The Effect of Antipsychotics on the High-Affinity State of D2 and D3 Receptors

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101

The dopamine D 2 receptors exist in two states: a high-affinity state (D 2 high ) that is linked to second messenger systems, is responsible for functional effects, and exhibits high affinity for agonists; and a low-affinity state that is functionally inert and exhibits lower affinity for agonists. The dopamine D 3 receptors have high-affinity for agonist (eg dopamine) and the existence of the two affinity states is controversial. Although preclinical studies in animal models of psychosis have shown a selective increase of D 2 high as the common pathway to psychosis, the D 3 has been suggested to be involved in the pathophysiology of psychosis. We report the first study of the D 2 high and D 3 in schizophrenia using the novel PET radiotracer, [ 11 C]-( + )-PHNO. We recruited 13 patients with schizophrenia-spectrum disorder amidst an acute psychotic episode, drug free for at least 2 weeks, and 13 age-sex-matched healthy controls. The binding potential nodisplaceable (BP ND ) was examine in the main regions of interest (caudate, putamen, ventral striatum, globus pallidus, substantia nigra, and anterior thalamus) and in a voxel-wise analysis. The BP ND between patients and controls was not different in any of the regions. The voxel-wise analysis did not reveal any difference and no correlations were found between the BP ND and positive and negative syndrome scale subscales. Our results do not find support for the hypothesis linking psychosis to a selective increase in D 2 high and/or D 3 in schizophrenia. It is possible that receptors with high affinity are not accessible by [ 11 C]-( + )-PHNO because they are occupied by endogenous dopamine, a possibility that can be ruled out in future experiments.

Section: Discussionmentioning

confidence: 57%

The Dopamine D2 Receptors in High-Affinity State and D3 Receptors in Schizophrenia: A Clinical [11C]-(+)-PHNO PET Study

Graff‐Guerrero

Mizrahi

Agid

et al. 2008

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101

“…Nevertheless, the clinical importance of the D3 receptor to clozapine's clinical effect is likely small, as the D2 occupancy of therapeutic clozapine (20-60%) (Kapur et al, 1999;Nordstrom et al, 1995) is typically less than for the other antipsychotic, indicating that clozapine's D3 receptor occupancy in the clinical setting is likely also much lower than the 35% occupancy seen here. Indeed the recent PET study by our group in schizophrenic patients found that chronic clozapine treatment, while producing B50% occupancy in STR, did not reduce [ 11 C]-( + )-PHNO binding in the GP (Graff-Guerrero et al, 2009).…”

Section: Discussionmentioning

confidence: 87%

“…In general agreement with the distribution of D2 and D3 receptors, [ 11 C]-( + )-PHNO binding sites in CAU and PUT are thought to represent primarily D2 receptors, whereas those in GP and SN are thought to be primarily of the D3 receptor type (Ginovart et al, 2007;Narendran et al, 2006;Willeit et al, 2006). The pharmacological dissimilarity between [ 11 C]-( + )-PHNO binding sites in CAU/PUT and GP was first suggested by their anatomical distribution and the slower washout of the radiotracer from GP than from CAU and PUT (Ginovart et al, 2007;Willeit et al, 2006), but has since been supported by pharmacological evidence showing that [ 11 C]-( + )-PHNO binding potential with respect to non-displaceable binding (BP ND ) in the GP can be blocked in a regionally selective manner by the D3-selective drugs BP897 and SB277011 in baboon (Narendran et al, 2006;Rabiner et al, 2009), and pramipexole (Graff-Guerrero et al, 2009) and ABT-925 (Graff-Guerrero et al, 2008) in human. Further support for the binding of [ 3 H]-( + )-PHNO to both receptor subtypes is provided by mouse experiments showing that D2 receptor knockout abolishes [ 3 H]-( + )-PHNO binding in the striatum (STR) while leaving SB277011-sensitive binding in midbrain and cerebellum lobes 9 and 10 largely intact (Rabiner et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…A recent [ 11 C]-( + )-PHNO PET study in schizophrenic patients conducted at our center revealed that chronic treatment with the antipsychotic drugs olanzapine, clozapine, or risperidone, produced high levels of receptor occupancy in D2-rich CAU, PUT, and VS, but no receptor occupancy in D3-rich GP (Graff-Guerrero et al, 2009). The purpose of this study was to clarify this discrepancy by comparing ex vivo and in vitro D2 and D3 occupancy by olanzapine, clozapine, and risperidone, as well as the typical antipsychotic haloperidol, using [ 3 H]-( + )-PHNO autoradiography in rat brain.…”

Section: Introductionmentioning

confidence: 99%

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The Antipsychotics Olanzapine, Risperidone, Clozapine, and Haloperidol Are D2-Selective Ex Vivo but Not In Vitro

McCormick

Kapur

Graff‐Guerrero

et al. 2010

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In a recent human [ 11 C]-( + )-PHNO positron emission tomography study, olanzapine, clozapine, and risperidone occupied D2 receptors in striatum (STR), but, despite their similar in vitro D2 and D3 affinities, failed to occupy D3 receptors in globus pallidus. This study had two aims: (1) to characterize the regional D2/D3 pharmacology of in vitro and ex vivo [ 3 H]-( + )-PHNO binding sites in rat brain and (2) to compare, using [ 3 H]-( + )-PHNO autoradiography, the ex vivo and in vitro pharmacology of olanzapine, clozapine, risperidone, and haloperidol. Using the D3-selective drug SB277011, we found that ex vivo and in vitro [ 3 H]-( + )-PHNO binding in STR is exclusively due to D2, whereas that in cerebellar lobes 9 and 10 is exclusively due to D3. Surprisingly, the D3 contribution to [ 3 H]-( + )-PHNO binding in the islands of Calleja, ventral pallidum, substantia nigra, and nucleus accumbens was greater ex vivo than in vitro. Ex vivo, systemically administered olanzapine, risperidone, and haloperidol, at doses occupying B80% D2, did not occupy D3 receptors. Clozapine, which also occupied B80% of D2 receptors ex vivo, occupied a smaller percentage of D3 receptors than predicted by its in vitro pharmacology. Across brain regions, ex vivo occupancy by antipsychotics was inversely related to the D3 contribution to [ 3 H]-( + )-PHNO binding. In contrast, in vitro occupancy was similar across brain regions, independent of the regional D3 contribution. These data indicate that at clinically relevant doses, olanzapine, clozapine, risperidone, and haloperidol are D2-selective ex vivo. This unforeseen finding suggests that their clinical effects cannot be attributed to D3 receptor blockade.

“…Overall, these results are suggestive of a decline in DRD3 binding with age, in particularly among ADP. No previous [ 11 C]PHNO study has reported a relationship between age and DRD2/3 binding (Boileau et al, 2009;Boileau et al, 2012;Ginovart et al, 2007a;Graff-Guerrero et al, 2009a;Graff-Guerrero et al, 2009b;Shotbolt et al, 2012a;Willeit et al, 2006), which could be due to the narrower age range in their reports and/or to the effect of alcohol.…”

Section: D3 Receptors In Alcoholismmentioning

confidence: 97%

In Vivo Imaging of Cerebral Dopamine D3 Receptors in Alcoholism

Erritzoe

Tziortzi

Bargiela

et al. 2014

Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [ 11 C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [ 11 C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [ 11 C]PHNO binding between the groups at baseline. However, baseline [ 11 C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (V T : 16.5±4 vs 13.7±2.9, p ¼ 0.040), a region in which the [ 11 C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (V T ) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in V T following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [ 11 C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse.