Commentary Schizophrenia : More dopamine , more D 2 receptors

S is a major therapeutic challenge of modern medicine, and one of the last frontiers of brain research. The illness is defined by delusions, hallucinations, disorganized behavior, and cognitive difficulties such as memory loss. It occurs in '1% of the world population and usually first appears in early adulthood. Although antipsychotic medications have dramatically improved the lives of patients with schizophrenia, the causes of the illness remain unknown. Of the many contemporary theories of schizophrenia, the most enduring has been the dopamine hypothesis. As originally put by Van Rossum in 1967 (ref. 1, p. 321), ‘‘When the hypothesis of dopamine blockade by neuroleptic agents can be further substantiated, it may have fargoing consequences for the pathophysiology of schizophrenia. Overstimulation of dopamine receptors could be part of the aetiology . . . [emphasis added].’’ Indeed, this speculative sentence by Van Rossum foreshadows the title of the important work by Abi-Dargham et al. (2) in this issue of PNAS: ‘‘Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.’’ The discovery of the antipsychoticy dopamine receptor (3, 4), now commonly known as the dopamine D2 receptor, led to repeated confirmation that it is the primary site of action for all antipsychotics (3–5), including clozapine and quetiapine (6). All these drugs have different potencies at the receptor. The potency depends on the drug’s dissociation constant at D2, which, in turn, relates to the rate of release of the drug from the D2 receptor. For example, the dopamine D2 receptor releases clozapine and quetiapine more rapidly than it does any of the other antipsychotic drugs (7, 8). Given the tight correlation between the clinical potency and the D2-blocking action of the antipsychotic medications, dopamine overactivity could be the common denominator in the psychotic element of schizophrenia. This possibility has been actively investigated. Dopamine overactivity can be presynaptic (an excess of dopamine release from dopamine nerve terminals) or postsynaptic (an increase in the density of D2 receptors or an increase in postreceptor action). The innovative report by Abi-Dargham et al. (2) sheds light on both preand postsynaptic aspects by using an indirect method to measure the levels of endogenous dopamine in patients and controls. Although numerous postmortem studies have consistently revealed D2 receptors to be elevated in the striata of patients with schizophrenia (9), the majority of the postmortem tissues examined have come from patients who have been treated with antipsychotics, raising the probability that the drugs themselves contributed to the elevation of D2 receptors. To measure the density of D2 receptors in never-medicated patients with schizophrenia, D2selective ligands have been used with in vivo brain imaging methods (10–12). The results have not been consistent. Data with [11C]methylspiperone show elevated D2 receptors in schizophrenia (ref. 10, but see also ref. 12), whereas data with [11C]raclopride do not show such elevation (ref. 11 and discussed later in this paper). One major reason for this discrepancy is the quantitatively different effects of endogenous dopamine on [11C]methylspiperone and [11C]raclopride (see references in ref. 7). Hence, one way to resolve this discrepancy is to measure D2 receptors after partial depletion of endogenous dopamine in patients. The work of AbiDargham et al. (2) provides this resolution. Fig. 1 summarizes the principle used by Abi-Dargham et al. Fig. 1 (Top) illustrates that the radiobenzamide (S)-(2)-3[123I]iodo-2-hydroxy-6-methoxy-N-[(1ethyl-2-pyrrolidinyl)methyl]benzamide ([123I]IBZM) binds to the same number of D2 receptors in control and schizophrenia individuals. That is, the ‘‘binding potential’’ was the same in both sets of subjects. However, after partial depletion of endogenous dopamine by oral ingestion of a-methylparatyrosine over 2 days, the binding of [123I]IBZM rose by 19% in schizophrenia but only by 9% in control subjects (Fig. 1, Bottom). In fact, when Abi-Dargham et al. examined the number of D2 receptors after partially removing the obscuring effect of endogenous dopamine, the D2 receptors were significantly elevated in schizophrenia patients as compared with control subjects. When the authors examined the data by subgroups, the results of increased receptors reached significance for previously medicated patients, but exhibited only a trend for patients who had never been medicated with antipsychotic drugs. Despite this lack of statistical significance in this latter group of patients, the empirical findings of AbiDargham et al. indicate that an increase in dopamine D2 receptors must occur, because it is not possible for patients to show a greater increase yet not have a higher number of D2 receptors. Thus, the paper by Abi-Dargham et al. provides support for both an increase in the level of dopamine as well as an increase in the number of D2 receptors in schizophrenia, compared to control subjects. Schizophrenia, as compared with control subjects, also is associated with an increased releasability of dopamine (13, 14). A high release rate of dopamine reduces the binding of radiobenzamides to tissues (15, 16), but enhances the binding of radiospiperone (17, 18). Competition with endogenous dopamine, as well as dopamine-induced internalization of the D2 receptors, may account for the lessened binding of radiobenzamides to the tissue (13, 14), because the benzamides are generally water-soluble and have less ready access to vesicle-associated receptors. Radiospiperone compounds, by contrast, are highly lipid-soluble and readily permeate cell membranes to reach internalized receptors. In addition to the two schizophreniaassociated factors of increased D2 receptors and increased dopamine release, there is a third factor. Dopamine D2 receptors exist in monomer, dimer, and oligomeric forms (19). The D2 monomer, but not the D2 dimer, is selectively labeled by a photolabel of radiospiperone (19). This finding is in contrast to a benzamide photolabel (for nemonapride), which readily binds to both monomers and dimers of D2 (19). This important distinction between benzamides and butyrophenones may ex-