BRAIN IMAGING
TO DEVELOP TREATMENTS FOR DRUG ABUSE
Addictive disorders pose tremendous costs to the individual and to society, yet effective therapies to treat these conditions are elusive. The dearth of therapeutic approaches stems in part from the longstanding view that drug abuse is a social problem to be addressed by the criminal justice system or by interdiction. Lately, more emphasis has been placed on the rational development of drug abuse treatment based on knowledge of the ways in which drug dependencies can induce neurological pathology. This goal can be accomplished best by assessing the structural and functional integrity of the brain using non-invasive imaging techniques.
Brain imaging has become more advanced since development of the CAT scan, which uses X-irradiation to delineate morphology on the basis of differences in tissue density. Technological advances now allow for the mapping of regional activity in slices across the brain using nuclear medicine tomographic procedures. The use of radiolabelled probes that have specific binding affinity to receptor subtypes within a neurochemical system can provide information about occupancy of those receptors or the biochemical effects following administration of a putative pharmacotherapy. The target medication is labeled with a positron-emitting radionuclide (e.g., 11C, 13N, 18F, 15O) for positron emission tomography (PET) or with 99mTc or 123I for single photon photon-emission computed tomography (SPECT) scanning. Structural and functional studies using magnetic resonance imaging (MRI) can also provide high resolution images of the brain without exposure to ionizing radiation.
In the application of brain imaging techniques to the study of drug abuse, each stage of an “addictive cycle” presents potential targets for investigation and therapeutic intervention. These stages include the immediate effects from the abused drug, including intoxication, as well as the chronic effects, manifested by obvious signs of physical dependence or behavioral alterations. More subtle chronic effects, such as the persistent craving that leads to relapse, must also be considered. In addition, chronic abnormalities in the brains of substance abusers are likely to contribute to cognitive deficits and to the perpetuation of addiction.
Interest in the brain mechanisms that mediate the acute effects of abused drugs has been derived from the view that the rewarding properties of the drugs lead to their compulsive use. In laboratory studies, it has been shown that drugs that are self-administered generally share the property of increasing neurotransmission in the mesolimbic system, in which dopamine is a critical neurotransmitter. Much of this work has involved lesions to selective regions of the brain to determine their importance in self-administration, local injections of drugs into brain, and measurements of neurotransmitter dynamics.
Biochemical assays such as these are valuable in determining the pharmacology of drugs of abuse, but they do not directly assess how an abused drug affects mood or feeling states. PET scanning advances the field in this regard by allowing for a dual assessment of the human response to drugs of abuse both physiologically and psychologically. The [18F]-fluorodeoxyglucose (FDG) method is used with PET to measure rates of cerebral glucose metabolism, which provide an index of local brain function. Determining brain function can be combined in the same session with questionnaires about how a subject is feeling in response to a drug or exposure to specific experimental conditions. First, FDG is injected intravenously and is taken up into the brain over 30 min. Since glucose is the primary fuel of the brain, whatever regions of the brain are most active will use the most glucose or, in the experimental condition, [18F]-fluorodeoxyglucose. A PET scanner is then used to visualize and quantify the radioactive signal, indicating which parts of the brain were activated or deactivated by an experimental variable. Using this method, it was shown that when human subjects who generally used cocaine by the intravenous route were given a dose of intravenous cocaine, they reported euphoria on psychological tests and showed reduced glucose metabolism globally on their PET scans (Fig. 1).1 Reductions of cerebral glucose metabolism, at least in cortical areas, have been reported in human studies when drugs from most abused classes, including stimulants, opiates, alcohol, and benzodiazepines, were administered. It still is not known whether the decrease in cerebral metabolism, induced by cocaine and other drugs of abuse, is part of the mechanism by which the drugs produce euphoria or rather is a response to the drug-induced positive affect. It has been suggested, however, that decreases in cortical glucose metabolism could be secondary to enhanced dopaminergic tone in the mesolimbic system, which is consistent with data demonstrating that drugs of abuse increase dopaminergic neurotransmission.
