Who are Cocaine’s Primary Victims?

The answer may surprise you.

They are not necessarily the poor, the desperate, or the weak-willed. A National Institute of Drug Abuse (NIDA) study by Dr. Michael Nader and coworkers at Wake Forest University demonstrates that they are likely to be people with innately low levels of dopamine receptor availability. This flaw, possibly genetic, renders them more sensitive to the rewarding effects of cocaine. Put simply: Individuals with less dopamine naturally available in the brain may have an inherited predisposition for cocaine addiction. [Brains Scans at right: Dopamine receptor availability in yellow falls markedly after 6 and 12 months of cocaine self-administration.]

Dopamine D2 receptors, a crucial part of the brain’s primary reward system, are normally occupied by dopamine molecules—although at any given moment, many of the receptors are empty and remain available until a stimulus like cocaine increases dopamine levels and the empty receptors help mop up the excess. Dr. Nader believes that lower D2 receptor availability could be a precursor of addiction to drugs like cocaine. “Perhaps an individual with low availability gets a greater kick from cocaine because the drug-induced dopamine release stimulates a greater percentage of their receptors,” Dr. Nader told staff writer Lori Whitten in a recent edition of NIDA Notes. “Another possibility is that the drug prompts some individuals’ brain cells to release dopamine in particularly high quantities that are sufficient to fill the great majority of vacant D2 receptors, and this augments the high.”

An obvious question hangs over studies of this kind: Are the D2 receptor differences innate, or do they represent changes induced by drug use? To answer this question, Dr. Nader’s team worked with rhesus monkeys in order to take D2 density measurements with PET scans before the animals had ever been exposed to cocaine. Sure enough, the monkeys with the lowest baseline level of D2 receptor availability went on to self-administer cocaine at much higher rates than their D2-normal compatriots. Offering food to the low-dopamine animals did not prove to be a substitute of cocaine, so the effect does not appear to increase all kinds of reward.

There is no doubt that the use of cocaine itself does lead to a rapid reduction of available dopamine receptors, as the brain seeks to achieve a new equilibrium in the face of regular dosings of dopamine-active chemicals. In five monkeys that self-administered cocaine for a year, three of the monkeys showed a strong recovery of receptor availability after only a month of abstinence. However, two of the monkeys showed slower recovery of previous D2 receptor levels. Dr. Cora Lee Wetherington, a neuroscience researcher at NIDA, said that the research thus posed the question of whether people whose dopamine receptor levels recover more slowly during abstinence might prove to be those most likely to relapse.

Medications that increase D2 receptor availability without themselves being highly rewarding represent another promising avenue for treatment. The drugs most likely to help, Dr. Nader thinks, are drugs that act indirectly on dopamine levels through alterations of serotonin and GABA levels in the brain. In addition, researchers are pursuing environmental enrichment experiments in animals and human subjects. Some studies have shown that enriching the environment results in greater D2 receptor levels, Dr. Nader says.

Photo Credit: NIDA

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