Striatal D2 Dopamine Receptor Characteristics in Neuroleptic-Naive Schizophrenic Patients Studied With Positron Emission Tomography

Hietala, Jarmo; Syvälahti, Erkka; Vuorio, Klaus; Någren, Kjell; Lehikoinen, Pertti; Ruotsalainen, Ulla; Räkköläinen, Viljo; Lehtinen, Ville; Wegelius, U

doi:10.1001/archpsyc.1994.03950020040004

Cited by 167 publications

(76 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The binding characteristics of some of the subjects have been previously published. 2,29,30 The subjects were clinically examined and were found to be free of psychiatric and neurologic disorders. None was a regular smoker and all had normal CT or 1.5 T MRI brain scans.…”

Section: Subjectsmentioning

confidence: 99%

The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers

et al. 1998

View full text Add to dashboard Cite

Positron emission tomography (PET) studies have revealed significant interindividual variation in dopamine D 2 receptor density in vivo in human striatum. 1 Low D 2 receptor binding in vivo has been found to associate with alcohol/substance dependence. [2][3][4][5][6] It has been suggested that the A1 allele of human D 2 receptor gene might be associated to a specific type of alcoholism 7 and possibly to a reduced D 2 receptor density in vitro. 8 We have determined D 2 dopamine receptor-binding density (B max ), affinity (K d ) and availability (B max /K d ) in 54 healthy Finnish volunteers using PET and [ 11 C]raclopride in order to determine whether the A1 allele is associated with a 'baseline' difference in D 2 receptor characteristics in vivo. A statistically significant reduction in D 2 receptor availability reflecting an alteration in receptor density was observed in the A1/A2 genotype group compared to the A2/A2 group. There was no difference in apparent K d between the two groups. In conclusion, the association between the A1 allele and low D 2 receptor availability in healthy subjects indicates that the A1 allele of the TaqIA polymorphism might be in linkage disequilibrium with a mutation in the promoter/regulatory gene element that affects dopamine D 2 receptor expression. This study provides an in vivo neurobiological correlate to the A1 allele in healthy volunteers.The dopaminergic system plays a major role in the regulation of movement, hormone secretion, mood and various motivational behaviors related to reward and reinforcement. While the contribution of the dopaminergic system has frequently been implicated in the etiology of alcohol/drug dependence, the mechanisms underlying this have remained unclear. It has been suggested that genetic factors might contribute individual differences in the regulation of D 2 receptor density and liability for predisposition to alcohol/drug dependence. This is supported by recent positron emission tomography (PET) studies which have consistently demonstrated that alcohol, 2,3 cocaine 4,5 and opiate 6 abusers have lower striatal D 2 receptor availability in vivo compared to healthy volunteers. The molecular basis of the possible hereditary factors in the dopaminergic system affecting predisposition to alcohol/drug dependence have remained unknown. The three nucleotide substitutions causing alteration in amino acid sequence found in the coding region of the D 2 dopamine receptor gene have been revealed to be relatively rare 9 and without clear effect on the D 2 receptor function in vivo. 10 While some regulatory sequences and promoter regions have been identified for human D 1 , 11 D 5 12 and rat D 2 13-15 receptors within the 5′ flanking region, little is known about the molecular events that regulate the transcription of the human D 2 receptor. From the several polymorphic gene markers, the A1 allele of TaqIA RFLP within the D 2 receptor gene suggests association with a specific type of alcoholism. 7 Despite numerous case-control studies, 16 the role of the A1 al...

show abstract

Section: Subjectsmentioning

confidence: 99%

The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers

et al. 1998

View full text Add to dashboard Cite

show abstract

“…Mukherjee et al (1995) could not detect specific receptor binding, when they extracted the main lipophilic metabolite of [ 18 F]fallypride from blood plasma of humans and incubated it in rat brain slices containing the striata. For determination of D 2 receptor occupancy, averaged BPs of control subjects were used as the common baseline value, based on the assumption that there is no difference in B max between patients and healthy control subjects when measured with benzamide radiotracers (Farde et al, 1987;Hietala et al, 1994). BP images were stereotactically normalized for calculation of D 2 /D 3 receptor occupancy.…”

Section: Data Acquisition and Analysismentioning

confidence: 99%

The Striatal and Extrastriatal D2/D3 Receptor-Binding Profile of Clozapine in Patients with Schizophrenia

Gründer

Landvogt²,

Vernaleken

et al. 2005

Neuropsychopharmacol

View full text Add to dashboard Cite

Positron emission tomography (PET) studies reveal that clozapine at clinically used doses occupies less than 60% of D 2 /D 3 dopamine receptors in human striatum. Here, the occupancy of D 2 /D 3 dopamine receptors by clozapine in patients with schizophrenia was determined to test the hypothesis that clozapine binds preferentially to extrastriatal dopamine receptors. A total of 15 clozapine-treated inpatients with schizophrenia underwent a [ 18 F]fallypride PET scan. Receptor occupancy was calculated as percent reduction in binding potential relative to unblocked values measured in seven normal volunteers. Mean D 2 /D 3 receptor occupancy was statistically significantly higher in cortical (inferior temporal cortex 55%) than in striatal regions (putamen 36%, caudate 43%, po0.005). While the maximum attainable receptor occupancy E max approached 100% both in the striatum and cortex, the plasma concentration at 50% of E max (ED 50 ) was much higher in the putamen (950 ng/ml) than in the inferior temporal cortex (333 ng/ml). Clozapine binds preferentially to cortical D 2 /D 3 receptors over a wide range of plasma concentrations. This selectivity is lost at extremely high plasma levels. Occupancy of cortical receptors approaches 60% with plasma clozapine in the range 350-400 ng/ml, which corresponds to the threshold for antipsychotic efficacy of clozapine. Extrastriatal binding of clozapine may be more relevant to its antipsychotic actions than striatal. However, further studies with an intraindividual comparison of untreated vs treated state are desirable to confirm this finding.