Recently, a new imaging technique, known as functional magnetic resonance imaging (fMRI), has also been used to map the response of the brain to administration of cocaine.2 One study using fMRI found that cocaine infusions activated the nucleus accumbens, an area of the brain that has high concentrations of dopamine receptors and is associated with pleasurable responses, and decreased activity in the amygdala and the frontal cortex, which participate in emotional memory and other cognitive processes, respectively. An advantage of fMRI is that changes in brain physiology can be assessed much faster than with PET. The ability of fMRI to make rapid measurements allowed researchers to show a direct correlation between the time course of the cocaine-induced “high” and subsequent “crash” to changes in activation of specific brain structures in the mesolimbic system.
Although it is of interest to understand how drugs of abuse produce emotional states that contribute to conditioning and dependence, it is not clear how this knowledge could be translated into successful therapeutic approaches. Simply blocking the ability of the brain to respond to drugs is not an ideal strategy because individuals with addictive disorders would likely be non-compliant in taking medication that would prevent them from feeling “high.” This has been shown to be true in the treatment of opioid dependence, where administration of an opioid antagonist (naltrexone) is a therapeutic success only in highly motivated patients. Even though methadone maintenance is successful against heroin abuse, methadone only acts as an “agonist substitute” for heroin and does not address the underlying abnormalities that may be present in the brains of addicts in the absence of an acute drug reaction. Discovering and identifying specific brain dysfunction in drug abusers may be particularly important for cocaine abuse since there are currently no effective therapies for this condition.
Because craving for drugs often leads to continued drug use, the development of treatments to reduce craving, especially for cocaine, has been the focus of considerable research effort. This work has been substantially hampered, however, by a lack of knowledge of the brain processes associated with the subjective state of craving. Recently, though, a picture of brain activity when a subject is craving cocaine has been provided from PET scans that assay cerebral glucose metabolism.3 In this study, we presented cocaine users with a videotape depicting cocaine use and with cocaine-related items, such as a crack pipe, a mirror and razor blade. The subjects reported higher craving in this condition compared to a control condition when they viewed a videotape showing arts and crafts activities. The enhancement of cocaine craving was associated with increased metabolism in the amygdala, a sub-cortical area of the limbic system that mediates emotional memory, and in a portion of the prefrontal cortex that maintains information for ongoing activities (working memory). Identifying the neural networks that are involved in cocaine craving may determine which brain regions could be targets for pharmacological intervention. Measurement of activity in these brain regions could also provide an objective index of the progress and effectiveness of therapeutic regimes.
Despite the potential benefits of drug abuse treatment at times of active drug seeking, behavioral and cognitive problems typically exist long after drug use has stopped. Brain imaging techniques recently have demonstrated that these persistent abnormalities may be related to changes in brain structure and function in drug abusers. For example, PET was used to show that availability of D2-like dopamine receptors in the basal ganglia is reduced in abstinent cocaine abusers.4 This change probably represents a functional adaptation of the brain to repeated increases in synaptic dopamine levels following cocaine self-administration. In addition, it appears that a part of the brain involved in higher cognitive functions, the frontal cortex, may be especially susceptible to abnormalities following prolonged drug use. This susceptibility was demonstrated recently in our laboratory in an MRI study where the volume of the prefrontal cortex was shown to be smaller in polydrug abusers who have been abstinent for at least two weeks compared to control subjects who were matched for gender, age and demographic factors.5 We also have shown that after varying times of abstinence from drugs of abuse, PET scans from polydrug abusers show a relatively higher rate of glucose metabolism in the orbitofrontal cortex, part of the prefrontal cortex, following adjustment for rates of glucose metabolism in the brain as a whole.6 Since the orbitofrontal cortex is important to the ability to make judgments about the consequences of behaviors, it is not surprising that drug abusers have abnormal functioning of this brain region. Work in our laboratory using a card task, developed to identify behavioral impairments associated with damage to the orbitofrontal cortex, has shown that drug abusers have an impairment in their ability to appreciate long-term consequences over short-terms benefits.7 Although it is difficult to determine whether the brain dysfunctions in drug abusers are the result of drug use per se or reflect pre-existing conditions, knowing which areas of the brain are not functioning normally in drug abusers can drive research efforts to identify novel treatments.
