Dopamine, More D2 Receptors Philip Seeman* and Shitij Kapur†

Commentary

Schizophrenia: More dopamine, more D2 receptors Philip Seeman* and Shitij Kapur†

Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, ON Canada M5S 1A8

chizophrenia is a major therapeutic on both pre- and postsynaptic aspects by significance for previously medicated pa- Schallenge of modern medicine, and using an indirect method to measure the tients, but exhibited only a trend for pa- one of the last frontiers of brain research. levels of endogenous dopamine in patients tients who had never been medicated with The illness is defined by delusions, hallu- and controls. antipsychotic drugs. Despite this lack of cinations, disorganized behavior, and cog- Although numerous postmortem stud- statistical significance in this latter group nitive difficulties such as memory loss. It ies have consistently revealed D2 recep- of patients, the empirical findings of Abi- occurs in Ϸ1% of the world population tors to be elevated in the striata of patients Dargham et al. indicate that an increase in and usually first appears in early adult- with schizophrenia (9), the majority of the dopamine D2 receptors must occur, be- hood. Although antipsychotic medications postmortem tissues examined have come cause it is not possible for patients to show have dramatically improved the lives of from patients who have been treated with a greater increase yet not have a higher patients with schizophrenia, the causes of antipsychotics, raising the probability that number of D2 receptors. Thus, the paper the illness remain unknown. the drugs themselves contributed to the by Abi-Dargham et al. provides support Of the many contemporary theories of elevation of D2 receptors. To measure the for both an increase in the level of dopa- schizophrenia, the most enduring has been density of D2 receptors in never-medi- mine as well as an increase in the number the dopamine hypothesis. As originally put cated patients with schizophrenia, D2- of D2 receptors in schizophrenia, com- by Van Rossum in 1967 (ref. 1, p. 321), selective ligands have been used with in pared to control subjects. ‘‘When the hypothesis of dopamine block- vivo brain imaging methods (10–12). The Schizophrenia, as compared with con- ade by neuroleptic agents can be further results have not been consistent. Data trol subjects, also is associated with an 11 substantiated, it may have fargoing con- with [ C]methylspiperone show elevated increased releasability of dopamine (13, sequences for the pathophysiology of D2 receptors in schizophrenia (ref. 10, but 14). A high release rate of dopamine schizophrenia. Overstimulation of dopamine see also ref. 12), whereas data with 11 reduces the binding of radiobenzamides to receptors could be part of the aetiology . . . [ C]raclopride do not show such eleva- tissues (15, 16), but enhances the binding [emphasis added].’’ Indeed, this speculative tion (ref. 11 and discussed later in this

of radiospiperone (17, 18). Competition COMMENTARY sentence by Van Rossum foreshadows the paper). One major reason for this discrep- with endogenous dopamine, as well as title of the important work by Abi-Dargham ancy is the quantitatively different effects 11 dopamine-induced internalization of the et al. (2) in this issue of PNAS: ‘‘Increased of endogenous dopamine on [ C]methyl- D receptors, may account for the less- baseline occupancy of D receptors by do- spiperone and [11C]raclopride (see refer- 2 2 ened binding of radiobenzamides to the pamine in schizophrenia.’’ ences in ref. 7). tissue (13, 14), because the benzamides The discovery of the antipsychotic͞ Hence, one way to resolve this discrep- are generally water-soluble and have less dopamine receptor (3, 4), now commonly ancy is to measure D receptors after 2 ready access to vesicle-associated recep- known as the dopamine D receptor, led partial depletion of endogenous dopa- 2 tors. Radiospiperone compounds, by con- to repeated confirmation that it is the mine in patients. The work of Abi- trast, are highly lipid-soluble and readily primary site of action for all antipsychotics Dargham et al. (2) provides this resolu- (3–5), including clozapine and quetiapine tion. Fig. 1 summarizes the principle used permeate cell membranes to reach inter- (6). All these drugs have different poten- by Abi-Dargham et al. Fig. 1 (Top) illus- nalized receptors. cies at the receptor. The potency depends trates that the radiobenzamide (S)-(Ϫ)-3- In addition to the two schizophrenia- 123 associated factors of increased D2 recep- on the drug’s dissociation constant at D2, [ I]iodo-2-hydroxy-6-methoxy-N-[(1- which, in turn, relates to the rate of release ethyl-2-pyrrolidinyl)methyl]benzamide tors and increased dopamine release, 123 there is a third factor. Dopamine D2 re- of the drug from the D2 receptor. For ([ I]IBZM) binds to the same number of ceptors exist in monomer, dimer, and oli- example, the dopamine D2 receptor re- D2 receptors in control and schizophrenia leases clozapine and quetiapine more rap- individuals. That is, the ‘‘binding poten- gomeric forms (19). The D2 monomer, but idly than it does any of the other antipsy- tial’’ was the same in both sets of subjects. not the D2 dimer, is selectively labeled by chotic drugs (7, 8). However, after partial depletion of endog- a photolabel of radiospiperone (19). This Given the tight correlation between the enous dopamine by oral ingestion of finding is in contrast to a benzamide pho- ␣ clinical potency and the D2-blocking ac- -methylparatyrosine over 2 days, the tolabel (for nemonapride), which readily tion of the antipsychotic medications, do- binding of [123I]IBZM rose by 19% in binds to both monomers and dimers of D2 pamine overactivity could be the common schizophrenia but only by 9% in control (19). This important distinction between denominator in the psychotic element of subjects (Fig. 1, Bottom). In fact, when benzamides and butyrophenones may ex- schizophrenia. This possibility has been Abi-Dargham et al. examined the number actively investigated. Dopamine overactiv- of D2 receptors after partially removing ity can be presynaptic (an excess of dopa- the obscuring effect of endogenous dopa- See companion article on page 8104. *To whom reprint requests should be addressed at: Depart- mine release from dopamine nerve termi- mine, the D2 receptors were significantly ments of Psychiatry and Pharmacology, Medical Science nals) or postsynaptic (an increase in the elevated in schizophrenia patients as com- Building, Room 4344, University of Toronto, 8 Taddle density of D2 receptors or an increase in pared with control subjects. When the Creek Road, Toronto, ON Canada M5S 1A8. E-mail: postreceptor action). The innovative re- authors examined the data by subgroups, [email protected]. port by Abi-Dargham et al. (2) sheds light the results of increased receptors reached †E-mail: [email protected].

