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Dopamine and schizophreniaFrom Scholarpedia

Philip Seeman (2007), Scholarpedia, 2(10):3634. revision #37269 [link to/cite this article]

Curator: Dr. Philip Seeman, Psychiatry, University of Toronto, CANADA

Estimates of the prevalence of schizophrenia vary between 0.4% and 1.7%. Schizophrenia is the most common of themany psychotic disorders, which include schizoaffective disorder (~0.3%), major depressive disorder with psychoticfeatures (~0.4%), substance-induced psychotic disorders (~0.4%) and psychotic disorders due to a general medicalcondition (~0.2%).

Although the abnormalities in brain development associated with schizophrenia may begin in utero, childhood-onsetschizophrenia is relatively uncommon. Typically, the symptoms of schizophrenia emerge gradually during theteenage years, with affected individuals meeting the criteria for diagnosis in the late teenage years or early twenties.The protective effect of estrogen may delay its onset in women (M.V. Seeman and Lang, 1990). However, there aresome patients who will have their first episode of illness in the fourth or fifth decade of life. The signs and symptomsof schizophrenia generally include the so-called negative signs such as self-isolation and withdrawal from family andfriends, and the positive symptoms such as apparently bizarre and unexplainable behaviour, and hallucinations anddelusions.

The currently used antipsychotics alleviate most of the symptoms, but approximately 20% of symptoms such asapathy, lack of ambition, memory and interpersonal difficulties, are often resistant to antipsychotics.

Contents1 The dopamine hypothesis of schizophrenia2 The dopamine D2 receptor is the main target for antipsychotics3 The dopamine D2 receptor and schizophrenia4 In vitro measurement of D2 receptors in schizophrenia brain5 High- and Low-affinity states of the D2 receptor; the D1-D2 link6 In vivo measurement of D2 receptors in schizophrenia brain7 Dopamine supersensitivity in psychosis8 Which of the three D2-type dopamine receptors is hyperactive in schizophrenia?9 What aspects of antipsychotic action provide an insight to the psychotic process?10 Animal models of psychosis11 Measurement of D2High dopamine receptors12 Elevation of D2High in dopamine-supersensitive animals13 Biochemical factors controlling the D2High state14 Acknowledgements15 References16 External links17 See Also

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The dopamine hypothesis of schizophrenia

The role of dopamine receptors in schizophrenia is intertwined with the pharmacology of antipsychotics. The firstantipsychotic, chlorpromazine (RP 4560), emerged as a potent antihistamine that enhanced analgesia and causedsurgical patients to be “calm and somnolent, with a relaxed and detached expression”. A 1952 report by Delay et al.showed that within three days chlorpromazine alleviated hallucinations and stopped internal “voices” in eightpsychotically disturbed patients. The rapid onset of antipsychotic action within days is consistent with a brainreceptor target for the antipsychotics (Kapur et al., 2005; Agid et al., 2006).

Soon after the clinical introduction of chlorpromazine and haloperidol for psychosis, the Parkinsonian side-effect(akinesia, tremor, rigidity) of these medications became obvious. Because these side-effects mimicked Parkinson’sdisease, and because Ehringer and Hornykiewicz (1960) found that dopamine was low in the brains of patients whodied with Parkinson’s disease, it was widely speculated that antipsychotics interfered with dopamineneurotransmission.

The earliest outline of the dopamine hypothesis of schizophrenia is from J. Van Rossum (1967; Baumeister andFrancis, 2002) who wrote:

“…When the hypothesis of dopamine blockade by neuroleptic agents [now called antipsychotic drugs]can be further substantiated it may have fargoing consequences for the pathophysiology ofschizophrenia. Overstimulation of dopamine receptors could then be part of the aetiology….”

Early speculation by Carlsson and Lindqvist (1963) was that antipsychotics might block the monoamine receptors fornoradrenaline, dopamine and serotonin, because they found that chlorpromazine and haloperidol increased theproduction of metabolites of adrenaline and dopamine, and they stated that these antipsychotics also blockedserotonin. Such experiments, however, did not identify which receptor was selectively blocked. For example,although Andén et al. (1970) reported that antipsychotics increased the turnover of dopamine and noradrenaline, theycould not show that the antipsychotics were selective in blocking dopamine; that is, chlorpromazine enhanced theturnover of noradrenaline and dopamine equally.

