Regional dopamine synthesis in patients with schizophrenia using L-[β-11C]DOPA PET

doi:10.1016/j.schres.2008.11.006

Schizophrenia Research

Volume 108, Issues 1–3, March 2009, Pages 78-84

https://doi.org/10.1016/j.schres.2008.11.006 Get rights and content

Abstract

The dopamine hypothesis has been the most widely known theory concerning schizophrenia. However, the exact mechanism including presynaptic dopaminergic activity and its relationship with symptom severity still remains to be revealed. We measured presynaptic dopamine synthesis using positron emission tomography (PET) with L-[β-¹¹C]DOPA in 18 patients with schizophrenia (14 drug-naïve and 4 drug-free patients) and 20 control participants. Dopamine synthesis rates, expressed as k_i values, were obtained using a graphical method, and the occipital cortex was used as reference region. Regions of interest were placed on the prefrontal cortex, temporal cortex, anterior cingulate, parahippocampus, thalamus, caudate nucleus, and putamen. Psychopathology was assessed with the Positive and Negative Symptom Scale (PANSS). We found significantly higher k_i values in patients than in controls in the left caudate nucleus, but not in the other regions. The k_i values in the thalamus exhibited a significant positive correlation with the PANSS total scores. Furthermore, a significant positive correlation was observed between the PANSS positive subscale scores and k_i values in the right temporal cortex. Patients with schizophrenia showed higher dopamine synthesis in the left caudate nucleus, and dopaminergic transmission in the thalamus and right temporal cortex might be implicated in the expression of symptoms in schizophrenia.

Introduction

Positron emission tomography (PET) has allowed us to investigate the dopamine hypothesis in living human brain. Since there is no ideal animal model of schizophrenia, PET investigation is still the most useful method for investigating neurotransmission in patients. As for postsynaptic dopaminergic receptors, several studies have investigated striatal (Farde et al., 1990, Nordström et al., 1995, Wong et al., 1986) and extrastriatal (Suhara et al., 2002, Yasuno et al., 2004) D₂ receptor (D₂R) binding by the use of PET. Although studies investigating D₂R in the striatum in schizophrenia have reported inconsistent findings, those focusing on extrastriatal D₂R binding have repeatedly reported its reduction in the anterior cingulate cortex (Suhara et al., 2002) and the thalamus in schizophrenia (Talvik et al., 2003, Yasuno et al., 2004). Regarding intrasynaptic function, striatal dopamine release was reported to be enhanced in schizophrenia (Breier et al., 1997, Laruelle et al., 1996). On the other hand, many studies did not find any change in dopamine transporter binding in the striatum of schizophrenia (Laakso et al., 2000, Laruelle et al., 2000, Schmitt et al., 2005, Yang et al., 2004). These findings suggest that patients with schizophrenia may have elevated presynaptic dopamine synthesis, and investigations on presynaptic dopaminergic function in extrastriatal regions might be critical for providing an understanding of the pathophysiology of schizophrenia.

Radiolabeled L-DOPA, a precursor of dopamine, has been used to investigate presynaptic dopamine synthesis. L-DOPA is transported through the blood–brain barrier (BBB), taken up by presynaptic monoaminergic neurons, and metabolized to dopamine by aromatic amino acid decarboxylase (AADC). Previous studies on the dopamine synthesis of schizophrenia used 6-[¹⁸F]fluoro-L-DOPA (Dao-Castellana et al., 1997, Elkashef et al., 2000, Hietala et al., 1995, Hietala et al., 1999, McGowan et al., 2004, Reith et al., 1994;) or L-[β-¹¹C]DOPA (Gefvert et al., 2003, Lindström et al., 1999). The studies with 6-[¹⁸F]fluoro-L-DOPA, which is widely used in schizophrenia research, indicated elevated dopamine synthesis (Hietala et al., 1995, Hietala et al., 1999, Lindström et al., 1999, McGowan et al., 2004, Reith et al., 1994), elevated dopamine turnover (Kumakura et al., 2007), only higher variability (Dao-Castellana et al., 1997), and even reduced synthesis (Elkashef et al., 2000) in the striatum.

