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Targeting the dopamine D2 receptor in schizophrenia-dopamine pathways in schizophrenia pdf

Review
Central & Peripheral Nervous Systems
Targeting the dopamine D2
receptor in schizophrenia
Philip Seeman
1. Introduction University of Toronto, Pharmacology and Psychiatry Departments, Faculty of Medicine,
2. Before the discovery Medical Science Building, Room 4344, 1 King's College Circle, Toronto, M5S 1A8, Canada
of dopamine receptors
After a 12-year search for the antipsychotic receptor, the binding site was
3. Therapeutic concentrations discovered and labelled by [3H]haloperidol in 1975. Of the various neuro-
of antipsychotics transmitters, dopamine was the most potent in inhibiting the binding of
4. Actions of antipsychotic [3H]haloperidol, indicating that the antipsychotic receptor was a dopamine
drugs on neurons receptor, now named the dopamine D2 receptor, a major targeting site in
5. The dopamine D1 receptor schizophrenia. All antipsychotic drugs, including traditional and newer
6. Discovery of the antipsychotic antipsychotics, either bind to D2 in direct relation to their clinical potencies
dopamine D2 receptor or hinder normal dopamine neurotransmission, as in the case of partial
7. Nomenclature of dopamine agonists. In fact, the antipsychotic concentrations found in the
dopamine receptors plasma water of treated patients closely match the predicted therapeutic
8. Therapeutic concentrations absolute concentrations, adjusted for the 60 - 75% D2 occupancy needed
of all antipsychotics occupy for clinical efficacy. Antipsychotics that elicit low or no Parkinsonism or pro-
lactinaemia are loosely attached to D2 and rapidly dissociate from D2,
60 - 75% of D2
whereas those eliciting Parkinsonism stay tightly attached to D2 for many
9. `Fast-off-D2' theory of atypical hours. Because animal models of psychosis (amfetamine sensitisation, brain
antipsychotic action lesions) all show a marked elevation in the number of high-affinity states of
10. Are serotonin receptors a D2, the antipsychotics are thought to specifically target these D2
High states in
clinical target for atypical psychosis in general and schizophrenia in particular.
antipsychotics?
14. Additional evidence for D2 Keywords: antipsychotic, brain imaging, domperidone, dopamine receptor, psychosis,
as the therapeutic target schizophrenia, supersensitivity
for antipsychotics
Expert Opin. Ther. Targets (2006) 10(4):515-531
15. No evidence for D3 as
an antipsychotic target 1. Introduction
16. No evidence for D4 as
an antipsychotic target The discovery of dopamine receptors is closely associated with the discovery of
17. D2
High as the antipsychotic drugs. The research in this field started with the synthesis of antihista-
antipsychotic target mines after World War II, particularly with H Laborit using such compounds to
18. Non-dopamine receptor targets
enhance surgical analgesia. In patients receiving these various antihistamines, Laborit
noticed a `euphoric quietude', and that the patients were `calm and somnolent, with
19. Expert opinion and a relaxed and detached expression.' Of this series of Rh?ne Poulenc compounds,
future outlook RP4560, now known as chlorpromazine, was the most clinically acceptable.
Chlorpromazine was soon tested for various medical illnesses. Although Sig-
wald and Bouttier [1] were the first to use chlorpromazine as the sole drug for a
For reprint orders, psychotic patient, they did not report their findings until 1953, after a 1952
please contact: report by Delay et al. [2] that chlorpromazine alleviated hallucinations and stopped
ben.fisher@informa.com internal `voices' in eight patients. An important feature of the action of chlorpro-
mazine was that it was effective within three days. This relatively fast improve-
ment, especially during the first week of antipsychotic treatment, has been
observed many times, as summarised by Agid et al. [3].
The clinical success of chlorpromazine fostered the search to locate the therapeu-
tic target and mode of action of chlorpromazine. The assumption then, as now, was
that finding such a therapeutic target would open the avenue to uncovering the
biochemical cause of psychosis and possibly schizophrenia.