The dopamine D2 receptor is the main target for antipsychotics

In searching for the “antipsychotic receptor”, it was first essential to know the therapeutic aqueous concentration of atypical antipsychotic such as haloperidol in the plasma water or the spinal fluid of haloperidol-treated patients(Seeman, 1980). This was calculated to be ~1-2 nM (Seeman, 1992, 2002). Second, because antagonists havenanomolar dissociation constants for their receptors, it required a specific activity higher than 10 Ci/mmole to labelthe antipsychotic receptor in vitro with [3H]haloperidol (Seeman et al., 1974, 1975).

The correlation between the daily clinical doses ofantipsychotics and the antipsychotic dissociation constants (Kivalues to inhibit the binding of [3H]haloperidol) indicated thatthe “antipsychotic receptor” had finally been successfullyidentified and directly labeled (Seeman et al., 1975). Thisrelation is in 1. Although chlorpromazine and thioridazine donot fit the correlation shown on the left, these fit along thecorrelation on the right (data from Seeman, 1992, 2006)]] ,using [3H]raclopride and human cloned dopamine D2 receptors.

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The name “antipsychotic/dopamine receptor” was re-named thedopamine D2 receptor to distinguish it from the dopamine D1receptor, to which many antipsychotics did not bind, as shownin 2.

Becausedopaminewas the mostpotentendogenouscompound toinhibit thebinding of

[3H]haloperidol, the antipsychotic receptor was a dopamine receptor (Seeman et al., 1975, 1976; Burt et al., 1976).

The dopamine D2 receptor and schizophrenia

The dopamine D2 receptor was cloned in 1988 (Bunzow et al.)(3 While many studies have not found an association betweenschizophrenia and D2 polymorphisms, there are two significantpolymorphisms of D2 (3) associated with schizophrenia,including serine311cysteine which occurs in 3.6% of 5,363control individuals, compared to 7.1% of 3,707 individualswith schizophrenia (Glatt and Jönsson, 2006).

In vitro

Figure 1: Antipsychotic doses correlate with theiraffinities for dopamine D2 receptors. Left: Relation

between clinical daily doses of antipsychotics, includingaripiprazole and bifeprunox, and their dissociationconstants at D2. Cloned D2Long dopamine, using

[3H]raclopride (Seeman, 2001, 2002, 2006). Right: Thetherapeutic free concentrations of the antipsychotics (inplasma water or spinal fluid) are related to the Ki values

at D2.

Figure 2: The daily antipsychotic clinical doses donot correlate with their dissociation constants (Kivalues) at the dopamine D1 receptors (labeled by

[3H]SCH 23390) in homogenized calf braincaudate nucleus. (Seeman, 1987, adapted with

permission).

Figure 3: Dopamine D2 receptor polymorphismsassociated with schizophrenia. D2 has two

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measurement of D2 receptors in schizophrenia brain

The in vitro densities of D2 receptors in post-mortem schizophrenia striata fall into two groups with values of ~13 (4and 5) and ~26 pmol/g (5), with an overall average of about 20 pmol/g, an increase of about 50% compared tocontrol (Seeman, 1987). Many of the tissues came from non-medicated individuals.

High- and Low-affinity states of the D2 receptor; the D1-D2 link

At least half the neurons in the striatum that have D2 receptorsalso have D1 receptors, and these receptors interact. Anexample is in 6, where very low concentrations of dopamine, 1

polymorphisms associated with schizophrenia: serine atposition 311 is replaced by cysteine in more individualswith schizophrenia. Second, the proline at position 319is more often coded by CCC in schizophrenia than byCCT. Although this shows D2short from the rat, the

human amino acid sequence is similar. D2Long has aninsert of 29 amino acids shown by the arrow. Standardsingle letter amino acid code. (© Philip Seeman, 2007.

Published by Elsevier Ltd. All rights reserved.)

