol (Diana et al., 1992). Studies have demonstrated that the stimulation of dopaminergic neurons may indirectly activate serotonergic pathways. The low levels of serotonin have been reported to be a risk factor for development of alcoholism (Lovinger, 1991).

#### **4.2 Alcohol and neurotransmitter amino acids**

Several studies have demonstrated the actions of ethanol on neurotransmitter amino acids which consist of glutamate-main excitatory neurotransmitter in the central nervous system. It has N-methyl-D-aspartate (NMDA) and amino-3-hydroxy-5-methyl-4 isoxazoleproprionate (AMPA), and kainate receptors. The NMDA receptors are controlled by several regulatory sites. To open the channel of NMDA receptor, presence of glycine is required. Glycine is an amino acid which has its own site, acting as a coagonist. Alcohol has been reported to act on glycine binding site therefore, inhibiting the function of NMDA receptor (Woodword, 1994). The receptor has been found to play an important role in learning and memory and in development of alcohol tolerance (Longo et al., 2002). Glutamate, a neurotransmitter has been found to play a significant role in the pathogenesis of alcohol dependence by mediating excitatory pathways (Sander et al., 2000). Chronic alcohol use has been found to be associated with upregulation of NMDA receptors. Alcohol shows lower affinity for AMPA and kainate glutamate receptors (Ferreira & Morato, 1997). In case of acute ethanol withdrawal, NMDA receptor releases increased amount of glutamate which is associated with tremors, anxiety, ataxia, and convulsions.

Alcohol produces sedative-hypnotic effects mediated via GABA, an inhibitory neurotransmitter. There are three types of GABA receptors, GABA A, GABA B, and GABA C in brain. GABA A receptors are responsible for the intoxicating effects of alcohol such as motor incoordination, anxiolysis and sedation. The neurobehavioral effects of ethanol mediated via neurotransmitter GABA are directly dose-dependent. The effects of alcohol at GABA A receptors vary across brain regions. This might be due to the differential expression of GABA A receptor subunits (Loh et al., 1999).

Another neurotransmitter, Neuropeptide Y (NPY) is an amino acid peptide which has been associated with reward, appetite and anxiety. The association of NPY has also been reported with alcohol dependence in animal models. NPY-deficient mice have been reported to show higher alcohol consumption as compared with wild type mice (Thiele et al., 1998).

#### **4.3 Alcohol and calcium ion channels**

Voltage sensitive calcium channels (VSCCs) play a major role in gating synaptic calcium influx and thereby modulating a range of calcium dependent intracellular processes, membrane potential, and neurotransmitter release (Kennedy & Liu, 2003). The types of

Ethanol affects the release of the main neurotransmitters present in central nervous system, such as dopamine, gamma amino butyric acid (GABA), serotonin, noradrenaline and opioid peptides (Kianmaa &Tabakoff, 1983; Tabakoff, 1977, 1983). Alcohol activates the firing of dopaminergic neurons in the ventral tegmental area and nucleus accumbens structures which together are a part of mesolimbic pathway and play an important role for the rewarding effect of ethanol (Diana et al., 1992). Studies have demonstrated that the stimulation of dopaminergic neurons may indirectly activate serotonergic pathways. The low levels of serotonin have been reported to be a risk factor for development of alcoholism

Several studies have demonstrated the actions of ethanol on neurotransmitter amino acids which consist of glutamate-main excitatory neurotransmitter in the central nervous system. It has N-methyl-D-aspartate (NMDA) and amino-3-hydroxy-5-methyl-4 isoxazoleproprionate (AMPA), and kainate receptors. The NMDA receptors are controlled by several regulatory sites. To open the channel of NMDA receptor, presence of glycine is required. Glycine is an amino acid which has its own site, acting as a coagonist. Alcohol has been reported to act on glycine binding site therefore, inhibiting the function of NMDA receptor (Woodword, 1994). The receptor has been found to play an important role in learning and memory and in development of alcohol tolerance (Longo et al., 2002). Glutamate, a neurotransmitter has been found to play a significant role in the pathogenesis of alcohol dependence by mediating excitatory pathways (Sander et al., 2000). Chronic alcohol use has been found to be associated with upregulation of NMDA receptors. Alcohol shows lower affinity for AMPA and kainate glutamate receptors (Ferreira & Morato, 1997). In case of acute ethanol withdrawal, NMDA receptor releases increased amount of

glutamate which is associated with tremors, anxiety, ataxia, and convulsions.

expression of GABA A receptor subunits (Loh et al., 1999).