PNAS ͉ July 5, 2000 ͉ vol. 97 ͉ no. 14 ͉ 7673–7675 Downloaded by guest on September 27, 2021 control individual has three D2 receptors, two in the dimer form and one in the monomer form. It is proposed that in schizophrenia, under the influence of increased release of endogenous dopamine, all three exist in the monomer form. Thus, radioraclopride binding would show no difference, but the binding of radiospiperone would be higher in the schizophrenia brain (as compared to controls) because of an increased number of monomers. The dopamine hypothesis has been much criticized. For instance, although therapeutic doses of most antipsychotics occupy 60% to 80% of the D2 receptors in patients, clozapine and quetiapine have been apparent exceptions, exhibit- Fig. 2. Possible model to account for the in- ing clinical efficacy with only 10% to creased number of dopamine D2 receptors in 45% occupation of D2 receptors (see schizophrenia seen with [11C]methylspiperone but references in ref. 7). It therefore has not with [11C]raclopride. It is known that the pho- been suggested that the dopamine hy- tolabel of spiperone ([125I]azidophenethylspiper- pothesis of schizophrenia be extended one) primarily or selectively labels monomers of D2 into a serotonin-dopamine hypothesis. receptors, whereas the benzamide photolabel ([125I]azido-iodo-nemonapride) unselectively la- However, recent work on imaging both bels monomers, dimers, and oligomers of D2 recep- D2 and serotonin-2 receptors in patients tors (see text). These findings suggest that even if taking antipsychotics fails to find evi- there is no increase in the total population of D2 dence for a contribution from the occu- receptors in schizophrenia, an increase in the pro- pation of serotonin receptors (20). For portion of monomers caused by the increased level example, the threshold for clinical anti- of dopamine in schizophrenia (see Fig. 1) would psychotic action remains at 65% occupa- result in an increase in the binding of [11C]methylspiperone (red triangle with S) in schizophrenia but tion of D2 receptors in first-episode pa- 11 tients, whether one uses haloperidol, not with [ C]raclopride (white triangle with R). which has no serotonin-receptor block- Fig. 1. Method and findings of Abi-Dargham et ing action, or risperidone or olanzapine, al. (2) to reveal an increased occupancy of dopa- phrenia precede and outlive the psychosis. which block all serotonin-2 receptors but The hypothesis of dopamine dysregulation mine D2 receptors in schizophrenia. (Top) The num- at doses far below those needed for is the best explanation for the psychotic ber of dopamine D2 receptors, measured by the clinical efficacy. Similarly, the threshold [123I]IBZM binding potential (green triangles with Ϸ episode in schizophrenia; the pathophys- I), were the same in the brain striata of control and for extrapyramidal signs, which is 80% iology of other psychological and cogni- schizophrenia subjects. The levels of synaptic do- D2 occupancy, remains unaltered despite tive abnormalities in schizophrenia pamine (pink triangles with D), which is higher in the presence of 100% block of seroto- remains unclear. A combination of patients compared to control subjects, normally nin-2 receptors for risperidone or susceptibility genes (21) and other factors occupies most of the D2 receptors, masking the olanzapine. It should also be noted that contributes to schizophrenia, and the net difference between control and schizophrenia in- therapeutic doses of clozapine and result dysregulates the dopamine neuro- dividuals. (Bottom) After partial depletion of en- quetiapine transiently occupy high levels dogenous brain dopamine by oral ingestion of transmission system, leading to high re- of D2 receptors in patients, but the effect ␣-methylparatyrosine over 2 days, the binding of lease of dopamine, more D2 receptors, [123I]IBZM rose in both the control and schizophre- lasts for only the first few hours (6). and an apparent predominance of mono- nia subjects, but that for the patients rose signifi- Thus, the D2-occupying properties of mer forms of D2. This dopamine dysregu- cantly higher. clozapine and quetiapine are remarkable lation leads to the psychotic episode. Fur- only for their short duration of action; ther research needs to uncover underlying they otherwise support the dopamine mechanisms that predispose the brain to plain why more D2 receptors are detected hypothesis of schizophrenia, as originally the dysregulation of the dopamine system in schizophrenia (as compared to con- outlined by Van Rossum (1). (22). Until then, the dopamine hypothesis trols) by radiospiperone, even without de- There is more to schizophrenia than remains the main path to the origin and pletion of endogenous dopamine. This psychosis. The psychological abnormali- treatment of clinical signs and symptoms finding is illustrated in Fig. 2, where the ties and cognitive difficulties in schizo- of psychosis in schizophrenia.

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