Figure 4: In vitro density of dopamine D2 receptors inpost-mortem control human striata (from Seeman et al.,

1987 with permission).

Figure 5: In vitro density of dopamine D2 receptors inpost-mortem schizophrenia striata. Each box indicates a

different striatum from an individual who died withschizophrenia (bottom) or from control individuals

(top). The causes of death in both groups were usuallymyocardial infarct or cancer. Although the absolute

density in the control group was about 13 pmol/g, theschizophrenia tissues fell into two groups (~13 and 26

pmol/g). (from Seeman, 1987, with permission.)

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to 10 nM, inhibited the binding of [3H]raclopride to rat striatalhomogenate to the D2High receptors in the presence of a D1-blocking drug.

Moreover, each of these receptors has a state of high affinity,D2High, and a state of low affinity for dopamine, D2Low, with

D2High being the functional state in the anterior pituitary(George et al., 1985; McDonald et al., 1984) and in nigraldopamine terminals.

The example of the D1-D2 link in 6 suggests that a reductionin the density of D1 receptors or a reduction in the strength ofthe link can lead to an overactive D2 or D2High receptor.

Moreover, as diagrammed in 7 (top right), the high-affinity state of the D2 receptor, D2High, is constantly andquickly interconverting with the low-affinity state, D2Low, the desensitized and non-functional state of D2. The D1

receptor, when stimulated by an agonist, accelerates the shift of D2High into D2Low, consistent with the data in 6.

Any reduction in the D1-D2 link (7middle) would cause more D2High, an overactive D2 and hyperactive behaviouror psychosis (see later).

Figure 6: Very low concentrations of dopamine, 1 to 10nM, inhibit the specific binding of [3H]raclopride to the

population of D2High receptors in rat striatalhomogenate in the presence of a D1-blocking drug

(from Seeman and Tallerico, 2003, with permission).

Figure 7: Top: The high-affinity state of the D2receptor, D2High, is constantly and quickly

interconverting into the desensitized low-affinity state,D2Low (right). The D1 receptor (left), when stimulated

by an agonist, accelerates the shift of D2High intoD2Low. Bottom: Reduction in the link between D1 andD2 would cause more of the D2 receptors to reside in

the active functional state of D2High

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An example of the D1-D2 link in post-mortem human striataltissue is shown in 8. High concentrations of dopamine, 400nM, inhibited the binding of [3H]raclopride to all D2 receptors,including D2High and D2Low, an effect that was reversed by thepresence of the D1-blocking drug SCH23390.

In post-mortem

schizophrenia tissue, however, the D1-blocking drug is not able to reverse the action of such high concentrations ofdopamine (400 nM) (9; Seeman et al., 1989).

In vivo measurement of D2 receptors in schizophrenia brain

In first-episode patients who have never been treated withantipsychotics, the concentration or density of D2 is elevatedby ~10% to 30% in the frontal cortex (Kessler et al., 2006) andstriatum (see Wong et al., 1997; Farde et al., 1990; Talvik etal., 2006; Nordström et al., 1995; Abi-Dargham et al., 2004;Laruelle et al., 2005; Corripio et al., 2006; Perez et al., 2003;Hirvonen et al., 2005), but reduced by 12-30% in the cingulatecortex (Suhara et al., 2002; Buchsbaum et al., 2006), the rightmedial thalamic nucleus (Buchsbaum et al., 2006; Yasuno etal., 2004; Talvik et al., 2003), and the midbrain (Tuppurainenet al., 2003, 2006) (10 (Kessler et al., 2006; Suhara et al., 2002;Buchsbaum et al., 2006; Seeman and Kapur, 2000).