**4.3 Alcohol and calcium ion channels** 

Alcohol produces sedative-hypnotic effects mediated via GABA, an inhibitory neurotransmitter. There are three types of GABA receptors, GABA A, GABA B, and GABA C in brain. GABA A receptors are responsible for the intoxicating effects of alcohol such as motor incoordination, anxiolysis and sedation. The neurobehavioral effects of ethanol mediated via neurotransmitter GABA are directly dose-dependent. The effects of alcohol at GABA A receptors vary across brain regions. This might be due to the differential

Another neurotransmitter, Neuropeptide Y (NPY) is an amino acid peptide which has been associated with reward, appetite and anxiety. The association of NPY has also been reported with alcohol dependence in animal models. NPY-deficient mice have been reported to show

Voltage sensitive calcium channels (VSCCs) play a major role in gating synaptic calcium influx and thereby modulating a range of calcium dependent intracellular processes, membrane potential, and neurotransmitter release (Kennedy & Liu, 2003). The types of

higher alcohol consumption as compared with wild type mice (Thiele et al., 1998).

**4.1 Alcohol and monoamines** 

**4.2 Alcohol and neurotransmitter amino acids** 

(Lovinger, 1991).

VSCC are of L-type (dihydropyridine-sensitive), N-type (neuronal), P-type (Purkinje), Rtype (Resistant), and T type (transient) channels. It has been found that alcohol (ethanol) blocks L-type channels. The L-type VSCC antagonists show some ethanol, like effects in rats. Evidence suggested that chronic administration of alcohol in mice up-regulates the number and function of N-type calcium channels. Ethanol actions at VSCCs may modulate its behavioral effects in humans (Zaleski et al., 2004). It has been reported that there is an increase in the inflow of Calcium ions through these channels, contributing to the development of withdrawal symptoms such as seizures and craving.

#### **4.4 Alcohol and other mechanisms of actions**

Studies assessing cognitive functions have associated the chronic ingestion of ethanol with the reduction in concentration of acetylcholine in humans as well as mice, caused by the degeneration of brain tissues which seems to be related to the development of tolerance of alcohol. Chronic consumption of alcohol may affect opioid receptor system thus exerting neurobehavioral effects such as reinforcement. The three major classes of opioid system are µ, δ and κ. Alcohol may stimulate the release of certain opioid peptides such as endorphins and enkephalins, which in turn, could interact with the centers (mesolimbic dopamine pathway) of the brain, associated with reward and positive reinforcement and may lead to further alcohol consumption (Vengeliene et al., 2008). Human and animal studies have suggested that µ opioid receptor is mainly involved in initial sensitivity and response to alcohol. The increased activity of brain opioid peptide systems, in response to ethanol exposure, may be important for initiating and maintaining high alcohol consumption and for mediating the positive reinforcing effects of alcohol (Gianoulakis et al., 1996).

## **5. Genetic variants of neurotransmitters**

Alcohol exerts its effects such as reward and reinforcement by acting on a number of neurotransmitter in the brain. Studies have revealed that polymorphisms in genes encoding for neurotransmitter may increase the risk of developing alcoholism (Radel & Goldman, 2001; Foley et al., 2006). The knowledge of gene variants affecting neurotransmitters is very important as it serves the basis for developing novel and targeted therapeutic agents in treatment of alcoholism. A few of the genetic variants of neurotransmitters associated with alcohol dependence are as:

#### **5.1 Glutamate**

Candidate gene studies have shown that individuals bearing G603A polymorphism of glial glutamate transporter gene (EAAT2) are at increased risk of alcoholism (Sander et al., 2000). The individuals with genetic variants of NMDA (subunit NR2A) and glutamate receptor metabotropic gene (mGLUR5) have been studied in a hospital based study in Germany (Schumann et al., 2008). It was found that carriers of the NR2A risk genotypes for rs2072450 CC and rs9924016 Del/Del had higher risk of developing alcohol dependence as compared to the individuals with protective genotypes rs2072450 AC and rs9924016 Del/Ins (Schuman et al., 2008). In the case of mGLUR5 gene, individuals of the risk genotypes rs3824927 C/C and rs 3462 G/G have been found to be at higher risk of developing alcohol dependence when compared with individuals bearing the protective genotypes rs3824927 CA and rs3462 GA.