show abstract

Section: Given Evidence For Excessive Striatal Dopamine Activity In Smentioning

confidence: 99%

“…In vivo studies using radioligands which bind to post-synaptic dopamine receptors have provided equivocal evidence for abnormalities of striatal receptors. Some investigators have reported greater receptor density (Gjedde et al 1996;Wong et al 1986), whereas many groups have failed to replicate these findings (Farde et al 1990;Hietala et al 1994;Nordstrom et al 1995;Pilowsky et al 1994).A more successful approach has been to measure the change in radioligand binding after the manipulation of synaptic dopamine concentration. Two groups have demonstrated that in response to amphetamine, patients with schizophrenia displace more dopamine D 2 -ligand than healthy subjects (Abi-Dargham et al 1998;Breier et al 1997;Laruelle et al 1996).…”

mentioning

confidence: 99%

In Vivo Measurement of the Vesicular Monoamine Transporter in Schizophrenia

Taylor

Koeppe

Tandon

et al. 2000

Neuropsychopharmacology

View full text Add to dashboard Cite

Given evidence for excessive striatal dopamine activity in schizophrenia, we sought to test the hypothesis that dopaminergic innervation in the striatum is abnormally elevated, and a secondary hypothesis that age-related loss is accelerated. Twelve schizophrenic subjects on stable doses of medications, along with 12 age and sex-matched healthy control subjects, underwent positron emission tomography (PET) studies with [ 11 C]dihydrotetrabenazine (DTBZ), which binds to the vesicular monoamine transporter, type 2 (VMAT2).Since the 1960's, indirect evidence has implicated dopamine systems in schizophrenia and psychosis (Angrist et al. 1974;Creese et al. 1976;Seeman 1987;Snyder 1972). In the last 10 years, neuroimaging studies targeting dopamine systems have begun to characterize the role of dopamine in schizophrenia, although many questions remain. In vivo studies using radioligands which bind to post-synaptic dopamine receptors have provided equivocal evidence for abnormalities of striatal receptors. Some investigators have reported greater receptor density (Gjedde et al. 1996;Wong et al. 1986), whereas many groups have failed to replicate these findings (Farde et al. 1990;Hietala et al. 1994;Nordstrom et al. 1995;Pilowsky et al. 1994).A more successful approach has been to measure the change in radioligand binding after the manipulation of synaptic dopamine concentration. Two groups have demonstrated that in response to amphetamine, patients with schizophrenia displace more dopamine D 2 -ligand than healthy subjects (Abi-Dargham et al. 1998;Breier et al. 1997;Laruelle et al. 1996). Additional evidence in support of increased dopamine activity comes from demonstrations of increased metabolism of [ 18 F]fluorodopa (Dao-Castellana et al. 1997;Hietala et al. 1995;Reith et al. 1994) and [ 11 C]L-DOPA (Lindstrom et al. 1999). The prevailing interpretation of these findings is that schizophrenic patients episodically release more dopamine (Breier et al. 1997;Laruelle et al. 1996), possibly in connection with up-regulated enzyme activity of dopa-decarboxylase induced by low tonic activity of dopaminergic neurons (Reith et al. 1994). Given the importance of this data to the pathophysiology of NO . 6 schizophrenia, alternative explanations need to be ruled out. For instance, schizophrenic patients may have greater dopaminergic innervation in the striatum. Regulation of transmitter release, and uptake, could be normal, while greater terminal density could lead to more release of dopamine after re-uptake blockade and vesicular release by amphetamine.Although post-mortem studies have found normal density of presynaptic dopamine markers, such as the dopamine transporter (Hirai et al. 1988;Joyce et al. 1988;Pearce et al. 1990) and expressed mRNA for tyrosine hydroxylase (Ichinose et al. 1994), excessive innervation could be obscured by normal aging and more rapid degeneration of terminals in schizophrenia. Dopamine receptors Volkow et al. 1996b), transporters (Volkow et al. 1996a), and vesicles (Frey et al. 1998 all declin...

show abstract

Striatal D2 Dopamine Receptor Characteristics in Neuroleptic-Naive Schizophrenic Patients Studied With Positron Emission Tomography

Abstract: There are no general changes in D2 dopamine receptor Bmax or Kd values in neuroleptic-naive schizophrenics, but there may be a subgroup of patients with aberrant striatal D2 dopamine receptor characteristics in vivo.

Cited by 167 publications

References 39 publications

The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers

The A1 allele of the human D2 dopamine receptor gene predicts low D2 receptor availability in healthy volunteers

The Striatal and Extrastriatal D2/D3 Receptor-Binding Profile of Clozapine in Patients with Schizophrenia

In Vivo Measurement of the Vesicular Monoamine Transporter in Schizophrenia

Contact Info

Product

Resources

About