However, never-medicated schizophrenia patients also reveal ageneral decrease in the concentration of dopamine D1 receptors

Figure 8: Example of the D1-D2 link in striatal tissue.High concentrations of dopamine, 400 nM, inhibit the

binding of [3H]raclopride to the entire population of D2receptors, including D2High and D2Low, in post-mortem

Parkinson’s diseased tissue (from 10 to 3 pmol/g), aneffect that is reversed by the presence of the D1-

blocking drug SCH23390 (from Seeman et al., 1989,with permission).Figure 9: Example of a reduced link between D1 and

D2 receptors in post-mortem schizophrenia striataltissue. Although high concentrations of dopamine, 400nM, inhibited the binding of [3H]raclopride to D2High

and D2Low to the striatal tissue, the D1-blocking drugSCH23390 was not able to reverse the action of such

high concentrations of dopamine (400 nM)(fromSeeman et al., 1989, with permission)

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general decrease in the concentration of dopamine D1 receptorsin the frontal cortex (Hirvonen et al., 2006; Karlsson et al.,2002), the cingulate gyrus (Hirvonen et al., 2006), the temporalcortex (Abi-Dargham, 2003), and the striatum (Hirvonen et al.,2006) (10). This reduction in D1 may contribute to anoveractive D2, as in 7.

Dopamine supersensitivity in psychosis

Because antipsychotics, including aripiprazole and bifeprunox.alleviate psychosis by inhibiting D2, it indicates that psychosisis associated with a hyper-dopamine state (1).

Psychotic symptoms in schizophrenia increase or intensifywhen the individual is administered a psychostimulant at dosesthat have little effect on control subjects. As reviewed byLieberman et al. (1987) and by Curran et al. (2004), 74-78% of patients with schizophrenia have new or intensifiedpsychotic symptoms after being given amphetamine or methylphenidate even when patients are taking antipsychotics.This compares to 0-26% in control subjects. The data indicate that dopamine supersensitivity is prevalent in patientswith schizophrenia.

Psychotic symptoms occur not only in schizophrenia but in many brain diseases, and also as a result of the use ofsteroids, amphetamine, cocaine, or phencyclidine.

Which of the three D2-type dopamine receptors is hyperactive in schizophrenia?

After the human D2 receptor was cloned and sequenced, twoadditional D2-like receptors were identified, D3 and D4, asshown in 11 and 12, with

Figure 10: Dopamine receptor alterations in brainregions of non-medicated schizophrenia subjects, as

detected by brain imaging of radioligands. None of thesubjects had ever been treated with antipsychotics(patients of Kessler et al. were off medication). D2

receptors were increased in the frontal cortex, decreasedin the cingulate gyrus, increased by up to 18% in the

striatum, and decreased by 16-29% in the thalamus, thetemporal cortex and the mid-brain (substantia nigra).

D1 receptors were generally decreased. Although[11C]NNC112 revealed an increase in D1, this

radioligand is not selective. The superscripts 18, 11, and123 before each radioligand indicate [18F], [11C], and[123I], respectively. Background image adapted from

Okubo et al., 1999, with permission.

Figure 11: The amino acid sequence of the humandopamine D3 receptor (Sokoloff et al., 1990). A

polymorphism occurs in the ninth amino acid, and aframe shift has been reported. Standard amino acid

code. (© Philip Seeman, 2007. Published by ElsevierLtd. All rights reserved.)

Figure 12: The amino acid sequence of the human

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anatomical localizations shown in 13.

The D3 receptor has been extensively investigated for linkageand association to schizophrenia (Sokoloff et al., 1990), but theresults remain controversial. The only D3-selective drug thathas been tested against schizophrenia is BP897 at 10 mg perday for 4 weeks, a dose that did not attain a significantantipsychotic effect.

Likewise, the D4 receptor, although earlier thought to beelevated in schizophrenia, has not been found to be a maintarget for schizophrenia treatment.

While all the antipsychotic therapeutic concentrations occupyapproximately 70% of the D2 receptors, the D3 and D4receptors are occupied by some antipsychotics but not by all, asshown in 14(Seeman,2002).

Anexampleof D2

dopamine D4 receptor. This receptor has many variantsof the number and amino acid composition of the 16-

amino acid segment shown, of which the most commonis 4 segments in the D4.4 receptor. The D4.7 receptor is

also shown. Standard amino acid code. © PhilipSeeman, 2007. Published by Elsevier Ltd. All rights

reserved.

