A Cocaine Addiction Gene? Let's Not Get Ahead of Ourselves...

A recent survey has reported that 64% of teens have tried illicit drugs by the age of 18 (1). Some of these kids will develop a profoundly devastating drug addiction while others will not. This phenomenon has lead researchers to ask why. Why are some individuals, who experiment with drugs, more susceptible to drug addiction while others do not? By addressing this question, researchers hope to develop better preventative measures as well as better treatment for drug dependent individuals.

Many researchers have taken a neurobiological approach to this question. Studies have revealed that most recreational drugs travel to the limbic system and enter the orbitofrontal as well as the nucleus accumbens, a brain region that conveys pleasurable and rewarding sensations. Drugs stimulate this reward system by mimicking or stimulating the release of neurotransmitters, primarily dopamine. This stimulation gives rise to euphoria and positively enforced behavior (2). This positive enforcement pathway is what naturally causes one to exhibit repeated behaviors, such as feeding as well as other repeated behaviors that are necessary for survival. Tinkering with this pathway may be quite enjoyable but also dangerous.

Addiction develops when the reward system becomes desensitized to the natural levels of dopamine in the brain. Small dosages of endogenous dopamine (dopamine released naturally during pleasurable experiences) will not stimulate the individual's pleasure circuit. Only copious amount of exogenous dopamine (through the use of drugs) will give satisfaction to the individual. Furthermore, in the absence of drugs, the desensitized dopaminergic brain will cause withdrawal symptoms and unbearable cravings for exogenously-induced stimulation (2).

Such a biological basis of drug addiction suggests that genetic factors may play a role in susceptibility to drug addiction. Twin studies support this claim. The comorbidity of drug addiction among monozygotic twins (twins with the same DNA), who were raised together, was significantly greater than the comorbidity of drug addiction among dizygotic twins (twins with different DNA) who were also raised in the same environment (3). This finding supports a genetic underlying mechanism behind drug addiction and has lead research teams to search for the involved genes. One study conducted by Lohoff et al. sought to determine a genetic factor that predisposes people to cocaine dependence. The study argued that finding genes linked to cocaine addiction susceptibility could give way to the development of an FDA-approved treatment (4).

Lohoff et al. tested to see whether cocaine addiction was influenced by the catechol-O-methyltransferase (COMT) gene. The COMT protein is involved with degradation of catecholamines, a class of neurotransmitters that includes dopamine. Shortly after neurotransmitters are released between the synapse of two neurons, a series of proteins clear the neurotransmitter from the synapse though reuptake or degradation. This phenomenon serves to regulate neural signaling. Problems with these reuptake and degradation proteins may lead to unregulated neurotransmission, and unregulated neurotransmission can cause deleterious effects. Unregulated dopamine signaling may theoretically help desensitize the pleasure pathways and lead to addiction. Hence, the COMT is a plausible genetic candidate for cocaine dependence.

Depending on the individual's DNA sequence, the COMT gene may encode a valine or methionine amino acid at amino acid position 158 on the COMT protein. Although the biological chemistry of COMT is not fully understood, it is suggested that the methionine version of the gene may handicap the proteins ability to degrade catecholamines in comparison to the valine version. Lohoff et al. found that among a cocaine dependent population (n=330), 35% have the methionine version of COMT while among the control population (n=255), only 27% have the methionine version. This difference in the frequency of the methionine version of COMT between the two populations is statistically significant and suggests that this variation in the COMT gene plays a role in susceptibility to cocaine dependence (4).

However, saying that COMT is the cocaine gene is a gross overstatement as COMT only plays a small part in cocaine dependence susceptibility. If COMT was the only factor involved with cocaine dependence, we would expect to see the methionine version of COMT in 100% of the cocaine dependent population and in 0% of the control population.

In addition to revealing an association between COMT and cocaine dependence, the results give insight on the nature of cocaine addiction. Since, there was no 100% COMT-cocaine addiction linkage, there are 2 implications. First, there is more than one gene that plays a role in the complex phenotype of cocaine dependence. Already, studies have revealed many other genes that play a small, contributory role in cocaine addiction. The second implication is that there are more than just genetic factors that play a role in cocaine dependence. Environmental factors must also be taken into account when accessing one's susceptibility to cocaine addiction.

"Virtually all behavior is influenced by genes. Virtually no behavior is determined by genes" (6). In addition to genes, environmental factors also play a large role on behavior. Neighborhood socioeconomic status, access to education, crime rates, and personal networks may all affect one's exposure to drugs and risk to subsequent addiction (7). In poorer neighborhoods where crime rate is high, many juveniles are encompassed in lives where drugs are prevalent. Children of drug dependent individuals are naturally predisposed to drug addiction - not only because they share common genes with their parents but also because of the ‘monkey see, monkey do' phenomenon. Still, environmental factors do not take into account all of non-genetic influences on cocaine addiction susceptibility.

Even when genetic and environmental (including cultural) information is accounted for, there is still a certain lack of predictability for one's behavior. This lack of predictability gives rise to a third factor: the "self". One's own self can choose its own fate in opposition to both genetic and environmental influences (8). Hence, the self is a factor that cannot be ignored in conversations involving mental health. It is hard to describe, characterize, and predict behavior as influence by the self. Many describe this factor as free will, and free will is nearly unpredictable. Still, the self helps give rise to one's character, and one's behavior can be predicted by one's character.

Genetics is the new frontier of medicine. Researchers are linking new genes with old diseases every year. Such links provide both researchers and clinicians greater insight in developing more effective treatment (5). However, when addressing mental health issues, such as cocaine addiction, many additional factors convolute the pure genetic approach.

In developing potential therapies for cocaine addiction, elucidating genetic factors is certainly not useless, for genetics definitely contributes a role. However, solving the genetic question alone will not yield ground for more effective treatment. Only when all factors, including genetics, environmental, and the self are taken into account, new and better treatment will arise.

References:

1) Annonymous. "Two-Thirds of Teens Try Drugs." BBC News: Health. 1998 http://news.bbc.co.uk/1/hi/health/168430.stm

2) Pietras, Nicole. "Drug Addiction: A Brain Disease?" Serendip. 2008 "/exchange/node/1891

3) Kendler KS, Aggen SH, Tambs K, Reichborn-Kjennerud T. "Illicit psychoactive substance use, abuse and dependence in a population-based sample of Norwegian twins." Psychological Medicine. 2006.

4) Lohoff FW, Weller AE, Bloch PJ, Nall AH, Ferraro TN, Kampman KM, Pettinati HM, Oslin DW, Dackis CA, O'Brien CP, Berrettini WH. "Association Between the Catechol-O-Methyltransferase Val158Met Polymorphism and Cocaine Dependence." Neuropsychopharmacology. 2008.

5) Turner, J., Cardon, L.R., Hewitt, J. Behavior Genetic Approaches in Behavioral Medicine. Springer-Verlag. New York, NY 1995

6) Grobstein, P. and Kaney, T., "Genes, Brain, Behavior: A Work in Progress." Serendip. /gen_beh/

7) Patzelt, Julia. "Drug Addiction: What comes first - Brain or Behavior- and Does it Matter?" Serendip.2006. /bb/neuro/neuro06/web1/jpatzelt.html

8) Grobstein, P. "Genes, Environment, and Individual Choice." Serendip. 1994. /gen_beh/Lett-NYT-12-94.html