*2.2.1. Glutamate*

Heavy or continuous consumption of alcohol can lead to the liver injury. The liver is the chief organ responsible for converting alcohol into nontoxic byproducts and taking them out of the body. Excessive alcohol consumption leads to prolonged liver dysfunction which may also harm the brain, leading to a severe fatal brain disorder known as **hepatic encephalopathy** [5]. Studies have confirmed that at least two toxic substances, **ammonia and manganese,** play an

**Treatment—**Strategies that have been used to treat or prevent the development of hepatic

Alcohol consumption during pregnancy can lead to changes in the physical, learning and behavioral effects in the developing brain and it is known as **fetal alcohol syndrome (FAS)** [8].The brains of these people may have less size (i.e., microencephaly) and also a small amount of brain cells (i.e., neurons) that function accurately resulting in long-lasting prob-

**Treatment:** Researchers are looking forward to treat or prevent brain damage, such as associ-

important role in the progress of hepatic encephalopathy.

**1.** L-ornithine L-aspartate: it lowers the concentration of blood ammonia

**2.** Artificial livers: it clears patients' harmful toxins present in the blood [6]

encephalopathy are as follows:

**Figure 1.** Effect of alcohol on various brain centers.

16 Drug Addiction

**3.** Liver transplantation [7]

*2.1.2. Alcohol and the developing brain*

lems in learning and behavior.

ated with FAS.

Glutamate receptors include metabotropic glutamate receptor (mGlu), *N*-methyl-D-aspartic acid (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Glutamate exhibits its action on binding to these receptors, resulting in the activation of G-proteins which further leads to amplification of phospholipase C, diacylglycerol (IP3DAG) and calcium-dependent protein kinases [11].

During alcohol drinking, there is a release of excessive glutamate leading to neuronal cell death. This occurs through two pathways:


A study has been carried out on 13 abstinent young alcoholics showing a major increase in glutamate to creatine ratio by proton magnetic resonance spectroscopy and magnetic resonance imaging [15]. Furthermore, an alteration in glutamate is linked to altered short memory loss. Immediate administration of alcohol (acute dose) prior to the microdialysis experiment would end up into an increased glutamate release. Earlier studies showed that administration of either 2 or 3 g/kg ethanol to immature rats elicits a decrease or no modification in the release of glutamate into the N-acetyl cysteine (NAC) [16]. Researchers showed that there is a genetic component that probably contributes to the brain injury occurring in "binge drinking" alcoholics [17]. In binge drinking, alcohol models, there are no reports of increased NMDA receptors [18]. In one study, "binge- drinking" individuals with compensated alcoholic cirrhosis, dosing 80 g of ethanol, showed a transient increase in serum nitrates and nitrite resulting in an increase in NO production in certain tissues (liver and brain) [19]. During the period of chronic alcohol toxicity, basal concentration of glutamate seems to be normal in various regions of the brain though blood alcohol levels are high as 2 g/l [20].

During chronic alcohol consumption, NMDA receptor (NMDAR1 and NMDAR2B) levels seem to be increasing in numbers and decreasing in sensitivity [21] in the nucleus [22], the striatum [23] and the hippocampus [20].

## *2.2.2. Gamma-amino-butyric acid*

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

Inhibition of serotonin reuptake was done through fluoxetine. The milnacipran blocks both serotonin and norepinephrine reuptake. Both fluoxetine and milnacipran are found to be effective in reducing alcohol consumption in the rats model [44]. Consumption of alcohol (5%) every third day for 18 days leads to disturbance in serotonin function within the nucleus

Effect of Alcohol on Brain Development http://dx.doi.org/10.5772/intechopen.73693 19

Alcohol consumption in an individual leads to biochemical changes that are correlated with complex signaling pathways such as phosphorylation of proteins, synthesis of nitric oxide

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

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

**Neurotransmitters Effect of alcohol in the brain References** Glutamate Inhibits glutamate receptor function [13, 14] GABA Potentiates GABA receptor function [24] Dopamine Increases dopamine concentration [31] Serotonin Decreases serotonin neurotransmission [39]

**Neurotransmitters Drug found to reduce alcohol consumption References** Glutamate Amitriptyline [46] GABA Benzodiazepines (positive allosteric modulator of GABAA) [27, 28]

Dopamine Aripiprazole (D2 dopamine receptor agonist) [36] Serotonin Fluoxetine and milnacipran [44]

Dansetron (5-HT3 receptor antagonist) [47]

accumbens [45] (**Tables 2** and **3**).

*2.3.1. Generation of free radicals*

the brain which is affected.

*2.3.2. Changes in phosphorylation*

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

Gabapentin (anticonvulsant) Topiramate (anticonvulsant)

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

**2.3. Biochemical chan***g***es associated with alcohol intoxicity**

(NO), NF*κ*Band MAP kinase pathways in certain regions of the brain [48].