Pharmacogenetics – A Treatment Strategy for Alcoholism 241

manipulation of serotonergic transmission therefore affecting the rate of development of

Evidence from genetic studies suggested that alcohol dependence as well as cigarette smoking in families share the genetic vulnerability. Research studies have identified a missense mutation (rs16969968) in exon 5 of the nicotinic receptor (CHRNA5) gene and a variant in the 3′-UTR of the CHRNA3 gene in association with alcoholism and nicotine dependence (Wang et al., 2009). Cholinergic muscarinic 2 receptor (CHRM2) SNP (rs1824024) has been significantly associated with the pathogenesis of depression and

Bart et al. (2005) have identified positive association between A118G polymorphism and increased risk of alcohol dependence in individuals from Sweden. The single nucleotide polymorphism A118G in exon 1 of opioid receptor gene (OPRM1) results in increase in 3 fold binding capacity of beta endorphin. However, the results of a number of research studies are contradictory. Few studies have failed to find the association between the A118 G allele and alcoholism (Bergen et al., 1997; Franke et al., 2001; Gelernter et al., 1999; Kim et al., 2004; Kranzler et al., 1998; Schinka et al., 2002), while few others have found positive association between the A118 allele and alcoholism (Town et al., 1999). The explanations for these conflicting reports may be small sample size of the populations under study and the

In Humans, Leu7Pro polymorphism in NPY gene has been established to affect the release of mature NPY. Individuals with Pro7/Leu7 allele have 42% higher plasma concentration of NPY as compared with Leu7/Leu7 variant. Kauhanen et al. (2000) reported that Pro7allele is associated with more (34% higher) alcohol consumption in a cohort of Finnish middle aged men. Lappalainnen and others have reported that NPYPro7 allele significantly contributes towards the heritability of alcohol dependence in European American population

The first step in the treatment of alcoholism is detoxification assisted by medical treatment (Wertheimer and Chaney 2003). Detoxification is required to manage the clinical and psychological symptoms of alcoholism. After detoxification there is need for counseling or psychotherapy and rehabilitation (Williams, 2001). The pharmacological agents or medicines in use for alcoholism treatment act on specific neurotransmitter systems. The treatment is aimed at normalizing the alcohol specific neuroadaptations (Krishnan-Sarin et al., 2008). The selection criteria for treatment of alcoholism is based on the length of illness and additional amount of alcohol related problems (Wertheimer

tolerance and alcohol dependence (Yoshimoto et al., 1996).

alcohol dependence disorders (Jung et al., 2011; Luo et al., 2005).

**5.6 Cholinergic and nicotinic receptor gene** 

**5.8 Other neurotransmitters (Neuropeptide Y)** 

**5.7 Opioids** 

ethnic variation.

(Lappalainnen et al., 2002).

&Chaney, 2003).

**6. Pharmacotherapy of alcoholism** 

#### **5.2 Gamma amino butyric acid**

Association of genetic variants of GABARA1 and GABAR6 with alcoholism has been reported in Korean population (Park et al., 2006).The GG genotype of GABAA1 receptor has been found to be significantly associated with early onset and severity of alcoholism in Korean population (Park et al., 2006). It has been also been reported that Pro385Ser substitution in GABA A6 is associated with alcohol dependence and with antisocial alcoholism (Sander et al., 1999).

#### **5.3 Norepinephrine**

Studies have suggested that alcohol produces biphasic effects on norepinephrine turnover in the brain, with low doses increasing turnover and higher doses depressing turnover. The sensitivity of noradrenergic systems to ethanol effects varies among brain regions. A few studies have been attempted to see the effect of genetic variants of norepinephrine on alcoholism. Huang et al. (2008) reported that norepinephrine transporter polymorphisms T-182C and G1287A are not associated with alcohol dependence and its clinical subgroups in Han Chinese population.

#### **5.4 Dopamine**

Research studies have revealed that there is a positive association between polymorphism in Dopamine receptor gene (DRD) with alcoholism. Ponce et al. (2008) reported that the two SNPs (-141C Ins/Del) and TaqI A, present on DRD2 gene locus were associated with alcoholism in North Indian population. Studies from South Indian population have reported no association between TaqI A polymorphism and alcoholism.

