Cocaine addiction: Phase-specific biology, treatment?

Addiction is characterized by a transition from strategic drug-seeking (i.e., where a decision is made to try a drug to generate a desired effect) to habitual drug-seeking (i.e., where the behavior is triggered by the availability of drugs, particularly in contexts associated with drug use). Habitual drug use is less dependent than strategic use on whether the person actually enjoys the effects of the drug or whether there are negative subjective effects or problems associated with taking the substance. The transition from strategic to habitual drug-seeking is associated with changes in the brain, where dopamine systems are involved in shifting the representation of drug-taking in the striatum region of the brain from the lower (ventral) part of the striatum, implicated in reward, to the higher (dorsolateral) striatum, implicated in habits.

Researchers now have identified the stages of this process that are sensitive to blockade of dopamine receptors, potential therapeutic targets, and the important role that impulsivity plays in this process. They report their results in the current issue of Biological Psychiatry.

They administered a dopamine receptor-blocking drug, α-flupenthixol, directly into the dorsolateral striatum of rats at different phases of addiction. They found that the rats transitioned from insensitivity to sensitivity to the drug's inhibitory effects on cocaine-seeking, but that this transition was also influenced by the inherent impulsivity of the rats.

Early in the addiction process, all rodents were insensitive to the drug's effects, but it did suppress drug-seeking in animals with long-standing cocaine self-administration.

They also found that highly impulsive animals made the transition from drug insensitivity to sensitivity more slowly than animals with low levels of impulsivity.

"The results of this study are important because they show that although both impulsive and non-impulsive rats developed cocaine-seeking habits, this was delayed in high impulsive rats," said first author Dr. Jennifer Murray, from University of Cambridge.

These data suggest that impulsivity does not simply promote compulsivity through the facilitation of habits, but rather that these are interacting independent processes. Murray added, "It is suggested that vulnerability to addiction conferred by impulsivity is less influenced by the propensity to develop drug-seeking habits and more by the inability of an individual to regain control over these habits that are rigidly and maladaptively established in the brain."

"The notion that particular brain mechanisms are engaged only at particular phases of the addiction process strikes me as an important insight that has yet to be harnessed in developing new medications for addiction treatment," said Dr. John Krystal, Editor of Biological Psychiatry. "This study highlights that dopamine receptor blockers might play a role, but only at particular phases of the addiction process."