Many studies show how alcohol affects the brain and many of the physical aspects of the body. What this article seeks to explain is the body systems that are tied to addiction. There are many different reasons that a person might initially become alcohol dependent. A person might drink because he or she is impulsive, stressed, depressed or seeking some form of pleasure experience. Once a drinking pattern is established, there is a common neurobiology experienced by all people and this article aims to explain some of the neurobiological changes that are involved in addiction.⁵

The Neurotransmitter System
To understand how alcohol use associated with alcohol dependence affects brain function, it is important to understand how neurons communicate with each other through electrical and chemical signals. Nerve signals are transmitted from one region of the brain to another region of the brain or to the rest of the body through communication between two or more neurons located next to each other.^15(p.165) When a neuron is activated, an electrical signal is generated which travels along the membrane surrounding the neuron body and the axon – the long extension protruding from the neuron body. When the signal reaches the end of the axon, it triggers the release of neurotransmitters from the cell. These neurotransmitters travel across the narrow space separating one neuron from another (i.e., the synaptic cleft). On the signal-receiving neuron, the neurotransmitter molecules then interact with receptors, and this interaction either promotes or prevents the generation of new electrical signals in that neuron, depending on the neurotransmitters involved.^15(p.165)

Many neurotransmitters can have both excitatory and inhibitory effects, depending on which brain region is studied and which receptors are present on the signal-receiving neurons. Neurotransmitters that often have excitatory effects include dopamine, glutamate, and serotonin; the neurotransmitter that primarily has inhibitory effects is gamma-aminobutyric acid (GABA).^{15 (p.165)} Alcohol is said to possess acute positive reinforcing effects because of its interactions with individual transmitter systems within the general reward circuitry of the brain. The intracellular events elicited by alcohol can lead to changes in many other neural processes, including those that trigger long-term alcohol effects which eventually lead to tolerance, dependence, withdrawal, sensitization and, ultimately, addiction. The general reward circuitry of the brain centers on connections between the ventral tegmental area and the basal forebrain (which includes the nucleus accumbens, olfactory tubercle, frontal cortex, and amygdala). Because the neurotransmitters help to complete these connections in the brain, they are primary elements in the neurobiological study of addiction.^{8, 10 (p12), 14 (p. 103)}

Inhibitory Neurotransmitters
Inhibitory neurotransmitters are neurotransmitters that reduce the excitability of neurons and prevent the generation of a new nerve signal.

GABA
Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter in the mammalian central nervous system that carries signals between certain nerve cells. It modulates the activity of neurons by binding to GABA-specific receptors (GABAA, GABAB, etc) in their cell membranes and literally inhibiting their ability to respond to signaling. GABA actions are mediated primarily by the GABAA receptor. Neurons that bear GABA receptors are especially abundant in the brain's frontal cortex where a widespread loss of GABA-induced inhibition can cause seizures, and seizure disorders. A more isolated loss of GABA-induced inhibition, however, is thought to be involved in behavioral impulsivity, which is a trait of a number of psychiatric disorders including substance abuse and chronic conduct problems.^{7, 9(p.300), 13 (p.1), 14 (p.104)}

Alcohol and GABA
Alcohol consumption causes motor incoordination and sedation as does high activity of inhibitory neurotransmitters, therefore researchers have suspected that GABA and the GABAA receptor contribute to alcohol's effects on the brain.^9(p.300) In a study done in 1995, researchers Nevo and Hamon discovered that alcohol appears to enhance the inhibitory actions of GABAl. Chronic alcohol consumption leads to a decline in the number of GABA receptors in the brain and thus reduces GABA's ability to bind to its receptors. Thus the body is forced to compensate for the reduction of GABA's inhibitory properties. These effects are a part of the changes in brain function that lead to tolerance and dependence on alcohol. When alcohol is withheld, however, and its stimulating effect on GABA is eliminated, the body suddenly has too few GABA receptors to balance the actions of the excitatory neurotransmitters. As a result, the brain experiences an excess of excitatory nerve signals. This phenomenon known as rebound hyperexcitability may contribute to the physical and psychological manifestations of alcohol withdrawal and addiction.^{15 (p.166)}

Excitatory Neurotransmitters
Neurotransmitters that increase the excitability of neurons and promote the generation of a new nerve signal