The -141 Ins/Del polymorphism in DRD2 gene has been found to be associated with alcoholism in several studies across different populations, but with inconsistent results. This promoter polymorphism plays a significant role in D2 receptor expression via altering the transcriptional activity. Johann et al. (2005) studied the association of -141I Del variant (- 141C) SNP in German alcoholics. It was found that -141 Del C variant of DRD2 gene might be a protective factor against development of alcoholism. On the other hand the -141 Ins allele has been found to be a genetic risk factor for alcoholism in Mexican-Americans. This can be correlated with decreased DRD2 receptor density in alcoholic patients which in turn stimulates craving-reward pathway- thereby promoting alcoholism.

Another polymorphism in DRD2 gene Taq I A in Ankyrin repeat and Kinase Domain containing (ANKK1)( rs 1800497) is one of the most frequently studied mutations. The DRD2 gene is actually not located on DRD2 but rather within the protein coding region exon 8 of the adjacent ANKK1gene (Neville et al., 2004). TaqI A SNP causes an amino acid substitution within the 11th ankyrin repeat of the putative protein and has been found to affect the substrate binding specificity (Ponce et al., 2008). In a meta-analysis, the single nucleotide variant TaqIA (rs 1800497) of the DRD2 gene has been found as a vulnerability gene for alcoholism in more than 40 studies, but with conflicting results.

#### **5.5 Serotonin**

The genetic variants of serotonin receptor gene for example rs1042173 may influence alcohol dependence (Jhonsan et al., 2011). The presence of genetic variation may lead to manipulation of serotonergic transmission therefore affecting the rate of development of tolerance and alcohol dependence (Yoshimoto et al., 1996).

#### **5.6 Cholinergic and nicotinic receptor gene**

Evidence from genetic studies suggested that alcohol dependence as well as cigarette smoking in families share the genetic vulnerability. Research studies have identified a missense mutation (rs16969968) in exon 5 of the nicotinic receptor (CHRNA5) gene and a variant in the 3′-UTR of the CHRNA3 gene in association with alcoholism and nicotine dependence (Wang et al., 2009). Cholinergic muscarinic 2 receptor (CHRM2) SNP (rs1824024) has been significantly associated with the pathogenesis of depression and alcohol dependence disorders (Jung et al., 2011; Luo et al., 2005).

#### **5.7 Opioids**

240 Pharmacology

Association of genetic variants of GABARA1 and GABAR6 with alcoholism has been reported in Korean population (Park et al., 2006).The GG genotype of GABAA1 receptor has been found to be significantly associated with early onset and severity of alcoholism in Korean population (Park et al., 2006). It has been also been reported that Pro385Ser substitution in GABA A6 is associated with alcohol dependence and with antisocial alcoholism (Sander et al., 1999).

Studies have suggested that alcohol produces biphasic effects on norepinephrine turnover in the brain, with low doses increasing turnover and higher doses depressing turnover. The sensitivity of noradrenergic systems to ethanol effects varies among brain regions. A few studies have been attempted to see the effect of genetic variants of norepinephrine on alcoholism. Huang et al. (2008) reported that norepinephrine transporter polymorphisms T-182C and G1287A are not associated with alcohol dependence and its clinical subgroups in

Research studies have revealed that there is a positive association between polymorphism in Dopamine receptor gene (DRD) with alcoholism. Ponce et al. (2008) reported that the two SNPs (-141C Ins/Del) and TaqI A, present on DRD2 gene locus were associated with alcoholism in North Indian population. Studies from South Indian population have reported

The -141 Ins/Del polymorphism in DRD2 gene has been found to be associated with alcoholism in several studies across different populations, but with inconsistent results. This promoter polymorphism plays a significant role in D2 receptor expression via altering the transcriptional activity. Johann et al. (2005) studied the association of -141I Del variant (- 141C) SNP in German alcoholics. It was found that -141 Del C variant of DRD2 gene might be a protective factor against development of alcoholism. On the other hand the -141 Ins allele has been found to be a genetic risk factor for alcoholism in Mexican-Americans. This can be correlated with decreased DRD2 receptor density in alcoholic patients which in turn

