Nora Volkow, M.D.
Brookhaven National Laboratory
Upton, NY

To understand the biochemical changes that occur in the brains of individuals who are addicted to cocaine, we have taken advantage of nuclear medicine techniques and targeted the dopaminergic system of detoxified cocaine users for PET studies. Involvement of dopaminergic systems in reinforcement is clear, but its role in the addictive processes is much less clear. We must understand the process that occurs between taking the drug because it is pleasurable and the addictive state, during which the drug is taken whether or not it is pleasurable. In other words, we must differentiate the components of the drug that give pleasure from the components involved in compulsive drug-taking.

What is the role of dopamine in addictive behaviors? The dopaminergic system is complex and functions classically (synaptically) and tonically (baseline state), and we must approach it from both perspectives. Our investigations of this system have been made in its basal state and during a pharmacological challenge. We have tried to determine whether there are abnormalities in the dopamine synapse in cocaine addicts. We assessed the integrity of the presynaptic terminal by measuring binding of dopamine uptake inhibitors such as methylphenidate and [11C]-cocaine to the dopamine transporter. Postsynaptically, we labeled the dopamine D2 receptor. (The dopamine D2 receptor resides both presynaptically and postsynaptically; however, because PET technology has relatively poor spatial resolution and the density of postsynaptic sites is greater than that of the presynaptic sites, most of the signal derives from binding of [11C]-raclopride to the postsynaptic sites.) We also measured the rates of glucose utilization in these same subjects to assess metabolic changes that might occur with prolonged cocaine use.

What have we found? Detoxified cocaine abusers bind less [11C]-raclopride to dopamine D2 receptors in the basal ganglia than normal controls because they have fewer dopamine D2 receptors. This deficit appears to be long-lasting; it persists even as long as 4 months after detoxification. We were also concerned that repeated cocaine use might lead to neurotoxicity such as that seen after methamphetamine, thinking that if the density of transporters were reduced, these subjects might be at a higher risk for Parkinson's disease. We found that detoxified cocaine abusers have dramatic decreases in [11C]-cocaine binding compared with controls. However, when only the high-affinity component of binding at the dopamine transporter in the striatum is examined, there are no differences compared with controls. These measures are highly variable in controls. We saw no degeneration of terminals after cocaine treatment, nor was there an increase in striatal dopamine transporters, regardless of length of time since the last cocaine treatment.

What is the functional significance of having a decrement in D2 receptors? We looked to brain glucose metabolism. Detoxified cocaine addicts show markedly less metabolic activity in the frontal cortex and a limited decrease in activity in the basal ganglia. However, these are persistent deficits. We then correlated the regional cerebral glucose metabolism with the availability of dopamine D2 receptors. The strongest correlations were specific and corresponded with the dopamine projections to the orbitofrontal cortex and cingulate gyrus (projections that go to the striatum). Low densities of dopamine D2 receptors were associated with decreased metabolism in the orbitofrontal cortex, whereas metabolism in other regions with dopamine D2 receptors was relatively normal.

Previously, we showed that a massive activation of metabolic activity of these same brain regions was associated with very intense craving for cocaine. Decreased metabolic activity in the orbitofrontal cortex is also associated with obsessive-compulsive disorder (OCD). This correspondence raises many interesting questions: Is the orbitofrontal cortex involved in craving? Does cocaine-taking by addicts represent a compulsive behavior? If the orbitofrontal cortex is destroyed, can behavior no longer be self-controlled? Or will individuals with a dysfunctional orbitofrontal cortex emit repetitive behaviors that cannot be terminated? How does the addict behave under conditions that will elicit drug-taking behavior or craving? Is the orbitofrontal cortex involved in cue-elicited behavior? Does the decreased metabolic activity reflect an inability to release dopamine? And how can changes in dopamine release be measured?

We measured relative changes in dopamine accumulation secondary to the occupation of the dopamine transporters by marking postsynaptic dopamine D2 receptors with [11C]-raclopride and then giving our subjects a dopamine uptake inhibitor (not radiolabeled). We used methylphenidate to inhibit uptake, because we could not give cocaine to normal controls. Inhibiting the uptake of dopamine should increase the amount of dopamine in the synapse, which should compete with the labeled raclopride. Thus, the binding of [11C]-raclopride would be related to the number of free dopamine D2 receptors and [11C]-raclopride occupation of the dopamine D2 receptors premethylphenidate and postmethylphenidate can be compared as a measure of synaptic transmission.

The responses in both the controls and detoxified cocaine users were quite variable. Some of the variability was due to age, not pharmacokinetic differences: The most robust responses were observed in young subjects (dopamine transmission decreases with increasing age). As expected, methylphenidate produced a striking change in [11C]-raclopride binding. Interestingly, the control subjects reported a more intense "high" than did the detoxified cocaine users after methylphenidate. Normal controls self-reported more restlessness. Cocaine abusers (3-6 weeks after last cocaine) reported that the methylphenidate made them crave cocaine, whereas the controls did not report such craving.

We did not expect to see the biochemical changes we obtained. Normal controls showed marked reductions in striatal [11C]-raclopride binding after methylphenidate, but the cocaine abusers did not. In fact, their dopamine D2 binding was much lower than controls. The self-reports of "high" or craving obtained from the detoxified users were very blunted compared with normal controls, suggesting that one of the long-term effects of repeated cocaine use may be a state of relative dopamine dysfunction. Considering that dopamine may impart salience and motivation to an action, the cocaine abuser may be much less responsive to normal stimulation. A downregulation in dopaminergic activity may help explain the anhedonia reported by cocaine users, and they may be taking cocaine to reverse the dysphoria (self-medication). To understand craving and the role of dopamine, it is necessary to understand that the craving likely occurs as the result of the ability of dopamine to facilitate the activation of specific brain regions, like the orbitofrontal cortex, the hippocampus, and the striatum. In addition, it is the pattern of activation that leads to craving, not just one brain region and not just the increase in dopamine. Profound disruptions are found in the dopamine system of cocaine addicts, but the dopamine system is not, by itself, responsible for craving or for addiction.

Acknowledgment

This research was supported by National Institute on Drug Abuse Grant No. DA-06891.

Selected References

Volkow, N.D.; Wang, G.J.; Fischman, M.W.; Foltin, R.W.; Fowler, J.S.; Abumrad, N.N.; Vitkun, S.; Logan, J.; Gatley, S.J.; Pappas, N.; Hitzemann, R.; and Shea, C.E. Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386:827-830, 1997.

Volkow, N.D.; Wang, G.J.; Fowler, J.S.; Gatley, S.J.; Ding, Y.-S.; Logan, J.; Dewey, S.L.; Hitzemann, R.; and Lieberman, J. Relationship between psychostimulant-induced "high" and dopamine transporter occupancy. Proc Natl Acad Sci U S A 93:10388-10392, 1996.

Volkow, N.D.; Wang, G.J.; Fowler, J.S.; Logan, J.; Gatley, S.J.; Hitzemann, R.; Chen, A.D.; Dewey, S.L.; and Pappas, N. Decreased striatal dopaminergic responsiveness in detoxified cocaine-dependent subjects. Nature 386:830-833, 1997.

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