10.1517/14728222.10.4.515 ? 2006 Informa UK Ltd ISSN 1472-8222 515
Targeting the dopamine D2 receptor in schizophrenia
2. Before the discovery of dopamine receptors 4. Actions of antipsychotic drugs on neurons
In searching for the therapeutic target and mechanism of Indirect evidence for the existence of distinct dopamine
action of chlorpromazine in the 1960s and 1970s, many receptors on neurons and their sensitivity to antipsychotics
types of physiological and biochemical experiments were came from in vitro and in vivo experiments, showing that
carried out. A variety of possible therapeutic targets were dopamine agonists can excite or inhibit neurons in the
explored for the mode of action of chlorpromazine, includ- nigrostriatal dopamine pathway. Moreover, other workers
ing its action on mitochondrial enzymes, sodium-potas- showed that direct application of dopamine on neurons also
sium-ATPase and related enzymes, as well as its stimulated or inhibited snail neurons [8], and that haloperi-
membrane-stabilising action, such as its strong potency to dol or fluphenazine could block these actions [9]. Here too,
inhibit membrane action potentials, and to stabilise however, the antipsychotic concentrations used were far
cellular and subcellular membranes from releasing their higher than those found in the plasma water or spinal fluid
contents [4]. It also became clear in 1963 that all antipsy- in patients; in fact, the concentrations used would be lethal
chotics were surface active, readily explaining their hydro- to humans.
phobic affinity for biomembranes. Some of these Additional work in vivo found that chlorpromazine and
non-receptor findings, such as the potent surface activities haloperidol increased the turnover of adrenaline and dopamine,
of the antipsychotics, showed an astonishingly excellent as shown by the increased production of normetanephrine and
correlation with clinical antipsychotic potencies [5]. methoxytyramine, respectively. To explain the increased pro-
Because high doses of chlorpromazine and other antipsy- duction of these metabolites, it was suggested that `the most
chotics (or `neuroleptics', as they were then called) also elic- likely [mechanism] appears to be that chlorpromazine and
ited Parkinsonism as an unwanted side effect, basic haloperidol block monoaminergic receptors in brain; as is
scientists soon focused on the antipsychotic action on brain well known, they block the effects of accumulated 5-hydrox-
dopamine pathways. The reason for examining the brain ytryptamine' [10]. In other words, these authors proposed that
dopamine pathway was based on the finding by Ehringer antipsychotics might block all three types of receptors for
and Hornykiewicz [6] that the Parkinsonism of Parkinson's noradrenaline, dopamine and serotonin, but they did not iden-
disease was associated with a major loss of brain dopamine. tify which receptor was selectively blocked or how to identify or
It was thought, therefore, that the unwanted side effect of test any of these receptors directly in vitro. This study [10] in
chlorpromazine-induced Parkinsonism, as well as the 1963 by Carlsson and Lindqvist is often mistakenly cited as dis-
antipsychotic action itself, might arise by antipsychotics covering `the dopamine receptor' and that antipsychotics selec-
interfering with dopamine neurotransmission. The work- tively acted on this receptor. However, in 1964 N-E And?n, a
ing hypothesis was that if the brain target or targets for student of A Carlsson, had a different view, and proposed that
antipsychotics could be found, then it was possible that `chlorpromazine and haloperidol delays the elimination of the
these targets could be overactive or underactive in psychosis (metabolites)' [11]. Moreover, seven years later, And?n et al. [12]
or schizophrenia. reported that antipsychotics increased the turnover of
both dopamine and noradrenaline, but they could not show
3. Therapeutic concentrations of that the antipsychotics were selective in blocking dopamine; for
antipsychotics example, chlorpromazine enhanced the turnover of noradrena-
line and dopamine equally. Therefore, it remained for in vitro
However, these early experiments in the 1960s revealed that radio-receptor assays to detect the dopamine receptor
the active concentrations in vitro of the antipsychotics were directly and to demonstrate antipsychotic selectivity for the
generally very high, between 20 nM and 100 nM [4]. Such dopamine receptor.