Dopamine
Dopamine is a chemical naturally produced in the body. We depend on our brain's ability to release dopamine in order to experience pleasure and to motivate our responses to the natural rewards of everyday life, such as social interaction, the sight or smell of food and the immediate reinforcing properties of all drugs of misuse, including alcohol.^{15 (p.167), 16} Activation of the mesolimbic pathway increases the firing of dopamine neurons in the ventral tegmental area (VTA) of the midbrain and subsequently increases dopamine release into the nucleus accumbens and other areas of the limbic forebrain, such as the prefrontal cortex. Alcohol activates the mesolimbic pathway indirectly, by activating beta-endorphins (naturally occurring opioids) that innervate the ventral tegmental area and the nucleus accumbens, producing a net effect of excitation as information is transmitted to the dopamine receptors in these brain areas.^{14 (p. 104)} It is thought that antagonists of dopamine, GABA, opioid, and serotonin, may decrease the rewarding properties of alcohol and drugs of abuse, resulting in reduced consumption.^{10 (p12-13)} Positron Emission Topography (PET) studies have allowed researchers to directly investigate the role of dopamine and the reward system in alcohol consumption in humans.^{15 (p.166)}

Alcohol and Dopamine
Drugs, such as nicotine, alcohol, opiates and marijuana work indirectly by stimulating neurons that modulate dopamine cell firing through their effects on various dopamine receptors.^8(p.964) Alcohol consumption produces very large and rapid dopamine releases enhancing the excitatory effect of dopamine in the nucleus accumbens (NAc) from ventral tegmental neurons.^{14 (p. 104)} Nerve signals are sent to the cortex, where they are registered as "experience" and memories of the rewarding effects of alcohol, such as its taste or the feelings of relaxation after drinking.^{15 (p.167)} The brain responds to the large dopamine release by reducing normal dopamine activity. Eventually, the disrupted dopamine system renders the alcohol dependent person incapable of feeling any pleasure even from the substance they seek to feed their addiction.¹⁶ Continual dopamine stimulation of the nucleus accumbens region of the brain from repeated substance use also strengthens the motivational properties of the substance, which does not occur for natural reinforcers of dopamine.

Specifically, it seems that the reinforcing effects of substances of dependence are due to their ability to surpass the magnitude (at least five- to tenfold) and duration of the fast dopamine increases that occur in the NAc when triggered by natural reinforcers such as food and sex.⁸ It seems that increases in dopamine are not directly related to actual reward but rather to the prediction of reward, the ability to affect attention and motivation, and the ability to facilitate conditioned learning (i.e. neutral stimuli like an environment associated with drinking can increase dopamine by itself) and behavior.⁸ This conditioned learning and behavior can lead to reward drinking or drinking intended to produce a particular pleasurable outcome by stimulating dopamine activity.^{15 (p.166)}

The HPA Axis – the stress response system
The hypothalamic-pituitary adrenal (HPA) axis is a hormone system that plays a central role in the body's stress response. This axis involves hormones that are produced in the brain's hypothalamus and anterior pituitary gland as well as in the adrenal glands atop the kidneys. This system, which controls a wide variety of metabolic functions, is activated in response to all kinds of stress, both physical and psychological. The major stress hormone of the HPA axis is cortisol. Cortisol is transported through the blood to numerous organs throughout the body, where it induces physiological stress responses (e.g., increases in blood sugar levels and breakdown of proteins and fat molecules). Stress-induced cortisol secretion represents a hormonal mechanism through which stressful experiences stimulate the activity of the mesolimbic dopaminergic system which can provide feelings of relief.

The HPA Axis and Alcohol
A person experiencing stress may be more likely to turn to alcohol to find relief (i.e. relief drinking) and thus may be more sensitive to the relieving effects of alcohol creating a pathway to heavy use and even dependence. Ingestion of small amounts of alcohol can biochemically prepare a person to cope with subsequent stress. However, chronic alcohol administration upregulates excitatory glutamate receptors and downregulates inhibitory GABA receptors, leading to a state of generalized central nervous system excitation. Chronic alcohol use activates the stress response system resulting in abnormalities in neurotransmitters involved in stress and the natural mesolimbic dopaminergic system.^{10 (p14)} Once a stressful event is terminated and the stress-induced activity of the HPA axis and dopamine secretion decline, a person might desire to drink to maintain the activity level of those hormonal and neuronal systems and avoid the return of symptoms of stress.¹² Studies have found that actively drinking alcohol dependents appear to have an abnormal hormonal response to stress, which also may be present in the offspring of alcoholics who are not yet heavy drinkers.^{15 (p.167)} The use of alcohol as a form of self-medication to manage stress is complicated by the fact that alcohol also exerts numerous pharmacological effects besides the stress response. In alcohol-dependent people, alcohol's initial, anxiety-reducing effect is short lived and followed by a period of increased anxiety, the extent and duration of which depends on the amount of alcohol consumed and the duration of alcohol dependence. Thus, alcohol consumption to relieve anxiety and stress (relief drinking) is often unsuccessful, becomes less effective with prolonged drinking, and is associated with a risk of developing alcohol dependence.^{12 (p. 209-210)}