Another polymorphism in DRD2 gene Taq I A in Ankyrin repeat and Kinase Domain containing (ANKK1)( rs 1800497) is one of the most frequently studied mutations. The DRD2 gene is actually not located on DRD2 but rather within the protein coding region exon 8 of the adjacent ANKK1gene (Neville et al., 2004). TaqI A SNP causes an amino acid substitution within the 11th ankyrin repeat of the putative protein and has been found to affect the substrate binding specificity (Ponce et al., 2008). In a meta-analysis, the single nucleotide variant TaqIA (rs 1800497) of the DRD2 gene has been found as a vulnerability

The genetic variants of serotonin receptor gene for example rs1042173 may influence alcohol dependence (Jhonsan et al., 2011). The presence of genetic variation may lead to

no association between TaqI A polymorphism and alcoholism.

stimulates craving-reward pathway- thereby promoting alcoholism.

gene for alcoholism in more than 40 studies, but with conflicting results.

**5.2 Gamma amino butyric acid** 

**5.3 Norepinephrine** 

Han Chinese population.

**5.4 Dopamine** 

**5.5 Serotonin** 

Bart et al. (2005) have identified positive association between A118G polymorphism and increased risk of alcohol dependence in individuals from Sweden. The single nucleotide polymorphism A118G in exon 1 of opioid receptor gene (OPRM1) results in increase in 3 fold binding capacity of beta endorphin. However, the results of a number of research studies are contradictory. Few studies have failed to find the association between the A118 G allele and alcoholism (Bergen et al., 1997; Franke et al., 2001; Gelernter et al., 1999; Kim et al., 2004; Kranzler et al., 1998; Schinka et al., 2002), while few others have found positive association between the A118 allele and alcoholism (Town et al., 1999). The explanations for these conflicting reports may be small sample size of the populations under study and the ethnic variation.

#### **5.8 Other neurotransmitters (Neuropeptide Y)**

In Humans, Leu7Pro polymorphism in NPY gene has been established to affect the release of mature NPY. Individuals with Pro7/Leu7 allele have 42% higher plasma concentration of NPY as compared with Leu7/Leu7 variant. Kauhanen et al. (2000) reported that Pro7allele is associated with more (34% higher) alcohol consumption in a cohort of Finnish middle aged men. Lappalainnen and others have reported that NPYPro7 allele significantly contributes towards the heritability of alcohol dependence in European American population (Lappalainnen et al., 2002).

## **6. Pharmacotherapy of alcoholism**

The first step in the treatment of alcoholism is detoxification assisted by medical treatment (Wertheimer and Chaney 2003). Detoxification is required to manage the clinical and psychological symptoms of alcoholism. After detoxification there is need for counseling or psychotherapy and rehabilitation (Williams, 2001). The pharmacological agents or medicines in use for alcoholism treatment act on specific neurotransmitter systems. The treatment is aimed at normalizing the alcohol specific neuroadaptations (Krishnan-Sarin et al., 2008). The selection criteria for treatment of alcoholism is based on the length of illness and additional amount of alcohol related problems (Wertheimer &Chaney, 2003).

Pharmacogenetics – A Treatment Strategy for Alcoholism 243

It has been found that acamprosate reduces neuronal hyperexcitability during alcohol withdrawal, due to reductions in glutamate levels, so as to normalize the balance between excitatory and inhibitory neurotransmitters produced in chronic alcohol consumption

In addition to the drugs approved by FDA for treating alcoholism there are other

Ondansetron is a 5HT3 receptor antagonist used mainly as antinausea medicine after postoperative nausea and as anticraving medicine in alcoholism. Human laboratory studies have demonstrated that ondansetron decreases alcohol preference and desire to drink (Johnson et al., 1993). The efficacy of ondansetron in reducing drinking behavior has also been reported in Clinical trials, especially in drinkers with early onset alcoholism (Kranzler

Baclofen, a GABA B receptor antagonist is used clinically for the treatment of muscle spasticity. The preclinical trials have shown the effectiveness of baclofen in reducing chronic alcoholism (Colombo et al., 2004). In a recent clinical trial, it was found that the drug is well tolerated in alcohol dependent patients with liver cirrhosis and has some efficacy in improving abstinence rates. However, more clinical research is needed to establish its

Topiramate is an antiseizure medication which has been shown to be effective in reducing alcohol use in recent clinical trials. Its action is mediated via antagonizing α amino-3 hydroxy 5-methylisoxazole 4-propionic acid (AMPA) and kainate glutamate receptors as well as inhibition of GABA A receptors, L type calcium channels, and voltage dependent sodium channels (SCN). Topiramate has been shown to reduce alcohol use in animal models (Farook et al., 2007). It also helps in reducing alcohol withdrawl induced convulsions. It has some side effects such as numbness, anorexia, cognitive difficulty, and taste distortion, as well as some rare incidents of visual side effects including myopia, glaucoma, and increased intraocular pressure. The clinical trials used a slow titration over several weeks to the