The current state-of-the-art in brain imaging studies offers a variety of techniques to assess brain structure and function with high anatomical, biochemical and temporal resolution. These methods are beginning to provide information that is critical to the development of medications for the addictive disorders. MRI allows volumetric structural assessments of individual brain regions that may show dysfunction in drug abusers, and can be used to assay transient changes in physiology that reveal functional responses to drugs or behavioral perturbations. PET scanning does not provide the same high level of anatomical and temporal resolution as that offered by MRI, but it has higher sensitivity. This means that PET can be used to determine neurochemical deficits in the brains of drug abusers compared to controls by detecting concentration differences of minute amounts of radiotracers at receptor sites. The future of drug abuse research depends on many scientific approaches, but brain imaging will be one of the most important for advancing the field technologically in the 21st century.
References
1. London, E.D., Cascella, N.G., Wong, D.F., Phillips, R.L., Dannals, R.F., Links, J.M., Herning, R., Grayson, R., Jaffe, J.H., and Wagner, H.N., Jr. “Cocaine-induced reduction of glucose utilization in human brain. A study using positron emission tomography and [fluorine 18]-fluorodeoxyglucose.” Archives of General Psychiatry, vol. 47, pgs. 567-574, (1990). 2. Breiter, H.C., Gollub, R.L., Weisskoff, R.M., Kennedy, D.N., Makris, N., Berke, J.D., Goodman, J.M., Kantor, H.L., Gastfriend, D.R., Riorden, J.P., Mathew, R.T., Rosen, B.R., and Hyman, S.E. “Acute effects of cocaine on human brain activity and emotion.” Neuron, vol. 19, pgs. 591-611, (1997). 3. Grant, S., London, E.D., Newlin, D.B., Villemagne, V.L., Liu, X., Contoreggi, C., Phillips, R.L., Kimes, A.S., and Margolin, A. “Activation of memory circuits during cue-elicited cocaine craving.” Proceedings of the National Academy of Sciences U.S.A., vol. 93, pgs. 12040-12045, (1996). 4. Volkow, N.D., Fowler, J.S., Wolf, A.P., Schlyer, D., Shiue, C.Y., Alpert, R., Dewey, S.L., Logan, J., Bendriem, B., Christman, D., Hitzemann, R., and Henn, F. “Effects of chronic cocaine abuse on postsynaptic dopamine receptors.” American Journal of Psychiatry, vol. 147, pgs. 719-724, (1990). 5. Liu, X,, Matochik, J.A., Cadet, J.L., and London, E.D. “Smaller volume of prefrontal lobe in polysubstance abusers: A magnetic resonance imaging study.” Neuropsychopharmacology, vol. 18, pgs 243-252, (1998). 6. Stapleton, J.M., Morgan, M.J., Phillips, R.L., Wong, D.F., Yung, B.C.K., Shaya, E.K., Dannals, R.F., Liu, X., Grayson, R.L., and London, E.D. “Cerebral glucose utilization in polysubstance abuse.” Neuropsychopharmacology, vol. 13, pgs 21-31, (1995). 7. Grant, S., Contoreggi, C., and London, E.D. “Drug abusers show impaired judgment of future consequences in a laboratory test of decision making.” submitted.
Edythe D. London is the Director of the Brain Imaging Center at the Intramural Research Program of the National Institute on Drug Abuse in Baltimore, Md. She may be contacted by e-mail at elondon@tracer.org.