Serotonin
The excitatory neurotransmitter serotonin helps regulate such functions as bodily rhythms, appetite, sexual behavior, and emotional states.^{14 (p.104)} Serotonin subtly modifies the function of neurons by interacting with receptors on the neuron's surface.^{9 (p.300)} It is an important modulator within what is called the behavior inhibition system and it is very likely influenced by genetics, and early stress experiences.⁵

Serotonin and Alcohol
Serotonergic dysfunction has been linked to a number of psychiatric disorders, as well as the development and maintenance of excessive alcohol consumption and alcoholism. Three behaviors or "mechanisms" in particular – disinhibition, anxiety and depression, and a low response to alcohol – may explain the relationship between serotonin and alcohol dependence.⁵ Researchers have found that alcohol-dependent people appear to have lower serotonin levels in their brains than do non-dependent people. Moreover, alcohol exposure affects the function of serotonin receptors, and medications that act on these receptors alter alcohol consumption in humans and animals.^{9 (p.300), 14 (p.104)} Serotonin has also been implicated in the rewarding effects of alcohol and alcohol dependence through an indirect effect on dopamine release as well.^10(p.14)

One goal of research on serotonin and other neurotransmitters in alcoholism is to identify distinct biological subtypes of alcoholism and biological markers for them, which may then help to develop more targeted treatment approaches. For example, if one biological subtype of alcoholism was characterized by defective serotonin transporter function, brain scans for the presence of the serotonin transporter could serve as a tool to obtain a biological marker for this alcoholism subtype. Similarly, repeated scans after the administration of a potential treatment for the serotonin transporter deficiency could help identify the effect of that treatment.^{15 (p.168-9)}

Glutamate
Glutamate exerts its effects by interacting with several types of receptors, including one called the N-methyl-D-aspartate (NMDA) receptor. Alcohol acts on these NMDA receptors, inhibiting their functions and thereby diminishing glutamate-mediated neurotransmission. NMDA receptors may play a role in memory formation. Prenatal, acute, or chronic alcohol exposure may hinder the person's ability to learn and to retain new information.^{15 (p.167)}

The Endogenous Opioid System
Endogenous opioids are small protein molecules (i.e., peptides) formed naturally in the body and chemically related to morphine and heroin. These opioids are produced primarily in the pituitary gland and brain. They apparently act like excitatory neurotransmitters to stimulate neurons. They are involved in various physiological processes, such as pain relief, stress response, euphoria, and the rewarding and reinforcing effects of various drugs, including alcohol. Three distinct families of endogenous opioids exist: endorphins, enkephalins, and dynorphins. The most potent endogenous opioid is beta-endorphin.^{12 (p.203)}

Endogenous Opioids and Alcohol
One-time alcohol ingestion in both humans and experimental animals may stimulate the release of endogenous opioids in both the brain and the rest of the body. Thus, the body may respond to alcohol as if the person had ingested a small quantity of an opioid drug. A special protein called the mu-opioid receptor, which is located in the membranes of nerve cells, detects internal opiate neurotransmitters, such as beta-endorphin, that the brain uses to allow nerve cells to communicate with each other.⁴ The mu-opioid receptor is encoded by a specific gene (named OPRM1). Research findings indicate that the G variant (allele) of this gene binds very strongly to beta-endorphin. This exceptional bond heavily activates the mesolimbic dopamine system cells thus producing greater subjective feelings of intoxication, stimulation, sedation and happiness when alcohol is introduced into the system. The increase in these subjective feelings may lead to increased craving, motivation to use alcohol, and/or maintenance of alcohol dependence. The implication is that the trajectory of alcohol dependence may be different among individuals with the G variant of the OPRM1 gene. If these individuals have a different level of sensitivity, they may also have a differential level of risk for developing alcohol dependence.^{4, 12 (p. 209), 15 (p.169-170)}

Genetics
It is estimated that 40–60% of the vulnerability to addiction is attributable to genetic factors. Genetic differences in the body's hormonal responses to stress and alcohol ingestion exists between people. Those differences likely play an important role in determining a person's sensitivity to alcohol's pleasurable effects, level of craving for alcohol, and extent of vulnerability to excessive drinking and alcohol dependence. In animal studies, several genes have been identified that are involved in responses to drugs and alcohol, and experimental modification of these genes has reduced the self-administration of drugs and alcohol by the animal subjects. In humans, several chromosomal regions have been linked to alcohol dependence. Alleles for the genes that encode enzymes involved in the metabolism of alcohol have been thought to be both protective against as well as associated with alcohol dependence (see the OPRM1 gene research above). Studies show that there is an association between alcohol dependence and the genes for the GABA type A (GABAA) receptors GABRG3 and GABRA2 as well as variants of the CHRM2 gene (involved in decision making and attention) which has also been linked with depression. ^{7, 8­, 10 (p.12-13)}  

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