Drug Abuse and Dependency: Etiology of Drug Dependency

Drug Abuse and Dependency: Etiology of Drug Dependency

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Etiology of Drug Dependency

Addiction or dependency may be viewed as a subset of brain and behavior disorders, which include all psychiatric diagnoses (such as schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder). Current recognition of addiction, acceptance of it as a medical disorder by the public, and treatment options for it roughly mirror conditions for schizophrenia, bipolar disorder, and major depressive disorder some 20 years ago.[44] Similarly, as for each of these diseases, major questions concern the etiology of addiction, including the relative roles of genetic and environmental factors, neurochemical and neuroanatomic changes, and the course of the illness.

Although addiction usually (but not always) begins with a conscious decision to use a drug, changes that occur in the brain at some point can turn drug use and then abuse into a chronic, relapsing illness. Some genetically predisposed individuals, however, become "addicted" almost immediately, with very little progression from use to abuse to dependency.[2]/

Neurophysiologic Changes

Some speculate that two events must occur for the addictive process to be initiated.[45] First, there is an activation of the brain's "pleasure pathway." This occurs in the medial forebrain bundle, which runs from the brain stem and midbrain through the hypothalamus to a variety of sites in the forebrain that are concerned with emotion, motivation, reward, and decision making. Dopamine is the transmitter that ascends to the subcortical and cortical structures of the limbic system (in the forebrain). Dopamine's role seems to be to provide steady (tonic) regulation of the activity of the nerve cells in the limbic system. When levels of dopamine rise significantly beyond physiologic levels (as with cocaine or amphetamine exposure), the entire medial forebrain bundle system linking dopamine-containing cell bodies with many regions of the forebrain may begin to function aberrantly.

Second, for the addictive response to be initiated, the neural response to the drug exposure must have a rapid onset and must also rebound below the initial baseline of neural activity before returning to it.[46] For example, in the case of inhaled cocaine, the drug blocks the transport of dopamine back into the nerve terminal, thereby elevating dopamine levels greatly. Dopamine levels rise rapidly to a peak that is typically severalfold greater than that achievable through physiologic stimulation (emotion, exercise) alone. Next, dopamine levels fall rapidly and drop below the normal baseline before returning to stable values. When exposure to cocaine is repeated, the brain adapts to these drug-induced effects. Two adaptations are of particular relevance to addiction: sensitization, an increased nerve cell response to repeated drug exposure;[47] and learning, a reflection of enduring changes in the emotional brain as a direct result of aspects of the drug exposure that resemble other types of conditioned behavior.[48]

There is some confusion about the "matching" of addictive drugs to specific neurotransmitter changes.[49] As noted earlier, cocaine's major direct action is to elevate levels of dopamine. Heroin's major direct action is to activate receptors for endorphins, the natural morphinelike substances. Alcohol can simultaneously enhance g-aminobutyric acid actions, inhibit glutamate actions, and generally reduce the receptor and postreceptor actions of dopamine and serotonin.[50]However, alcohol can also increase the release of dopamine in the nucleus accumbens, one of the major subcortical termination sites of the medial forebrain bundle.

While it is clear that different addictive drugs may not induce exactly the same changes in the brains of dependent individuals, all addictive drugs seem to share a few key features, such as increasing dopamine activity in the limbic system. This means that there may be a "final common pathway" for the addictive process in the medial forebrain bundle system.[20]

Genetic Risk Factors

A family history of drug problems seems to be one of the most powerful risk factors for the development of drug dependency. More specifically, genetic factors are believed to contribute 40% to 60% to the risk for alcoholism.[51,52]Research on the genetics of alcohol dependency or alcoholism suggests that the tendency to become alcoholic is inherited via presumed genetic mutations.[53] The altered gene functions due to mutation result in altered brain proteins (enzymes, receptors, other signaling proteins, transport proteins, structural proteins) and dysfunctional transmitter regulation. Exposure to an addictive substance may "normalize" brain chemistry so that more frequent drug use becomes more likely.

For example, in the case of a person with a mutation in the gene for the enzyme tyrosine hydroxylase (which is crucial for synthesizing dopamine), dopamine may be below optimum levels. Once cocaine is ingested, however, dopamine levels may reach "normal" values for the first time in that person's life because of cocaine's ability to inhibit dopamine transport into the nerve terminal.[54] Yet the changes in the limbic system dopamine levels may be so dramatic and so short-lived that the rebound then leads to a profound behavioral depression (of mood and motor activity). Furthermore, such dramatic increases and decreases in limbic dopamine levels cause equally dramatic alterations in the firing patterns of the nerve cells that receive dopamine inputs.

We can reasonably assume that addicts who become dependent early in life (and with little drug exposure) are the most heavily genetically predisposed to the disease. For example, some studies have shown that the inherited predisposition to alcoholism reflects a complex inheritance.[53] The maternal contribution is divided among several genes, whereas the paternal contribution is more focused on fewer genes. If the child inherits mutant genes from both parents, the likelihood of becoming alcoholic with alcohol exposure increases. Significantly, the greater the maternal "dose" of mutant genes, the greater the risk for the child of becoming alcoholic. Such a person may become dependent after only a few drinks. However, other addicts require months or years of drug use before they experience loss of control over their drug use. During this time, as indicated earlier, a variety of adaptations are produced in the user's brain chemistry, including sensitization and associative (learning) changes.

Expert opinion is mixed