Figure 13: Localization of dopamine D2-type receptorsin the human brain. Shaded and darkened regions

express relatively higher amounts of D2, D3 and D4receptors. (Adapted from Seeman, 1992, withpermission.) 3: Third ventricle; AC: nucleus

accumbens; AM: amygdala; C: caudate nucleus; Cx:cerebral cortex; G: globus pallidus; H: hypothalamus;Hipp: hippocampus; ICJ: Island of Calleja; L: lateralventricle; O: olfactory tubercle; H: P: putamen; SN:

substantia nigra; VTA: ventral tegmental area

Figure 14: Fraction of D2, D3 and D4 dopaminereceptors that are calculated to be occupied in human

brain at observed clinical concentrations ofantipsychotics in the spinal fluid or the plasma water.While all the antipsychotic therapeutic concentrations

occupy approximately 70% of the D2 receptors, the D3and D4 receptors are occupied by some antipsychotics

but not by all. See text for method of derivingoccupancies. Cloz.: clozapine; CPZ: chlorpromazine;

Flupen.: flupenthixol; Halo.: haloperidol: Molin.:molindone; Olan.: olanzapine; Per.: perphenazine;Raclo: raclopride; Remox.: remoxipride; Sulp.: S-

sulpiride; Thior.: thioridazine. From Seeman, 2002,

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occupancy is given in 15, where the % of D2 receptorsoccupied by risperidone is approximately 70% at the averagetherapeutic daily dose of 2 to 6 mg. The data in 14 and 15 areconsistent with the point of 1 that the main target forantipsychotic action is the D2 receptor.

What aspects of antipsychotic action provide aninsight to the psychotic process?

First, because all antipsychotics have antagonist or partialagonist action on D2, this convergence suggests that thepsychotic process entails an abnormality in the regulation ofD2, either pre- or post-synaptically.

Second, the onset of antipsychotic action occurs within days(Delay et al., 1952; Agid et al., 2006), suggesting a receptor-based action. The continued improvement over weeks andmonths may be depend on the slower processes involved in theextinction of the psychotic memories.

Third,several

antipsychotics, notably clozapine and quetiapine, are termedatypical insofar as they do not elicit Parkinsonism. While there are many hypotheses explaining this lack ofParkinsonism (Seeman, 2002), a unique feature of clozapine and quetiapine is that they rapidly dissociate from D2,including both the cloned D2 in vitro (16 as well as in the patient’s D2 (17). This “fast-off D2” property permitsmore neurotransmission of dopamine, for example, compared to haloperidol.

Because the “fast-off D2” nature of clozapine and quetiapine yields a low D2 occupancy for at least 12 hours or more(17), it indicates that D2 in patients need not be continuously occupied for much of the 24 hour day. This observation

with permission.

Figure 15: Representative data showing that theoccupancy of D2 receptors is approximately 70% at theusual daily dose of 2-6 mg risperidone per day. Data re-

graphed from Kapur et al. Refs in Seeman, 2002

Figure 16: Several atypical antipsychotics, especiallyclozapine and quetiapine, rapidly dissociate from the

human cloned D2 receptor in vitro. This “fast-off D2”property may account for the atypical nature of

clozapine and quetiapine in avoiding the side-effect ofParkinsonism. Adapted from Seeman, 2002, with

permission

Figure 17: Clozapine and quetiapine rapidly dissociatefrom striatal D2 dopamine receptors in patients, in

contrast to traditional antipsychotics such as haloperidolthat remain attached to D2 for several days. Adapted

from Seeman, 2002, with permission.

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suggests that the psychotic process may not be continuous but may be pulsatile or may have a considerable timedelay until psychotic brain regions have time to recruit sufficient neuronal or biochemical activity for psychoticsymptoms.

Antipsychotic drugs themselves can occasionally induce an increase in the high-affinity state of dopamine D2receptors and the associated state of behavioural dopamine supersensitivity. Therefore, withdrawal of an antipsychoticcan unmask the dopamine supersensitivity and precipitate an episode of supersensitivity psychosis (see Chouinard etal., 1978; Chouinard and Jones, 1980; Chouinard, 1991).

