NIDA-funded researchers mapped the dynamic of drug-induced brain activity and emotional responses that occur during a cocaine abuser's typical binge-like pattern of self-administration. Dr. Robert Risinger and colleagues at the Medical College of Wisconsin found that craving corresponds with increased activity in key brain areas underlying reward and motivation, while the cocaine-induced "high" is linked with decreased activity in these same regions. "Our results suggest that, as one takes multiple 'hits' of cocaine, pleasure accumulates with each successive dose, but lasts for a shorter time—a pattern that would compel people to keep abusing," he says.
"My colleagues and I wanted to know what cocaine does to the brain to compel drug-seeking behavior in addicted people—particularly, why taking a small amount of the drug can lead to a binge. Understanding this could help identify interventions to stop such abuse," says Dr. Risinger.
Dr. Risinger's team recruited six cocaine-addicted men who were not seeking treatment. The men, aged 23 to 41, had abused crack cocaine for 11 years, on average. They completed a medical examination, received counseling on the health consequences of cocaine abuse, and were offered (but all declined) addiction treatment before the study.
Each man participated in two 1-hour sessions of cocaine self-administration. At the beginning of the first session, he learned how to press a joystick button to receive infusions of cocaine through an intravenous catheter. After a 5-minute baseline period, he saw a computer-displayed signal that the joystick was activated, and for the next 55 minutes he pressed the button at will. Each press delivered a 20 mg/70 kg of body weight dose of the drug—except that, for safety reasons, doses could not be repeated at intervals of less than 5 minutes, and total doses over the course of the hour were limited to six. Meanwhile, in response to prompts on a computer display, the volunteer used a joystick to rate his cocaine craving, high feelings, and other sensations once per minute. During the second session, the researchers used functional magnetic resonance imaging (fMRI) to obtain brain scans synchronized with the subjective reports. After each session, each man underwent a brief physical examination and left the facility once his vital signs returned to baseline levels and he no longer showed drug effects or reported craving.
Participants administered 4.5 injections a session, on average, spacing the doses about 7.4 minutes apart. Only two administered the maximum six doses. "For many patients, the amount of cocaine consumed during a self-administration session was less than they typically abused," says Dr. Risinger.
As anticipated, the men's feelings of being high decreased before and increased after cocaine administration. From the first through the fourth injection, the intensity of each successive high was greater, and its duration shorter. Craving peaked about 1 minute before each injection and decreased to a low point about 2 minutes after cocaine administration, before rising again during minutes 3 to 4. Absolute levels of craving decreased with each successive injection, but the pre-administration increase in craving rose more sharply.
Dr. Risinger says the participants' reports match other abusers' accounts of their feelings during binges: "People often talk about 'chasing the high.' They abuse the drug several times in an episode, feel increasingly high with the first few hits, and experience a rapid dropoff in the duration of pleasure with repeated use—which may explain consuming larger amounts and more frequently over a session. Consuming cocaine satisfies craving only briefly, and then the feeling increases again before another administration, which may also contribute to the binge pattern."
"It is not clear whether the subjective feeling of craving was directly responsible for driving the participants to self-administer , or whether some other process, perhaps response-outcome learning, was responsible for initiation of self-administration," says Dr. Steven Grant of NIDA's Division of Clinical Neuroscience and Behavioral Research.
Cocaine-induced craving was associated with increased neural activity in brain areas involved in reward anticipation, emotional response, and control over actions: the nucleus accumbens (NAc), the orbitofrontal cortex, and the anterior cingulate cortex. The findings accord well with those of cue-induced craving studies, which generally indicate that the anticipation of a reward is accompanied by activation of the dopamine-rich mesolimbic pathway—a neural circuit involved in reward, motivation, and directing attention to stimuli. Such a neural response is thought to "set up" the brain to experience reward and to drive goal-directed behavior.
The researchers also found that cocaine-induced euphoria depressed activity in the areas activated by craving (see figure above). In prior studies, Dr. Risinger's team has observed NAc suppression in participants who reported experiencing a cocaine-induced high. Although researchers do not yet fully understand the neurobiological mechanisms underlying the high, some have speculated that suppression of NAc firing may be an important component, perhaps reflecting altered receptor sensitivity or weakened stimulation from other brain structures. Another research team found that participants who reported feeling high after receiving a single researcher-controlled dose of cocaine exhibited increased activity in the NAc. The different findings may reflect the teams' divergent experimental methods.
The study represents an important step in correlating drug-induced craving and high with neural activity in specific regions of the human brain. "It provides insight into the neurobiology involved in drugtaking binges, a very common and dangerous behavior associated with the disease of addiction," says Dr. Risinger.
"Dr. Risinger's study is a good example of translational research, which applies a well-established technique in animal research to people. Although the results need replication in a larger number of participants, the findings are provocative because they raise good questions about the relationship between the various neurobiological responses—the fMRI signal and dopamine release, for example. We currently do not have a complete picture of how neurochemical responses and neural activation patterns exactly relate to the entire drug-taking experience, but this issue can be addressed in reverse translational research—animal imaging studies of self-administration and passive cocaine delivery," says Dr. Grant. NIDA-funded investigators are developing such techniques, he adds.
Risinger, R.C., et al. Neural correlates of high and craving during cocaine self-administration using BOLD fMRI. NeuroImage 26(4):1097-1108, 2005. [Abstract]