The 3-O-methyl metabolite of L-DOPA crossing the BBB can reportedly cause an error in quantification of the dopamine synthesis rate (Dhawan et al., 1996, Melega et al., 1990, Wahl et al., 1994). However, 3-O-methylation of L-[β-¹¹C]DOPA does not take place readily and rapidly when compared with 6-[¹⁸F]fluoro-L-DOPA (Ito et al., 2006, Melega et al., 1990, Torstenson et al., 1999). Recently, we evaluated the accuracy of quantitative analyses of L-[β-¹¹C]DOPA PET studies (Ito et al., 2006). In the current study, we investigated regional dopamine synthesis and its relationship with the severity of positive and negative symptoms in patients with schizophrenia using L-[β-¹¹C]DOPA.

Section snippets

Participants

Fourteen (8 males and 6 females) drug-naïve and 4 (2 males and 2 females) 3-month drug-free patients (35.6 ± 7.4 years, mean ± SD) meeting the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association, 1994) criteria for schizophrenia or schizophreniform disorder were recruited from the outpatient units of university hospitals, their affiliated psychiatric hospitals, and a mental clinic. On the day of the PET study, the diagnosis was re-evaluated

Demographic data

The demographic data of schizophrenia patients and controls are shown in Table 1. There were no significant differences between patients and controls in terms of age, gender, education, handedness, and the injected dose and specific radioactivity of L-[β-¹¹C]DOPA. The duration of illness and the PANSS scores are also shown in Table 1.

Regional L-[β-¹¹C]DOPA uptake in schizophrenia and control subjects

Univariate analysis of covariance revealed no significant interaction between group and age in any of the regions, and a significant group difference in k_i values

Discussion

In the present study, we found increased dopamine synthesis in the left caudate nucleus in patients with schizophrenia compared to normal controls. In addition, we observed a significant correlation between regional dopamine synthesis in the thalamus as well as in the right temporal cortex and symptom severity in patients.

Most of the previous studies with 6-[¹⁸F]fluoro-L-DOPA have reported elevated dopamine synthesis mainly in the striatum of patients with schizophrenia (Hietala et al., 1995,

Conclusion

We measured the dopamine synthesis rate in patients with schizophrenia and normal control subjects by using PET with L-[β-¹¹C]DOPA. Patients had higher dopamine synthesis in the left caudate nucleus than controls, which was in line with the results of most previous studies that indicated an increase in dopamine synthesis in the striatum. Moreover, correlation analyses between k_i values and symptoms suggested that dopamine synthesis in the thalamus and right temporal cortex might be implicated

Role of funding source

This study was supported by a consignment expense for the Molecular Imaging Program on “Research Base for Exploring New Drugs” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japanese Government.

Contributors

S. Nozaki, F. Yasuno, A. Takano, and T. Suhara designed the study and wrote the protocol. S. Nozaki, M. Kato, F. Yasuno, M. Ota, A. Otsuka, and Y. Okubo recruited the patients and made psychiatric evaluations. S. Nozaki, H. Takano, M. Okumura, R. Arakawa, R. Matsumoto, and Y. Fujimura participated in the data analysis. S. Nozaki wrote the first draft of the manuscript. S. Nozaki, M. Kato, H. Takano, H. Takahashi, H. Ito, H. Kashima and T. Suhara had discussions and corrected the manuscript. All

Conflict of interest

All the authors have no conflict of interest.

Acknowledgement

We thank Mr. Katsuyuki Tanimoto, Mr. Takahiro Shiraishi, and Ms. Yoshiko Fukushima for their assistance in performing the PET experiments at the National Institute of Radiological Sciences.

