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. 2011 Apr;17(2):118-32.
doi: 10.1111/j.1755-5949.2010.00162.x.

All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2(high) receptors

Philip Seeman  1
Affiliations

All roads to schizophrenia lead to dopamine supersensitivity and elevated dopamine D2(high) receptors

Philip Seeman. CNS Neurosci Ther. 2011 Apr.

Abstract

Background: The dopamine D2 receptor is the common target for antipsychotics, and the antipsychotic clinical doses correlate with their affinities for this receptor. Antipsychotics quickly enter the brain to occupy 60-80% of brain D2 receptors in patients (the agonist aripiprazole occupies up to 90%), with most clinical improvement occurring within a few days. The D2 receptor can exist in a state of high-affinity (D2(High) ) or in a state of low-affinity for dopamine (D2Low).

Aim: The present aim is to review why individuals with schizophrenia are generally supersensitive to dopamine-like drugs such as amphetamine or methyphenidate, and whether the D2(High) state is a common basis for dopamine supersensitivity in the animal models of schizophrenia.

Results: All animal models of schizophrenia reveal elevations in D2(High) receptors. These models include brain lesions, sensitization by drugs (amphetamine, phencyclidine, cocaine, corticosterone), birth injury, social isolation, and gene deletions in pathways for NMDA, dopamine, GABA, acetylcholine, and norepinephrine.

Conclusions: These multiple abnormal pathways converge to a final common pathway of dopamine supersensitivity and elevated D2(High) receptors, presumably responsible for psychotic symptoms. Although antipsychotics alleviate psychosis and reverse the elevation of D2(High) receptors, long-term antipsychotics can further enhance dopamine supersensitivity in patients. Therefore, switching from a traditional antipsychotic to an agonist antipsychotic (aripiprazole) can result in psychotic signs and symptoms. Clozapine and quetiapine do not elicit parkinsonism or tardive dyskinesia because they are released from D2 within 12 to 24 h. Traditional antipsychotics remain attached to D2 receptors for days, preventing relapse, but allowing accumulation that can lead to tardive dyskinesia. Future goals include imaging D2(High) receptors and desensitizing them in early-stage psychosis.

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Conflict of interest statement

The author is also affiliated with Clera, Inc., a pharmaceutical company, but has no other competing interests.

