Dopamine D2DR Gene
One genetic variation suspected to predispose people to addiction involves the gene that engineers the dopamine D2 receptor. Early addiction researchers found that alcoholics’ brains contained significantly fewer D2 receptors than normal drinkers. This suggested that alcohol abuse caused a defensive reaction to drug use: the brain reduces the number of receptors available to dock with dopamine. Shrinking the number of receptors renders the Reward System less efficient, blunting drug-induced overstimulation. This is the classic explanation of tolerance.
Subsequent experiments supported this hypothesis. Monkeys allowed to self-administer cocaine for a year had a 15-20% decrease in D2 receptors. (Nine months after the monkeys stopped being given cocaine, three returned to normal, while two did not).1 Similarly, tests of former methamphetamine addicts and a control group who had not used the drug found that dopamine transporters in a part of the Reward System called the striatum were on average 24% lower in the users.2
However, later studies demonstrated that this D2 mutation wasn’t only caused by drug abuse: it was found in rats who hadn’t been given any drugs. So-called “impulsive” rats were born with significantly fewer dopamine receptors than a less impulsive control group and were also more likely to self-administer intravenous cocaine if given the chance.3
Subsequently, people were also been found to have been born with this D2 mutation. Dr. Ernest P. Noble, a professor at UCLA, says they experience life less intensely because their Reward System neurons are innately under-stimulated. They self-medicate to compensate, he says.4 In a direct echo of the “born-addict“ stories heard at AA meetings, Dr. Noble says they describe their first drug-taking experience as filling a hole they’d always felt. They often reported the first time they felt normal was after their first drink or drug.5
Conversely, a genetic variation which elevates the numbers of D2 receptors provides protection against addiction even for those at high risk from other factors. In one study, the number of D2 receptors was compared between two groups of non-alcoholics: those with a family history of alcoholism and those without. (Researchers couldn’t study active alcoholics because, as noted, alcohol abuse itself causes a decrease in the number of D2 receptors). Members of the first group were considered at high risk of alcoholism but hadn’t succumbed to it and researchers wondered why. They found that this high-risk group had 10% more D2 receptors than their low-risk counterparts, which compensated for their higher risk. Personality tests revealed that “those individuals who had the highest level of dopamine D2 receptors were those who were extroverted and more motivated by positive rewards. This held true for both individuals with and without a family history of alcoholism.”6 People motivated by normal positive rewards don’t need the dopamine boost that drugs provide and are at lower risk of addiction.
Treatments are being studied to treat D2 deficiency. For example, researchers delivered the D2 gene “directly into the brain’s reward center” of rats bred to be heavy drinkers. They gave up drinking, experiencing an “alcoholism-quenching” effect, according to researcher Dr. Peter Thanos at the Brookhaven National Laboratory.7
However, therapy targeted at dopamine’s D2 system is complicated by the way neurotransmitters affect each other, which isn’t yet well understood.