Selective serotonin reuptake inhibitors such as fluoxetine, citalopram, and sertraline are used in the treatment of alcoholism because existing evidence has shown that lowering brain serotonin levels decrease preference for alcohol and SSRI. SSRI's are basically used in the treatment of depression, therefore the effectiveness has been found in depressed

(Spanagel et al., 1996; Dahchour et al., 1998; Littleton & Zieglgansberger, 2003).

medications which are in use because of some clinical evidence of efficacy.

**6.2 Other promising medicines** 

efficacy and tolerability in alcoholic patients.

desired dose to reduce the incidence of side effects.

alcoholics in some clinical trials.

**6.2.4 Selective serotonin reuptake inhibitors (SSRI)** 

**6.2.1 Ondansetron** 

et al., 2003).

**6.2.2 Baclofen** 

**6.2.3 Topiramate** 

#### **6.1 FDA approved drugs for treatment of alcoholism**

Some of the drugs approved by FDA for treatment of alcoholism are as follows (Krishnan-Sarin et al., 2008).

#### **6.1.1 Disulfiram**

Disulfiram has been in use to treat alcoholism since 1940. Disulfiram produces an aversive effect by disrupting alcohol metabolism. The proposed mechanism of action of disulfiram on alcohol use has been found to be primarily related to the inhibition of liver aldehyde dehydrogenase (metabolizing enzyme of alcohol) and secondarily related to central nervous system actions, via modulation of catecholamine neurotransmission. It blocks ALDH activity by forming intermolecular disulfide bridges resulting in acetaldehyde accumulation. Excessive buildup of acetaldehyde results in many unpleasant effects including lowered blood pressure, palpitation, nausea, vomiting, headache and difficulty in breathing.

In clinical doses, disulfiram inhibits the enzyme dopamine–β–hydroxylase, which converts dopamine to norepinephrine, leading to increase in dopamine levels in brain (Goldstein & Nakajima, 1967; Goldstein et al., 1964). It has been found in clinical trials of disulfiram that there are lower rates of relapse to drinking in those who are compliant with the medication (Fuller et al., 1986). However, due to aversive nature of this drug, noncompliance is one of the biggest problems encountered with its use. The use of disulfiram is supervised in many clinical settings.

#### **6.1.2 Naltrexone**

Naltrexone is a drug used mainly for the treatment of alcohol dependence, and is available as oral medication and in injectable form. The drug is well tolerated with primary gastrointestinal side effects (O'Malley et al., 1992; Volpicelli et al., 1992). The efficacy of naltrexone in reducing alcohol drinking is mediated via interactions between the endogenous opioid system and dopamine systems, specifically through antagonism of the μ−opioid receptors. The studies on animal models suggested that alcohol increases release of β−endorphins in certain portions of the brain known to be involved in alcohol reward (Marinelli et al., 2003; Zalewska-Kaszubska et al., 2006). Nalotrexane blocks the release of these endorphins. Naltrexone has also been shown to reduce drinking in animal models (Froehlich et al. 2003; Swift, 2000).

A number of clinical trials indicate that alcoholics receiving naltrexone treatment in combination with behavioral intervention have lower levels of relapse and reduced levels of alcohol craving (O'Malley et al., 1992). Recent reports (Bouza et al., 2004; Srisurapanont & Jarusuraisin, 2002) suggest that naltrexone has modest efficacy in preventing relapse to drinking. Although, naltrexone is well tolerated, the potential risk of toxicity of liver at high doses is the major cause of concern in patients with liver disease.

#### **6.1.3 Acamprosate**

Acamprosate is available in an oral, delayed release formula, Camprel. The mechanism of action is through antagonizing of the N-methyl D-aspartate (NMDA) glutamate receptor site or via modulation of glutamate neurotransmission (DeWitte et al., 2005; Harris et al., 2002). It has been found that acamprosate reduces neuronal hyperexcitability during alcohol withdrawal, due to reductions in glutamate levels, so as to normalize the balance between excitatory and inhibitory neurotransmitters produced in chronic alcohol consumption (Spanagel et al., 1996; Dahchour et al., 1998; Littleton & Zieglgansberger, 2003).

