Gene Trait Linked to Increased Risk of Severe Cocaine Abuse

Researchers at Ohio State University’s Department of Pharmacology have found that nearly 1 in 5 whites carry a genetic variant that can significantly increase their risk of severe cocaine abuse. Presence of the gene variant may help explain why some are more susceptible to cocaine addiction, cravings, and relapse.

Prior studies have already identified the type 2 dopamine receptor (D2DR), a key element to the brain’s reward circuitry, to play a significant role in susceptibility to mental disorders and substance addictions, including cocaine addiction. Dopamine is a neurotransmitter involved in normal brain activity; when cocaine is introduced into the body’s system, it blocks dopamine receptors from receiving dopamine that is naturally released by the brain. This excess of dopamine which eventually builds up outside the brain’s cells causes a state of euphoria. Over time, a cocaine user will develop a tolerance to the pleasuring effects of cocaine, and therefore will need to ingest progressively more cocaine in order to achieve the same satisfactory level of dopamine release needed to purge cravings. This need to compensate a satisfactory level with cocaine intake can be described as a brain dysfunction, called reward deficiency syndrome. The loss of D2DRs, caused by conditioned cocaine consumption, creates lower dopamine activity and requires the user to overcompensate cocaine intake just to normalize reward circuitry.

In their latest study, Professor Wolfgang Sadee and his colleagues have further explained how the mechanism behind D2DR is responsible for the relationship between gene function and susceptibility to cocaine dependency. D2DR is a genetic fragment, known as micro-ribonucleic acid (mRNA), and exists in two main forms on the same gene: a long form (D2L) involved in receiving dopamine, and a short form (D2S) involved in transmitting dopamine. Two tiny gene mutations (also known as genetic variants), called single-nucleotide polymorphisms (SNPs), can exist on this fragment. The SNPs, identified as rs2283265 and rs1076560, either alone or in combination, can affect how D2L and D2S regulate dopamine activity. The researches believe that this altered gene function is what ignites cravings among cocaine users in order to help elevate dopamine levels in the brain. In Sadee’s study, those who carry one or both SNPs were associated with a substantial increase in susceptibility to severe cocaine abuse compared to those who do not carry the gene variants.

To understand the role of the D2DR gene variants, the researchers collected brain autopsy tissues of the prefrontal cortex and putamen from people who had died of cocaine overdose (119 abusers) and compared the tissues to that of similarly aged people who had lived drug-free (95 controls). Then the researchers genotyped the D2DR SNPs from both groups. As a result, the presence of either one or both of the gene variants was more frequent among whites. More than 40% of the samples from whites who had abused cocaine contained the gene variants (one out of two or three white abusers), compared to 19% of the samples collected from whites who had lived drug-free (nearly one out of five drug-free whites). For whites, those who carried either one or both of the gene variants were 3.4 times more susceptible to cocaine abuse than whites who do not carry the variants. On the other hand, the gene variant was not as frequent among African Americans. Only one out of eight samples taken from African Americans carried either one or both of the gene variants.

The findings suggest that biological evidence might help clinicians understand why cocaine abuse may start or worsen, and possibly how individuals with these gene variants may respond to treatment for reward deficiency syndromes. However, more research will be needed to determine the gene variants’ influence over these factors. Nonetheless, the study does prove that a strong association exists between genetic variations and susceptibility for severe cocaine abuse.

For future investigation, the researchers will be studying whether these gene variants can affect a person’s response to pharmacological treatments that react with the D2DR gene. SNPs have become the newest focus in genetic studies since other research has found several gene variants to be linked with other psychiatric disorders, including anorexia, autism, food addiction/obesity, nicotine dependency, poor memory, and poor cognitive performance. Understanding these conditions on a genetic scale may help scientists create better approaches to therapy to which patients respond well.

The study is available in a future issue of the journal Neuropsychopharmacology, and is currently available online.

Posted on December 23rd, 2010
Posted in Cocaine

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