Figures

Figure 1
Figure 1
The clinical doses of antipsychotic medications are related to their affinities for the dopamine D2 receptor. The antipsychotic dissociation constants at D2, obtained using [3H]raclopride, are shown on the ordinate. The glutamate agonist LY404,039 [33] has an affinity for the dopamine D2High receptor with a dissociation constant of 10 nM at D2High (using [3H]domperidone, because [3H]raclopride does not readily reveal D2High receptors)[34]. This value of 10 nM predicts a clinical dose of approximately 60–100 mg/day, in general agreement with the dose of 80 mg/day used by Patil et al. [33]. Because of the very high binding (exceeding 98%) of chlorpromazine and thioridazine to plasma proteins [21], these antipsychotics require high daily doses. However, the final concentrations of all the antipsychotics (including chlorpromazine and thioridazine) in the plasma water in treated patients are almost identical to their dissociation constants [21, 23](Adapted from [23]; with permission from Scholarpedia; Reproduced from [31], with permission of Walsh Medical Media LLC.)
Figure 2
Figure 2
Top: The glutamate agonist LY404,039 inhibited the binding of 2 nM [3H]domperidone on dopamine D2Long receptors (in CHO cells). The inhibition occurred in two concentration phases of LY404,039, with 15.5% inhibition for the high‐affinity phase. 120 mM NaCl present. Data points are mean values (with SE; n = 3). The inhibition of 15.5% occurred at D2High receptors, all of which were converted to low‐affinity D2Low receptors in the presence of GN (200 μM guanylylimidodiphosphate). The dissociation constant, Ki High of LY404,039 was 8.2 ± 1 nM. Nonspecific binding was defined in the presence of 10 μM S‐sulpiride. Bottom: LY404,039 stimulated the incorporation of [35S]GTP‐γ‐S into dopamine D2Long receptors with 50% incorporation occurring at 80 ± 15 nM. The maximum amount of stimulation was 43% of that caused by 10 μM dopamine. The stimulation was blocked by 10 μM S‐sulpiride. Data points are means ± SE (n = 3). (Reproduced from [34], with permission of Wiley‐Liss, Inc.).
Figure 3
Figure 3
Left: Representative experiment on a control mouse striatal homogenate (average of duplicate measurements) showing competition between dopamine and [3H]domperidone for dopamine D2 receptors. The proportion of high‐affinity D2 receptors, D2High, was 14% in this tissue, with the average being 16.2 ± 2.5% in all the control tissues. The final concentration of [3H]domperidone was 2 nM. Nonspecific binding was defined by the presence of 1 μM S‐sulpiride. Right: Representative experiment showing competition between dopamine and [3H]domperidone for dopamine D2 receptors in a striatal homogenate from an mGlu2 receptor knockout mouse. The proportion of high‐affinity D2 receptors, D2High, was 53% in this tissue. The final concentration of [3H]domperidone was 2 nM. (Reproduced from [39] with permission of Wiley‐Liss, Inc.)
Figure 4
Figure 4
Animals that are supersensitive to dopamine‐like drugs (e.g., apomorphine, cocaine, methylphenidate, amphetamine) reveal elevated proportions of dopamine D2 receptors that are in the high‐affinity state for dopamine, D2High (left). The data summarized here were obtained on striata from animals found to be dopamine supersensitive under the following conditions (listed from the upper left top down; unless otherwise specified, details are found in [36, 38]: Mature rats with neonatal lesion of the hippocampus [46]. Rats sensitized by long‐term treatment with amphetamine. Rats socially isolated after weaning [40]. Knockouts of GABA B1(–/–) receptors in mice (B. Bettler and P. Seeman, unpublished). Knockouts of metabotropic glutamate mGlu3 receptors in mice [39]. Knockouts of metabotropic glutamate mGlu2 receptors in mice [39]. Five days of 10 mg/kg corticosterone treatment to rats. Knockouts of the DBH (dopamine‐beta hydroxylase) gene in mice. Long‐term ethanol treatment of rats [47]. Rats sensitized to phencyclidine. Rats treated for 14 days with cannabinoid HU210 at 20 μg/kg (Moreno et al., 2005; F.J. Bermudez Silva, F. Rodriguez de Fonseca, J. Suarez, and P. Seeman, unpublished). Knockouts of trace amine‐1 receptors in mice [48]. Rats sensitized by long‐term treatment with methamphetamine [49]. Rats sensitized and addicted by long‐term self‐treatment with cocaine [50]. Knockouts of the RGS9–2 (regulator of G protein signaling‐9) gene in mice. Knockouts of the dopamine D4 receptor gene in mice. Knockouts of the GPRK6 (G protein‐coupled receptor kinase) gene in mice. Cholinergic lesion in the cerebral cortex of rats. Long‐term high‐dose treatment of rats with caffeine [51]. Mice made dopamine‐deficient by tyrosine hydroxylase knockouts. Knockouts of alpha‐1b‐adrenoceptors in mice [52]. Rats with entorhinal lesions of the hippocampus [53]. Knockouts of PSD95 (postsynaptic density 95) gene in mice (M. Beaulieu, M. Caron, and P. Seeman, unpublished). Rats born by Caesarian section with anoxia. Rats treated with reserpine (5 mg/kg for 3 days; 2 days no drug). Mice with COMT (catechol‐O‐methyl transferase) gene knockouts. Rats with neonatal lesion of the hippocampus [54]. Rats treated with cannabinoid WIN 55,212–2 (4 mg/day for 14 days; F.J. Bermudez Silva, F. Rodriguez de Fonseca, J. Suarez, and P. Seeman, unpublished). Rats spontaneously active and explorative (no treatment)[55]. Mice with knockouts of dopamine transporter DAT or vesicle monoamine transporter‐2 VMAT‐2 [56]. Rats sensitized to quinpirole. Mice with knockouts of RIIbeta protein kinase A. The right side [36, 38] shows either the lack of elevation, a minor elevation, or an actual fall in the proportion of D2High receptors in mice with knockouts in the genes for glycogen synthase kinase (GSK3beta), metabotropic glutamate receptor mGluR5, dopamine D1 or D3 receptors, histamine H1, H2 or H3 receptors, and adenosine A2A receptors. Nine days of ketanserin treatment also had no effect on D2High receptors. (Adapted and extended from [38]; with permission from Wiley & Sons, Inc.; Reproduced from [31] with permission from Walsh Medical Media LLC).
Figure 6
Figure 6
Showing that the agonist ligand, [3H](+)PHNO, binds to D2High receptors in vivo. Ten μCi of [3H](+)PHNO was injected into the rat tail vein. Five minutes later, the brain striatum was removed, rapidly homogenized, and the [3H](+)PHNO allowed to dissociate (in the presence of 200 μM raclopride to prevent re‐binding). The time for 50% dissociation of [3H](+)PHNO was 72 seconds. However, in the presence of 200 μM guanine nucleotide (GN) to convert the receptors into their D2Low state, the dissociation of [3H](+)PHNO was much more rapid with a 50% dissociation time of 40 seconds. The ability of GN to accelerate the release of [3H]PHNO indicated that a significant amount of this ligand had been attached to D2High receptors in vivo moments before the striatum was removed [Seeman, unpublished].
Figure 5
Figure 5
Elevation of D2High receptors by amphetamine, and reversal by haloperidol. The control level of D2High receptors was 19.5 ± 0.6% (N = 20 rats). Haloperidol alone (0.25 mg/kg/day i.p. for 9 days) raised D2High to 28.6 ± 2% (N = 6 rats), while amphetamine alone (1.6 mg/kg/day i.p. for 9 days followed by a drug holiday for 10 days) resulted in a D2High level of 44.2 ± 1.3% (N = 6 rats). Haloperidol (0.25 mg/kg/day for 9 days), given after amphetamine, brought D2High down to 34.8 ± 1.6%, a reversal of 60%, where a full reversal would have corresponded to the level brought about by haloperidol alone. (Reproduced from [70] with permission of Elsevier Inc. and Copyright Clearance Center.)
Figure 7
Figure 7
Summary of biological roads to schizophrenia [104]. Many risk factors lead to elevated D2High receptors and dopamine supersensitivity that underly signs and symptoms of schizophrenia (from [104], reproduced with permission from SZ Publications).
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