It should also be mentioned that Parkinson's diseased patients are supersensitive to dopamine-like drugs as a result oftheir loss of dopamine neurons. Such individuals, therefore, may readily develop a psychosis when taking L-DOPAor related dopamine agonists. Clozapine or quetiapine are best used to alleviate such a psychosis, because these twoantipsychotics occupy D2 receptors for a much shorter time than haloperidol or olanzapine, thus minimizingParkinsonian side-effects. Although most dopamine agonists act on D2, L-DOPA produces endogenous dopaminewhich acts on D1 and D2. D1, therefore, may contribute to a psychotic episode, despite the fact that D1 antagonistshave not been found to have any significant antipsychotic action.

Animal models of psychosis

Many animal models for psychosis and schizophrenia have been proposed. The majority of these models showbehavioural dopamine supersensitivity and an elevation of D2High.

Various brain injuries or treatments related or unrelated to dopamine can result in dopamine supersensitivity, thelatter being an aspect of schizophrenia, as already noted.

Considering the many interconnecting pathways in the brain, it is not surprising that various types of injury to thebrain by drugs, brain lesions, or by gene mutations in specific neurotransmitter pathways can result in majorbiochemical alterations in another completely different pathway.

Measurement of D2High dopamine receptors

An advance in measuring D2High receptors was using[3H]domperidone for this purpose instead of [3H]spiperone or[3H]raclopride. The latter two ligands, for example, do notreadily reveal a clear distinction between D2High and D2Low(18) and 19

Figure 18: Using [3H]spiperone to label D2 receptors inporcine anterior pituitary tissue, dopamine inhibits the

binding of [3H]spiperone at low concentrations of

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[3H]domperidone, however, demonstrates a sharp demarcation between the two states of the D2 receptor (19 right)and provides an accurate measurement of the proportion of D2 receptors in the high-affinity state.

Elevation of D2High in dopamine-supersensitiveanimals

The factors that cause behavioural dopamine supersensitivityare listed in 20, all of which influence the proportion ofD2High.

Of themanyanimalmodelsofpsychosisthat havebeenproposed,themodel of

dopamine (i.e., at D2High) and at high concentrations ofdopamine (i.e., at D2Low). The presence of 200 µM

guanilylimidodiphosphate converts all the D2High

receptors into D2Low receptors. There is only a slightdiscontinuity between the high- and low-affinity

components.Figure 19: Left: Using [3H]raclopride to label D2receptors in mouse homogenized striata, dopamine

inhibits the binding of [3H]raclopride at lowconcentrations of dopamine (at D2High) and at highconcentrations of dopamine (at D2Low), but with an

unclear demarcation between the high- and low-affinitycomponents. Redrawn from data in Gainetdinov et al.,

2003. Right: Using [3H]domperidone to label D2receptors in mouse homogenized striata, dopamine

inhibits the binding of [3H]domperidone in two readilydemarcated phases for D2High and D2Low. Adapted

from Seeman et al., 2005b, with permission.

Figure 20: General types of factors that causebehavioural dopamine supersensitivity and an increasein the proportion of D2 receptors in the D2High state.Although the two states constantly interconvert in a

matter of seconds or minutes, there is a shift toward anincrease in the number of D2High states in response to

psychosis-inducing factors, as listed. Guanylnucleotides (such as GTP or guanilylimidodiphosphate)or anesthesia promote a shift to the low-affinity state.Examples of gene mutations or deletions are RGS9,

COMT, TH, and DβH. From Seeman et al., 2006, withpermission.

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amphetamine sensitization has received much support. Although the amphetamine-sensitized animal is supersensitiveto amphetamine, the density of D2 in the brain striatum is normal. The D2High receptors in the striatum, however,were elevated by 250% (21). Another example, using a different method, is in 22 (Seeman et al., 2002).

Many types of brain lesions have been proposed as models forschizophrenia, including lesions of the neonatal hippocampus(Lipska et al., 1993), cholinergic lesions of the cerebral cortex,the entorhinal cortex (Sumiyoshi et al., 2004, 2005), and themedial pre-frontal cortex.

Figure 21: Although the total density of D2 receptors isnormal in the amphetamine-sensitized rat, the

proportion of D2 receptors in the D2High state ismarkedly increased by 250% in the sensitized rat

striatum. From Seeman et al., 2002, with permission.