#### **6.2 Other promising medicines**

In addition to the drugs approved by FDA for treating alcoholism there are other medications which are in use because of some clinical evidence of efficacy.

## **6.2.1 Ondansetron**

242 Pharmacology

Some of the drugs approved by FDA for treatment of alcoholism are as follows (Krishnan-

Disulfiram has been in use to treat alcoholism since 1940. Disulfiram produces an aversive effect by disrupting alcohol metabolism. The proposed mechanism of action of disulfiram on alcohol use has been found to be primarily related to the inhibition of liver aldehyde dehydrogenase (metabolizing enzyme of alcohol) and secondarily related to central nervous system actions, via modulation of catecholamine neurotransmission. It blocks ALDH activity by forming intermolecular disulfide bridges resulting in acetaldehyde accumulation. Excessive buildup of acetaldehyde results in many unpleasant effects including lowered

In clinical doses, disulfiram inhibits the enzyme dopamine–β–hydroxylase, which converts dopamine to norepinephrine, leading to increase in dopamine levels in brain (Goldstein & Nakajima, 1967; Goldstein et al., 1964). It has been found in clinical trials of disulfiram that there are lower rates of relapse to drinking in those who are compliant with the medication (Fuller et al., 1986). However, due to aversive nature of this drug, noncompliance is one of the biggest problems encountered with its use. The use of disulfiram is supervised in many

Naltrexone is a drug used mainly for the treatment of alcohol dependence, and is available as oral medication and in injectable form. The drug is well tolerated with primary gastrointestinal side effects (O'Malley et al., 1992; Volpicelli et al., 1992). The efficacy of naltrexone in reducing alcohol drinking is mediated via interactions between the endogenous opioid system and dopamine systems, specifically through antagonism of the μ−opioid receptors. The studies on animal models suggested that alcohol increases release of β−endorphins in certain portions of the brain known to be involved in alcohol reward (Marinelli et al., 2003; Zalewska-Kaszubska et al., 2006). Nalotrexane blocks the release of these endorphins. Naltrexone has also been shown to reduce drinking in animal models

A number of clinical trials indicate that alcoholics receiving naltrexone treatment in combination with behavioral intervention have lower levels of relapse and reduced levels of alcohol craving (O'Malley et al., 1992). Recent reports (Bouza et al., 2004; Srisurapanont & Jarusuraisin, 2002) suggest that naltrexone has modest efficacy in preventing relapse to drinking. Although, naltrexone is well tolerated, the potential risk of toxicity of liver at high

Acamprosate is available in an oral, delayed release formula, Camprel. The mechanism of action is through antagonizing of the N-methyl D-aspartate (NMDA) glutamate receptor site or via modulation of glutamate neurotransmission (DeWitte et al., 2005; Harris et al., 2002).

doses is the major cause of concern in patients with liver disease.

blood pressure, palpitation, nausea, vomiting, headache and difficulty in breathing.

**6.1 FDA approved drugs for treatment of alcoholism** 

Sarin et al., 2008).

**6.1.1 Disulfiram** 

clinical settings.

**6.1.2 Naltrexone** 

(Froehlich et al. 2003; Swift, 2000).

**6.1.3 Acamprosate** 

Ondansetron is a 5HT3 receptor antagonist used mainly as antinausea medicine after postoperative nausea and as anticraving medicine in alcoholism. Human laboratory studies have demonstrated that ondansetron decreases alcohol preference and desire to drink (Johnson et al., 1993). The efficacy of ondansetron in reducing drinking behavior has also been reported in Clinical trials, especially in drinkers with early onset alcoholism (Kranzler et al., 2003).

#### **6.2.2 Baclofen**

Baclofen, a GABA B receptor antagonist is used clinically for the treatment of muscle spasticity. The preclinical trials have shown the effectiveness of baclofen in reducing chronic alcoholism (Colombo et al., 2004). In a recent clinical trial, it was found that the drug is well tolerated in alcohol dependent patients with liver cirrhosis and has some efficacy in improving abstinence rates. However, more clinical research is needed to establish its efficacy and tolerability in alcoholic patients.

