For decades it has been rare to pick up a psychiatry or neuroscience journal and not see several articles on aspects of the dopamine neurotransmitter system. Although the number of neurons using dopamine as a neurotransmitter is modest, its importance in brain function is great. Dopamine neurons with cell bodies in the midbrain, in particular, extend their axons and ramify to many sites in the brain, including the basal ganglia, prefrontal cortex, and, with a lesser density of innervation, the amygdala, hippocampus, insula, and thalamus. Dopamine signaling is thought to set a tone for neural activity in these areas (for example, see West et al. ) and, by so doing, be involved in numerous and diverse brain functions. Of relevance to neurology, dopamine innervation of the basal ganglia participates in the coordination of movement, and the loss of dopamine neurons leads to Parkinson’s disease. Of relevance to psychiatry, dopamine blockade by antipsychotic drugs can produce many of the symptoms of Parkinson’s disease (the so-called extrapyramidal side effects of the drugs). Even more important, through their many connections, dopamine neurons participate in the modulation of expectation, reward, memory, activity, attention, drives, and mood—the very substrates of psychiatric illness.
Evidence for altered dopamine system activity exists for schizophrenia, bipolar disorder, depression, and attention deficit disorder. Also, related to its role in reward, most if not all substances of abuse appear to have important direct or indirect effects on dopaminergic neurotransmission.
Drugs and medications with effects mediated through dopamine have an ancient and remarkable history. Cocaine, one of the earliest known recreational drugs, increases dopamine signaling, which is believed to underlie its euphorigenic effects. The earliest known drug therapy for psychosis, reserpine, mentioned in Vedic texts of India, depletes dopamine. Many current psychiatric medications still target dopamine, prominently including the stimulant drugs and direct dopamine agonists, which enhance dopaminergic signaling, and the antipsychotic drugs, which to varying degrees are antagonists of dopamine, especially at dopamine type 2 (D2)-like receptors. Some of the original studies on the role of dopamine in reward and motivation were based upon experiments in which laboratory animals were treated with dopamine-blocking antipsychotic drugs. This work led to the seminal theory that dopamine antagonists block motivational arousal and reward (2).
The report of Mizrahi and colleagues in this issue of the Journal advances our understanding of the relationship between dopamine receptor blockade by antipsychotic drugs and the dysphoric or anhedonic subjective feelings that often develop during drug treatment. The authors studied patients 2 weeks after they were randomly assigned to low or high doses of olanzapine or risperidone. Overall, higher drug occupancy (blockade) of dopamine receptors in the brain, as measured by PET, was strongly associated with higher ratings of negative subjective states on a self-report scale. In particular, blockade of dopamine receptors in the striatum was strongly correlated with a sense of impaired mental function and blockade of dopamine receptors in the temporal lobe with altered emotional regulation. Lesser blockade in the striatum, insular cortex, and parts of frontal and temporal lobe were associated with greater feelings of well-being. The authors speculate that negative subjective states, consequent to dopamine receptor blockade by antipsychotic drugs, may be responsible for the high rates of drug discontinuation observed in clinical practice and documented in treatment studies (3). While this innovative study was small (12 subjects), it provides important data regarding the associations between the molecular and regional effects of antipsychotic drugs and their therapeutic and side effects. In time, further research will reveal the precise relationships of dose and dopamine blockade by region to components of drug effects, including beneficial effects and the various elements of negative subjective effects, from dysphoria to agitation to impaired cognition. In the meantime it is notable that the Patient Perspectives suggest that many of the patients on low doses of drug showed substantial clinical improvement. Thus, one practical lesson of the study may be to confirm an older literature suggesting that beneficial effects can be achieved at doses that spare side effects (4). High doses rarely lead to greater therapeutic effects, but they almost always lead to greater side effects. Until brain monitoring of dopamine receptor blockade to optimize antipsychotic effects is routinely available, the low-tech solution of using lower doses, allowing time for the drug to work before raising doses, and monitoring side effects is strongly suggested by the results of this and past studies.
