January 7, 2013
NIDA Director, Dr. Nora D. Volkow

In previous posts I have described some of the very exciting science presented at NIDA’s mini-Convention in conjunction with the Society for Neuroscience meeting in New Orleans in October. There was too much research to mention it all, but I will highlight one additional presentation, by Pier Vincenzo Piazza. Piazza, director of Neurocentre Magendie, a multidisciplinary neurobiology research center that is part of INSERM, France’s equivalent to the NIH, gave an invited address in a special session to promote collaborations in drug abuse and addiction research between our two countries.

Piazza has done very interesting research on individual differences that contribute not only to vulnerability to drug taking and drug effects but also to an “addiction phenotype,” found in only a minority of people and animals exposed to drugs.

Many in the field maintain a “drug-centered perspective” of addiction, believing it to be an iatrogenic phenomenon—a more or less inevitable result of taking an addictive substance enough times. Piazza takes a conflicting view. In his animal research, he has found that only a limited number of rats that self- administer cocaine ultimately fulfill criteria analogous to the DSM-IV criteria for dependence (or addiction) in humans, and then only after long exposure.

Piazza defined his addiction phenotype in rodents using three behavioral measures: persistence in responding when the drug is no longer available (equivalent to difficulty limiting drug intake); break point in a progressive ratio reinforcement schedule, in which an animal is forced to exert greater and greater effort to acquire each subsequent drug reward (equivalent to motivation to obtain the drug); and resistance to punishment (equivalent to drug use despite harmful consequences). These behaviors only begin to emerge in a subset of rats after 30 to 40 days of self-administering cocaine, Piazza found. And only 17.2% of his rats fulfilled all three criteria.

Piazza describes the development of addiction as a two-stage process, beginning with sensitization of the dopamine system, which occurs more readily in animals that demonstrate a high reactivity to stress and show greater anxiety and impulsivity. This “abuse-prone” rat phenotype corresponds to similarly stress-reactive and dopamine-sensitized humans who like and want drugs and thus are prone to taking them repeatedly. They do not necessarily lose control over their drug intake, however. The second stage is crucial: After a few weeks of repeated cocaine exposure, all of Piazza’s animals show an impairment of synaptic plasticity (specifically the cellular process known as long-term depression, which is crucial to learning) in the nucleus accumbens, the brain’s “reward center”; yet in most animals, this plasticity returns to normal even with continued cocaine exposure. In a subset of animals, however, this impairment persists, and it is in this less adaptable “addiction-prone phenotype” that “abuse” turns into addiction proper. Similarly, Piazza suggests, a subset of human drug abusers may have a plasticity vulnerability, making them less able to adapt and thus prone to lose control over their drug use.

I believe it would be premature to completely throw out the iatrogenic theory of addiction in favor of the individual-centered view, but Piazza’s work does raise very interesting questions. Are there other variables that might raise that proportion of vulnerable individuals? For example what would happen if animals were exposed during their adolescence, or were challenged with early adversity or other environmental stressors or exposed to other drugs?

And what about the long length of time before addiction or loss of control manifests? Often in animal studies to understand the biology of addiction, we are not looking at animals that have been trained for as long as those in Piazza’s experiments. If Piazza is correct, could it be that what many addiction researchers are observing in their animals is something more akin to an abuse phenotype than an addiction phenotype? To study addiction, is it necessary to train animals over a duration of months, with the anticipation that only a percentage are ever going to meet strict criteria for addiction?

More research is clearly needed to understand the extent of individual vulnerabilities in drug addiction versus the effect of cumulative exposure, but a greater understanding of vulnerability phenotypes, as well as the “addiction resilient” phenotype that recovers normal plasticity in the nucleus accumbens, could ultimately lead to new therapies for addiction. Seeing such interesting work being done by colleagues in France was very exciting and gratifying.