Figure 22: Representative experiments illustrating theincrease in D2High in animals made behaviorally

dopamine supersensitive by repeated amphetamineadministration (top) by knockout of the RGS9-2 gene

(in collaboration with J. Schwarz). Bottom Fig. adaptedfrom Seeman et al., 2006, with permission

Figure 23: Increased dopamine D2High receptors inanimal models of psychosis. Elevated D2High receptorsin striata from animals made dopamine supersensitive

by a variety of lesions, drugs, and gene knockouts.Lesions included a cholinergic lesion of the cerebral

cortex (Mattsson) and the hippocampus (Lipska;Sumiyoshi). Dopamine D2High receptors were found in

the striata of gene knockouts for dopamine-β-hydroxylase (Weinshenker), GABA-B1 receptors

(Vacher), trace amine-1 receptors (Wolinsky), RGS9(Rahman), dopamine D4 receptors (Rubinstein),

GPRK6 (Gainetdinov), the Postsynaptic density 95 (J.-M. Beaulieu), α-1b adrenoceptors (Tassin), catechol-O-

methyltransferase (COMT), dopamine and VMATtransporters, tyrosine hydroxylase (Palmiter), and RII-β.

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Dopamine behavioral supersensitivity also occurs after many types of drug treatment and in mice with specific genedeletions. 22(bottom) and 23 summarize the enhanced levels of D2High receptors in the brain striata of such gene-deleted mice with behavioral dopamine supersensitivity.

While dopamine supersensitive knockout mice do not reveal elevation in the density of D2, an elevation occurs inD2High (but not D1 or D1High) in all the brain striata of knockout mice that had previously shown behavioraldopamine supersensitivity.

Deletions of genes that are not related to the dopamine system also yield animal models of behavioral dopaminesupersensitivity and at the same time reveal marked elevations in D2High receptors. These genes are listed in 23.

Knockouts of some genes (adenosine A2A receptors) lead to dopamine subsensitivity, where the D2High receptors arereduced by 75% (23).

An important animal model for schizophrenia is that of birth hypoxia during Caesarian section (Boksa and El-Khodor, 2003) where the adult striata also have elevated D2High receptors (23).

The psychostimulant animal models for human psychosis include phencyclidine (23), amphetamine, cocaine, andtetrahydrocannabinol.

Steroid-induced psychosis has its correlate in rats given high doses of corticosterone; they become dopaminesupersensitive. The striata from such rats show a 210% increase in D2High receptors (23)(Refs in Seeman et al., 2005,2006).

Although long-term haloperidol causes supersensitivity (Chouinard, 1991)THIS REFERENCE IS MISSING IN THEREFERENCES LIST. AUTHOR NEEDS TO ADD and increases the proportion of D2High receptors, this increasedissipates within days after withdrawal (24). SOME DATA ARE NOT IN AGREEMENT WITH THIS:This rapiddissipation is in contrast to the permanent elevation of D2High in the amphetamine-sensitized rat striatum or in thegene knockout mice.

Biochemical factors controlling the D2High state

D2High dopamine receptors were also elevated afterrepeated administration of amphetamine, phencyclidine,corticosterone, reserpine, and quinpirole. Adapted from

Seeman et al., 2006, with permission

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Biochemical factors controlling the D2High state

The rate of interconversion between the high- and low-affinitystates of a G protein-linked receptor may be minutes orseconds. There are many factors that increase the prevalence ofthe high-affinity state and, therefore, the sensitivity of thetissue to the agonist.

RGS9 co-localizes with D2 in the striatum and accelerates thetermination of D2-triggered events. A reduction in RGS9, asoccurs in RGS9 knockout mice, leads to behavioral dopaminesupersensitivity and a marked increase in the proportions ofD2High receptors in the striatum (23).

Thereduced

expression of RGS9-2 in schizophrenia hippocampus (25) is consistent with supersensitivity and increased D2High

levels.