concentrations, however, were far in excess of the nanomolar
concentrations (e.g., 1 - 2 nM for haloperidol) that exist in 5. The dopamine D1 receptor
the plasma water and in the spinal fluid in patients being
successfully treated with these medications, as determined With the advent of assays for adenylyl cyclase in the 1960s,
by plasma haloperidol measurements where the amount of it was found that dopamine stimulated adenylyl cyclase in
haloperidol bound by the plasma proteins (92%) was taken the superior cervical ganglion [13]. This receptor was later
into account [7]. It should be noted that an antipsychotic named the dopamine D1 receptor, selectively labelled by
drug can exist in either a positively charged form or in a [3H]SCH 23390, and subsequently cloned by three research
neutral uncharged form. The neutral form readily permeates groups in 1990.
cell membranes, and its concentration in the aqueous phase The dissociation constants at D1 for the antipsychotics are
in the plasma is expected to be identical to the aqueous con- given in Table 1. There is no correlation between the antipsy-
centration of the antipsychotic in the spinal fluid in contact chotic clinical doses and the dissociation constants of the
with the neurons. antipsychotic antagonists at D1, as illustrated in Figure 1.
516 Expert Opin. Ther. Targets (2006) 10(4)
Seeman
Figure 1. There is no correlation between the clinical antipsychotic doses and the antipsychotic dissociation constants
(or concentrations) that inhibit the binding of a D1 ligand ([3H]SCH233900) at dopamine D1 receptors in homogenised striatal
tissue. The high concentrations inhibiting the D1 receptor are far higher than those found clinically in the plasma water or
spinal fluid.
Adapted from [14] with permission.
These data suggested that D1 was not the major or common Specific binding of this new [3H]haloperidol to brain striatal
target for antipsychotics. Equally important, moreover, is the tissue was readily detected in 1975 [15]. It was soon found that all
fact that the antipsychotic molarities at D1 are between 10 nM the antipsychotics inhibited the binding of [3H]haloperidol in
and 10,000 nM, far in excess of the therapeutic concentrations direct relation to their clinical potencies [16], as shown in Figure 2.
in the spinal fluid of treated patients. The data in Figure 2, therefore, indicated that the `antipsy-
In addition to the lack of targeting D1 receptors by clinical chotic receptor' had finally been successfully discovered.
doses of the common antipsychotics, D1-selective antagonists Equally important, of the endogenous compounds tested,
have not been found effective as antipsychotics. dopamine was the most potent in inhibiting the binding of
[3H]haloperidol, indicating that the antipsychotic receptor
6. Discovery of the antipsychotic dopamine D2 was actually a dopamine receptor.
receptor
7. Nomenclature of dopamine receptors
In 1974 and 1975, in order to detect and discover the
dopamine receptors on which the antipsychotics presumably The antipsychotic dopamine receptor labelled by
acted, it was essential to label a receptor with a ligand, such as [3H]haloperidol was later termed the D2 receptor [17]. It is
radioactive haloperidol, having an affinity (or dissociation important to note that the data for the binding of
constant) of 1 nM, because, as indicated above, this was the [3H]haloperidol identifying the antipsychotic receptor [15]
haloperidol therapeutic concentration found in the spinal was very different from the pattern of [3H]dopamine binding
fluid or plasma water of treated patients. For this to occur, the described by Burt et al. [18] and Snyder et al. [19]. For exam-
specific activity of [3H]haloperidol would have to be at least ple, the binding of [3H]haloperidol was inhibited by
10 Ci/mmol. Although [3H]haloperidol donated in 1971 by 5000 nM dopamine, whereas that of [3H]dopamine was
Janssen Pharmaceutica only had a low specific activity of inhibited by 3 nM dopamine. For several years, this latter
0.07 Ci/mmole, I.R.E. Belgique custom synthesised [3H]dopamine binding site was termed the `D3site' [20], a
[3H]haloperidol (10.5 Ci/mmole) for Seeman's laboratory term which is not to be confused with the later discovery of
by June 1974. the dopamine D3 receptor [21].
Expert Opin. Ther. Targets (2006) 10(4) 517

Does increased dopamine cause schizophrenia?There is compelling evidence that presynaptic dopamine dysfunction results in increased availability and release of dopamine and this has been shown to be associated with prodromal symptoms of schizophrenia. Furthermore, dopamine synthesis capacity has also been shown to steadily increase with the onset of severe psychotic symptoms. [3]

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