Tolerance Can Be Inherited
When the brain perceives drug abuse to be a permanent change in its environment, it prompts both ever-increased tolerance, but also can cause genetic change in response. That genetic change means that tolerance can be inherited.
Addiction researchers have found that alcoholics’ brains contain significantly fewer D2 dopamine receptors than normal drinkers. This suggested that alcohol abuse caused a defensive reaction to dopamine overstimulation: reducing the number of receptors available to dock with dopamine, the Reward System’s primary neurotransmitter. Shrinking the number of receptors makes the system less efficient, blunting drug-induced overstimulation. That’s the explanation for how tolerance develops.
Subsequent experiments supported this hypothesis. Monkeys allowed to self-administer cocaine for a year had a 15-20% decrease in receptors. (Nine months after the monkeys stopped being given cocaine, three returned to normal, while two did not, indicating that for those two the change was permanent.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 were on average 24% lower in the users.2
However, later studies demonstrated that having fewer D2 receptors wasn’t only caused by drug abuse: it was found in rats who hadn’t been given any drugs. So-called “impulsive” rats had significantly fewer dopamine receptors than a less impulsive control group: they inherited it. They were also more likely to self-administer intravenous cocaine than normal rats, if given the chance.3
Subsequently, people were also found to have been born with this D2 difference. In other words, like the impulsive rats, they inherited the condition, indicating that their genetic code programmed fewer numbers of D2 receptors even though they hadn’t abused drugs.
Dr. Ernest P. Noble, a professor at UCLA, says people with this altered D2 genetic makeup experience life less intensely because the neurons in their Reward Systems are innately under-stimulated. They self-medicate to compensate, he says.4 These people 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, Dr. Noble added.5 This is a direct echo of stories often heard at 12-Step meetings by people who used alcohol or drugs addictively right from the beginning of their use. (For more on this subject, click on Are Some People Born Addicts?)
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 In other words, people motivated by normal positive rewards don’t need the boost that drugs provide.
Thus, genetic makeup can have profound impacts on the risk of addiction. Some people, like those with genes that engineer fewer D2 receptors in their Reward Systems, are at higher risk. Those with the opposite genetic makeup,which produces greater numbers of D2 receptors, have lesser risk.
Treatments are currently being studied in animals to reverse D2-receptor deficiency in order to lessen the risk of addiction. For example, researchers delivered the D2 gene directly into the Reward System of rats who were 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 Whether this type of gene therapy might work in humans has yet to be determined.