Figure 24: Reversible antipsychotic-induced increase inD2High. In contrast to the long-lasting increase inD2High caused by lesions and gene knockouts, theelevated D2High that occurs after antipsychoticsspontaneously reverses after several days of drug

withdrawal. While the antipsychotic elevates D2High,the antipsychotic at the same time inhibits the receptor

to prevent an overactive D2. This example is forhaloperidol continuously infused subcutaneously by

osmotic pump. Adapted from Samaha et al., 2007, withpermission

Figure 25: Reduced RGS9 in schizophreniahippocampus is consistent with dopamine

supersensitivity. The expression of RGS9-2, normalizedfor the expression of β-glucuronidase, in 29 post-

mortem human schizophrenia hippocampi was lowerthan that in the hippocampi from 29 individuals whodied of non-neurological causes. From Seeman et al.,

2007b, with permission

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Because D2High receptors are consistently elevated in all the animal models of the various human psychoses, andbecause the majority of psychotic episodes respond to D2 blockade, D2High may be a common target for theconvergence of the various psychosis pathways. Consistent with this hypothesis of D2High is the fact that mostpsychoses respond to treatment with D2 antagonists, including phencyclidine psychosis (Giannini et al., 1984; 1984-85). The treatment of phencyclidine psychosis by haloperidol is significant, because haloperidol does not blockNMDA receptors, indicating that the D2 target is critically active in phencyclidine psychosis (Refs in Seeman et al.,2005b, 2006).

Because D2High is the functional state of D2, the elevated D2High receptors and their fluctuations may be related tosome of the clinical signs and symptoms of psychosis. This relation will need to be tested when the selective imagingof D2High in patients becomes possible by radioactive D2High-selective agonists (Willeit et al., 2006).

If there are multiple neural pathways that mediate psychosis by converging onto a similar set of brain D2High targets,it suggests that there can be multiple causes and multiple genes associated with psychosis in general andschizophrenia in particular.

The negative aspects of psychosis, especially cognition, which is impaired in schizophrenia, may arise fromoverexpression of D2 in the striatum (Kellendonk et al., 2006).

Dopamine supersensitivity is likely to be a compensatory mechanism, the brain’s response to many different primaryneural defects. The primary defects probably lead to other secondary effects as well, thus accounting for the widevariation of clinical signs and symptoms, not only in schizophrenia but in psychosis in general.

Acknowledgements

Supported by Constance E. Lieber and Stephen Lieber of the Essel Foundation, NARSAD, the CIHR, the OMHF, theDr. Karolina Jus estate, the Medland family, the O’Rorke family, Mrs. S. Warner, and the Rockert family.

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Internal references

Peter Redgrave (2007) Basal ganglia. Scholarpedia, 2(6):1825.Valentino Braitenberg (2007) Brain. Scholarpedia, 2(11):2918.Jeremy Seamans (2007) Dopamine anatomy. Scholarpedia, 2(6):3737.Wolfram Schultz (2007) Reward. Scholarpedia, 2(3):1652.Wolfram Schultz (2007) Reward signals. Scholarpedia, 2(6):2184.S. Murray Sherman (2006) Thalamus. Scholarpedia, 1(9):1583.Leonid L. Rubchinsky, Alexey S. Kuznetsov, Vicki L. Wheelock MD, Karen A. Sigvardt (2007) Tremor.Scholarpedia, 2(10):1379.

External linksPhilip Seeman's website (http://www.utoronto.ca/seeman/)

See AlsoBasal Ganglia, Dopamine, Dopamine Anatomy, Dopamine Modulation, Reward, Reward Signals

Philip Seeman (2007) Dopamine and schizophrenia. Scholarpedia, 2(10):3634, (go to the first approved version)Created: 21 April 2007, reviewed: 4 October 2007, accepted: 4 October 2007Invited by: Dr. Eugene M. Izhikevich, Editor-in-Chief of Scholarpedia, the free peer reviewed encyclopediaAction editor: Dr. Eugene M. Izhikevich, Editor-in-Chief of Scholarpedia, the free peer reviewed encyclopediaRetrieved from "http://www.scholarpedia.org/article/Dopamine_and_schizophrenia"

Categories: Neuroscience

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