#### **6.2.3 Topiramate**

Topiramate is an antiseizure medication which has been shown to be effective in reducing alcohol use in recent clinical trials. Its action is mediated via antagonizing α amino-3 hydroxy 5-methylisoxazole 4-propionic acid (AMPA) and kainate glutamate receptors as well as inhibition of GABA A receptors, L type calcium channels, and voltage dependent sodium channels (SCN). Topiramate has been shown to reduce alcohol use in animal models (Farook et al., 2007). It also helps in reducing alcohol withdrawl induced convulsions. It has some side effects such as numbness, anorexia, cognitive difficulty, and taste distortion, as well as some rare incidents of visual side effects including myopia, glaucoma, and increased intraocular pressure. The clinical trials used a slow titration over several weeks to the desired dose to reduce the incidence of side effects.

#### **6.2.4 Selective serotonin reuptake inhibitors (SSRI)**

Selective serotonin reuptake inhibitors such as fluoxetine, citalopram, and sertraline are used in the treatment of alcoholism because existing evidence has shown that lowering brain serotonin levels decrease preference for alcohol and SSRI. SSRI's are basically used in the treatment of depression, therefore the effectiveness has been found in depressed alcoholics in some clinical trials.

Pharmacogenetics – A Treatment Strategy for Alcoholism 245

that G allele has a loss of function rather than a gain. Further, the results of the study testing the relationship between this SNP of the OPRM1 gene and alcoholism have shown inconsistent results, some support the association of this SNP and alcohol dependence while others have failed to replicate this association (Schinka et al., 2002; Kranzler et al., 1998; Town et al., 1999). Further, this SNP of OPRM1 gene has also been associated with a differential response in clinical trials of naltrexone. Oslin et al. (2003) has reported that this SNP is associated with clinical response to naltrexaone among alcohol dependent patients such that individuals with at least one copy of the G allele, coding for more potent OPRM1 receptor reported lower relapse rates and longer time to return to heavy drinking after treatment with

It has been reported that persons of Asian descent possess an ALDH2\*2 genetic variant (Quertemont et al., 2004). ALDH2\*2 genetic variant of the ALDH enzyme metabolizes slowly and leads to accumulation of acetaldehyde (Edenberg, 2007). When the individuals bearing this variant drink alcohol they develop high acetaldehyde blood concentration and experience of flushing reaction similar to that seen in combination of ethanol and disulfiram. ALDH2\*2 variation is the best characterized genetic factor protecting against the development of alcohol dependence. Pharmacogenomic studies suggest that it is highly unlikely that disulfiram will be helpful in treating the patients who have genetically

In addition disulfiram chelates copper and thus inhibits copper containing enzyme dopamine beta hydroxylase which further inhibits norepinephrine and dopamine in brain (Haile et al., 2009). The individuals harboring TT allele of dopamine beta hydroxylase (DβH) gene with C1021T polymorphism respond better to disulfiram treatment and need less dose whereas carriers (CT) would need intermediate dose and those with CC allele need

Acamprosate, is a drug used for abstinence and maintenance as it reduces craving in alcoholic patients who have undergone detoxification (De Witte et al., 2005). The effective acamprosate response in alcohol dependent subjects may be influenced by genetically controlled variation of NMDA receptor and the type of glutaminergic mGLU5 receptor. Confirmation of this hypothesis could lead to development of effective individualized treatment and recommendation for alcohol dependent patients based on

Ondansetron, an antagonist of serotonin is important in the treatment of alcoholism. Serotonin transporter gene is an important regulator of neuronal 5-HT's function. The genetic difference in this gene may modulate the severity of alcohol consumption and predict the therapeutic response to 5-HT3 receptor antagonist ondansetron. A variable tandem repeat polymorphism (5-HTT LPR) is common in the promoter region of 5-HTT gene which alters the transcriptional activity. Two important variants are long (insertion LL) and short (SS) version. It has been reported in a randomized clinical trial that individuals with LL genotype (Homozygous for the long version) of 5-HTT gene showed significant results in improvements of alcoholism with treatment of ondansetron as compared to LS

Another functional T/G polymorphism (rs1042173) as in the 3/ untranslated region of the 5- HTT gene may alter the therapeutic response in alcoholism treatment with ondansetron in

naltrexone, in comparison with individuals who were homozygous for the A allele.

compromised ALDH.

maximum concentration to reach the efficacy level.

pharmacogenetically relevant genetic variant.

and SS genotype (Johnson et al., 2011).
