Dopamine's Role in Addiction

The popular press has recently reported the possible existence of an "addiction gene". This website is devoted to to illuminating the discrepancies among what is reported in mainstream publications about dopamine's role in addiction and may actually be occurring in brain as a reaction to drugs as reported in scientific journals.

The impact of drug, alcohol, and nicotine addiction in the United States is devastating both on human health and in costs. Thus, medical breakthroughs that lead to a better understanding of addiction are important endeavors. Many people face the challenge of quitting an addiction each day.

An 1997 article in Time on addiction reports that dopamine is a neurotransmitter that has long been linked with the euphoric feelings associated with drug abuse and behavioral addictions such as gambling. Although dopamine is not the only chemical involved in this response, scientist contend that it may be an "end point" in the pathway. The scientific community has concluded that there are at least six neurotransmitters including dopamine that are known to play a role in addiction. They report that malfunctions in the dopamine pathway in concert with a social circumstances may lead to increased addiction in certain individuals.

Drugs such as amphetamines, cocaine, nicotine, heroin, and alcohol all affect the amount of dopamine present in the synapses junctions. The challenge of addiction includes the varying stages of dependence and the number of ways different drugs effect the brain. Figure 1. By creating genetically altered mice (knockout mice) lacking dopamine transport proteins, researchers at the Howard Hughes Research Institute at Duke University have mimicked the effects of drug abuse in "clean" mice. These mice are oblivious to the effects of cocaine, alcohol, and heroin. These facts have lead to a belief that differences in peoples' propensity to addiction are caused by "inherited variations" in the genes that support how a nerve cell processes dopamine. There are two types of receptors that cycle dopamine back into the cells that produced it, D2 and D4 receptors. The article claims that genetic differences in these two receptors could lead to decreased or increased sensitivity to dopamine and thus varied levels of addiction.

An article in the April 23, 2001 edition of highlights the effect of two alleles (A1 and A2) of the dopamine receptor (DRD2) on an individual's success in quitting smoking. The A1 allele is associated with greater addiction or more difficulty quitting. It mentions that DRD2 has been implicated as playing role in numerous other addiction such as "obesity, alcoholism, cocaine addiction, and pathological gambling". The researchers interviewed in this article hoped to use new technology to "tailor-make drugs for each genetic profile" rather than to "preorder or predetermine what is going to happen to people."

These articles highlight the effects of dopamine in the addiction cycle, but they simplify the process in light of all the processes involved on a cellular and systemic level that are involved in drug response and addiction.

The dopamine receptor receives the dopamine neurotransmitter and is is involved in increasing potassium channel activity and inhibiting adenylyl cyclase*. It is located on chromosome 11. Click here to view Structure. There are at least five known isoforms of the dopamine receptor.

An review article in Nature highlights some complex signaling pathway information. The Nature article distinguishes the cellular and molecular differences that characterize different stages of addiction: tolerance, sensitization, and dependence. Along with each of these stages the bodies' response to the drug and subsequent response changes. With current technologies in genomics and proteomics, researchers hope to characterize patterns of gene expression associated with each of the stages of addiction.

Researchers at the Paul Scherrer Institute in Villigen, Switzerland used PET scans to characterize which areas of the brain are associated with "reward processing" in people addicted to smoking and nonsmokers. From these scans they concluded that dopaminergic regions varied between the two groups in response to a reward. From this data they concluded that tobacco used influence the difference in reaction between the groups.

The difference in the region of the brain effected by rewards in those who are addicted and those who are not may be a result of dependence or tolerance of the drug for the euphoric feelings caused by dopamine. Chronic exposure to cocaine, as found in James Bibb's lab, increases the expression of the transcription factor DFosB, and subsequently cyclin-dependent kinase 5 (Cdk5). Overexpression of Cdk5 is believed to result in an altered signal from the D1 dopamine receptors.

An lab in France reports to Nature that the D2 receptor has two isoforms with different protein conformation because of alternative splicing. The isoforms have two separate functions. The D2L isosform is believed to function in postsynaptic sites while the D2S isoform functions as a presynaptic autoreceptor. D2L deficient mice are not affected by haloperidol as control mice and exhibit D2S as an inhibitor for D1 receptor mediated functions. Thus, there is an interface between isoforms of dopamine receptors (or at least D1 and D2) that is involved in dopamine response.

Both the D1 and D2 receptors have been implicated in drug sensitization. A lab at the Nation Public Health Institute concluded that conditioning with methylphenidate (psychostimulant) or D1-antagoinist SCH23390 or D2-antagoinist raclopride prevent reward property sensitization.

Once dopamine binds to a dopamine receptor a signal cascade in the cell ensues producing the euphoric feeling. The signal cascade is composed of protein receptors such as G-protein-coupled receptors. This G-protein-coupled receptors are implicated in receptor desensitization. With repeated exposure to drugs that enhance dopamine production it is possible that these G-protein receptors uncouple through receptor internalization.

The amount of dopamine present in synapse space is affected by dopamine intake into the pre and post synaptic space and dopamine degradation. Different molecules are involved in these processes. Hotlzmann found that GBR 12909 is a molecule that counters the normal effects of cocaine and methamphetamines at nerve terminals and thus may provide a treatment against addiction by limiting the drugs effects.

Thus, it is apparent that understanding the role of dopamine and its receptors is important to understanding and treating addiction, but this endeavor is not as clear cut as it first appears.

*NCBI Locus Link: DRD2 -dopamine receptor D2 - locusID 1813

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