Cocaine and related stimulants are known to directly affect dopamine release and reuptake, and with repeated use they lead to compensatory changes in dopamine neurotransmission that alter drive and reward and may underlie the development of addiction and the frequent tendency of those who abuse drugs to relapse. In the report by Martinez and colleagues in this issue, the authors, again using PET, tested whether they could document dysfunction in the dopamine system of the brain in 24 cocaine-dependent subjects compared with 24 healthy volunteers. Using techniques they developed, the authors observed a modest decrease in dopamine receptors but a substantial reduction in dopamine release in response to amphetamine in subjects with a history of cocaine dependence. This reduction was especially notable in parts of the basal ganglia related to the limbic system, which mediates emotion and choice. It is perhaps not surprising that the euphoric effect of amphetamine was blunted in subjects with reductions in dopamine release. In addition, a blunted dopamine response was associated with decisions of subjects to receive cocaine instead of a financial reward with a street value of more than the cocaine offered. A large animal study literature consistently documents marked degrees of change in dopamine systems, including blunting and supersensitivity, with repeated cocaine administration. This is one of the first studies to show changes in human drug users and advances the details of the findings to a level of regional analysis beyond those previously reported. It is interesting that, on the basis of animal models, it has been hypothesized that drug-induced increases (rather than decreases) in dopamine system function are the substrate of sensitized drug “wanting” in addicts (5). The opposite state described in the Martinez et al. report highlights the complexity of dopamine systems and their actions in the brain. Elements of supersensitivity and blunting may coexist, and the evidence presented in this study confirms clinical observations that stimulant users are in an abnormal physiologic state and locked in a cycle of needing to keep taking stimulants to enhance (or normalize) their brain dopamine systems. It is not clear how reversible dopamine abnormalities will be after years of drug use. It is likely that they cannot be reversed by the very drugs that cause them. Rather, resetting the dopamine system will require agents that work to restore responsivity and connections. As with the report by Mizrahi and colleagues, the novel technology developed and reported here may someday play a role in documenting and monitoring the effects of both damaging drugs and restorative treatments.
A shared feature of these new reports is their pointing to a particular role of dopamine, i.e., its role in emotional tone. Without adequate dopamine signaling, our patients do not feel “well.” When dopamine systems are dysfunctional, patients seek a change. This may involve stopping a medication, such as antipsychotic drugs that block dopamine. Alternatively, it may be manifest as taking a drug, such as cocaine, that enhances dopamine activity. Either way patients are probably seeking to restore dopamine function, and it is not surprising that our patients, who often have illness-related or drug-induced dysphoria, are frequent users of dopamine-enhancing drugs.
Despite all of the past research on dopamine, many details are missing on how dopamine acts to produce its effects in the brain. Equally important, as illustrated by this month’s reports, there is much more to be learned about modifying dopamine in the brain to produce desirable—and avoid undesirable—effects.
Most current medications that modify dopamine function, from antipsychotic drugs to stimulants, do so directly, following mechanisms that, as cited, go back to antiquity. As emphasized in both of the new reports, this may be a strategy that has been adequately played out. Although new theories touting the importance of ventral striatal D2 receptors in the antidepressant response (6) may contribute to a renaissance for dopamine-based therapies for depression, it may be more productive to seek ways to modify or restore dopamine systems through alternative or indirect means. One such approach involves drugs that target dynorphin and its receptor, the kappa receptor (7). Dynorphinergic neurons are in a feedback relationship with dopaminergic systems. Dynorphin-containing neurons appear responsive to changes in dopamine, and dynorphin levels appear altered in addiction. Changing dynorphin signaling has been shown to modify dopaminergic neurotransmission, and kappa antagonists have been suggested as having possible antidepressant effects. Conversely, kappa agonists may have antimanic effects.
Many other means to modulate dopamine systems in particular or the functions they subserve will be revealed with continued research. One possibility is that feeling good or feeling bad is not actually dependent upon dopamine per se but rather the intracellular consequences of dopamine receptor stimulation. Various treatments that cause aversive-like states in rats have common effects on dopamine-linked intracellular signaling pathways in the ventral striatum (8). An improved understanding of whether reduced D2 receptor function is necessary–or merely sufficient–to cause dysphoria will have critical implications for the development of improved treatments for mood disorders.
Studies of the genetics of psychiatric and substance abuse disorders are already yielding new targets for drugs to modulate mood, cognition, and attention. Only time will tell if any of these new approaches will lead to success anything like that of studying dopamine and developing agents that directly modify its effects. In the meantime, the more we can learn about the dopaminergic effects of existing agents, the better we will be in serving our patients who expose themselves or whom we expose to dopaminergic drugs.
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7.Carlezon WA Jr, Cohen BM: Potential utility of kappa ligands in the treatment of mood disorders, in Opioid Receptors and Antagonists: From Bench to Clinic. Edited by Dean RL III, Bilsky EJ, Negus SS III. Totowa, NJ, Humana Press (in press)
8.Chartoff EH, Mague SD, Barhight MF, Smith AM, Carlezon WA Jr: Behavioral and molecular effects of dopamine D1 receptor stimulation during naloxone-precipitated morphine withdrawal. J Neuroscience 2006; 26:6450–6457
Address correspondence and reprint requests to Dr. Cohen, Department of Psychiatry, Harvard Medical School, McLean Hospital, 115 Mill St., Belmont, MA 02478.
The authors report no competing interests.