*2.3.1. Generation of free radicals*

*2.2.2. Gamma-amino-butyric acid*

18 Drug Addiction

that is, gabapentin and topiramate [27, 28].

*2.2.3. Dopamine*

*2.2.4. Serotonin*

It is a chief inhibitory neurotransmitter. GABA binds to GABAA receptors, resulting in hyperpolarization of the cell membrane and inhibition of neural activity. Increased GABA release upon alcohol administration results due to inhibiting its degradation [24]. Alcohol intoxicity and alcohol's anti-anxiety reduce due to decrease in GABAA receptor activity. Chronic alcohol exposure decreases extrasynaptic GABA-mediated tonic current recorded from neurons in the hippocampus and cortex [25], and this corresponds to a decrease in extrasynaptic GABAA receptors containing the d subunit in hippocampus [26]. Benzodiazepines (the positive allosteric modulator of GABAA) are considered to be a standard for treating alcohol detoxification owing to their anticonvulsant and anxiolytic pharmacological profile. Improper alcohol interactions have shown some concern about their abuse and dependence responsibility. Therefore, researchers are trying to find out potential anticonvulsant agents as alternatives,

Transmission of dopamine is linked via two groups of G-protein-linked receptors: D1-like (D1 and D5 receptors) and D2-like (D2, D3 and D4 receptors). These receptors are classified on the basis of adenylatecyclase activity (stimulation or inhibition). Dopamine plays a central role in mediating alcohol compensation through mesocortical and mesolimbic pathways [29]. During chronic alcohol consumption, the release of dopamine depends on the large amount of the alcohol consumption, which gives pleasurable effect of alcohol intake. Reduction in dopamine release is observed during alcohol withdrawal. This ultimately reduces noticeable neuronal cells, leading to dysphoria and depression as a major part in the motivational and behavioral changes [30]. Chronic alcohol drinking has been reported to produce constant neurological changes in transmission of dopamine within the mesoaccumbens reward circuitry, including increased basal extracellular levels of dopamine in the NAC [31], increased firing rate in the ventral tegmental area (VTA) dopamine neurons [32] and changes in the function of dopamine receptor [33]. In comparison, withdrawal from chronic alcohol drinking due to increased dopamine uptake levels resulted in decreased VTA dopamine neuronal activity [34], and reduced basal levels of dopamine in the ventral and dorsal subregions of the striatum, possibly due to enhanced dopamine uptake [35]. The aripiprazole (D2 dopamine recep-

tor agonist) has shown some effectiveness in treating dependence of alcohol [36].

Serotonin exerts its known role in regulating various behaviors (e.g., feeding, sleep/arousal, aggression), mood and emotional behavior [37] via several metabotropic (5-HT1 and 5-HT2 subtypes) and ionotropic (5-HT3) receptors throughout the brain depending on the consumption of alcohol [38]. Alcohol elevates serotonin release in the central nervous system (CNS) affecting emotion, temper and thoughts. The 5-HT3 receptor function is altered by ethanol consumption through its actions on receptor proteins [39]. Chronic alcohol exposure reduces serotonin levels in several brain regions [40]. Researchers have focused on the treatment for alcohol dependence and comorbid depression [41], post-stress disorder [42] and anxiety [43]. Alcohol-induced brain damage may occur due to generation of free radicals [49] by acetaldehyde intoxicity [50] or microsomal ethanol oxidizing system (MEOS) [51]. This can be minimized, if there would be a reduction in glutathione (cytoprotection) in the specific regions of the brain which is affected.

## *2.3.2. Changes in phosphorylation*

Cell signaling events depend on phosphorylation of proteins (phosphorylation: protein kinase and dephosphorylation: protein phosphatases). During intoxication in hippocampal dentate gyrus,


**Table 2.** Neurotransmitters and its effect on the brain system.


**Table 3.** Neurotransmitters-associated drug to reduce alcohol toxicity in the brain.

the total phosphorylated c-AMP response element-binding protein (CREB) immunoreactivity is reduced in both chronic or binge drinking. In rat cerebellum, the dose of 3 g/kg alcohol (acute) shows an increase in a phosphorylated form of CREB. Research showed that protein phosphatase inhibitor (DARPP-32), when it undergoes phosphorylation changes, plays a crucial role in reducing ethanol inhibition of NMDA receptors [52].

**2.5. Genome profiling of alcohol-responsive genes**

*2.5.1. Microarray study*

*Nkx2-2* (myelin-related genes) [63].

protein 1B *(Mtap1b)* [64].

*2.5.2. Analysis of quantitative trait loci*

includes.

With recent technologies like direct sequencing and gene microarray, studying individual

Effect of Alcohol on Brain Development http://dx.doi.org/10.5772/intechopen.73693 21

First genome microarray studies were performed in post-mortem alcoholics' human brain; results revealed that myelin related genes expressed in oligodendrites (from frontal cortex) showed downregulation in the brains of human alcoholics compared with brains from control individuals [58], suggesting neuronal dysfunction. In the prefrontal cortex area of the brain, there were 54 genes which were upregulated and those belong to the class of heat shock protein, including *HSP70–2, CRYAB, HSP27–1* and *HSP40–1* in alcoholic abusive individuals [59]. An old study revealed that 100 mM ethanol (2 days) given to NG108–15 hybrid cell line determined that a number of genes were induced by heat shock and a few were induced by ethanol only. Heat-shock cognate proteins *Hsc 70* and *Hsc 110* were recognized as ethanol-inducible genes [60]. When *C. elegans* was given a high dose of ethanol, it showed activation of *glr-2*, a gene that encodes a subunit of the AMPA glutamate receptor subunit (homologous to mammalian GluR2) within 15 min [61]. Cultured cortical neurons given 75 mM of ethanol for 5 days showed increased levels of gene expression of *Hsp84, Hspa8* and *Hsp70* [62]. In a whole brain, when C57BL/6J and DBA/2J mouse strains were given acute doses of different ethanol preferences, they revealed downregulation of *Erbb3*, *Mobp* and

The researcher performed a genomic level along with a microarray experiment on neurons of mouse corticals given 60 mM ethanol or heat treatment at 42°C. Microarray results showed upregulation of a large number of genes by ethanol and heat shock [64]. Among the pool of genes, there were nine genes which showed greater than 50% stimulation. It

• gene-encoding proteins involved in synaptic plasticity and synaptic formation: glycopro-

• and gene-encoding proteins involved in microtubule assembly, microtubule-associated

A quantitative trait loci (QTL) refers to the trait that varies in degree and can be attributed to the interactions between two or more genes and their environment. Possible QTLs have been identified through microarray studies for alcohol uptake. An analysis is done across inbred mouse strains identified a group of genes for alcohol preference QTL on chromosome 9. These genes include *Arhgef12*, *Carm1*, *Cryab (heat shock protein)*, *Cox5a*, *Dlat*, *Fxyd6*, *Limd1*, *Nicn1*,

• gene-encoding proteins involved in synaptic neurotransmission: *Syt1* and *Spnb2;*

tein m6a (Gpm6a), neurogranin (*Nrgn*) and cadherin 13 (*Cdh13*);

*Nmnat3*, *Pknox2*, *Rbp1*, *Sc5d*, *Scn4b*, *Tcf12*, *Vps11* and *Zfp291* [65].

genes along with entire genome of an organism has been made possible.