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Citation Excerpt :
For example, schizophrenia is one of the most extensively examined diseases in terms of its DA hypothesis. While the elevated striatal DA synthesis capacity has been reported in patients with schizophrenia as well as individuals with prodromal symptoms of schizophrenia (Egerton et al., 2013; Hietala et al., 1999, 1995; Howes et al., 2009a, b, 2011a, b, 2013; Jauhar et al., 2017; Nozaki et al., 2009), recent reports showed that in some patients with schizophrenia, elevation in the DA synthesis capacity was not observed (Brugger et al., 2020; Demjaha et al., 2012; Kim et al., 2017). Inconsistent findings have also been reported regarding D2 receptor availability (Tune et al., 1993; Veselinović et al., 2018; Yasuno et al., 2004) and DA transporter availability in schizophrenia (Arakawa et al., 2009; Laakso et al., 2000; Mateos et al., 2005).
The dopamine (DA) neurotransmission has been implicated in fundamental brain functions, exemplified by movement controls, reward-seeking, motivation, and cognition. Although dysregulation of DA neurotransmission in the striatum is known to be involved in diverse neuropsychiatric disorders, it is yet to be clarified whether components of the DA transmission, such as synthesis, receptors, and reuptake are coupled with each other to homeostatically maintain the DA neurotransmission. The purpose of this study was to investigate associations of the DA synthesis capacity with the availabilities of DA transporters and D2 receptors in the striatum of healthy subjects.
First, we examined correlations between the DA synthesis capacity and DA transporter availability in the caudate and putamen using PET data with L-[β-¹¹C]DOPA and [¹⁸F]FE-PE2I, respectively, acquired from our past dual-tracer studies. Next, we investigated relationships between the DA synthesis capacity and D2 receptor availability employing PET data with L-[β-¹¹C]DOPA and [¹¹C]raclopride, respectively, obtained from other previous dual-tracer assays.
We found a significant positive correlation between the DA synthesis capacity and DA transporter availability in the putamen, while no significant correlations between the DA synthesis capacity and D2 receptor availability in the striatum.
The intimate association of the DA synthesis rate with the presynaptic reuptake of DA indicates homeostatic maintenance of the baseline synaptic DA concentration. In contrast, the total abundance of D2 receptors, which consist of presynaptic autoreceptors and postsynaptic modulatory receptors, may not have an immediate relationship to this regulatory mechanism.
The Topography of Striatal Dopamine and Symptoms in Psychosis: An Integrative Positron Emission Tomography and Magnetic Resonance Imaging Study
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Regional dopamine synthesis in patients with schizophrenia using L-[β-11C]DOPA PET

Abstract

Introduction

Section snippets

Participants

Demographic data

Regional L-[β-11C]DOPA uptake in schizophrenia and control subjects

Discussion

Conclusion

Role of funding source

Contributors

Conflict of interest

Acknowledgement

Lancet

Schizophr. Res.

Brain Res. Brain Res. Rev.

Schizophr. Res.

Schizophr. Res.

Psychiatry Res.

Brain Res.

Lancet

Schizophr. Res.

Biol. Psychiatry

Biol. Psychiatry

Biol. Psychiatry

Biochem. Pharmacol.

Psychiatry Res.

Neuropsychologia

Life Sci.

Trends Neurosci.

Psychiatry Res.

Clin. Psychol. Rev.

Biol. Psychiatry

Psychiatry Res.

Diagnostic and Statistical Manual of Mental Disorders DSM-IV

Symptom correlates of prepulse inhibition deficits in male schizophrenic patients

Am. J. Psychiatry

Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method

Proc. Natl. Acad. Sci. U. S. A.

PET and MRI of the thalamus in never-medicated patients with schizophrenia

Am. J. Psychiatry

Regional cerebral glucose metabolism in never-medicated patients with schizophrenia

Can. J. Psychiatry

Combined FDOPA and 3OMFD PET studies in Parkinson's disease

J. Nucl. Med.

D2 dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [11C]raclopride

Arch. Gen. Psychiatry

User's Guide for the Structured Clinical Interview for DSM-IV Axis I Disorders: SCID-1 Clinician Version

Regional dopamine synthesis in patients with schizophrenia using L-[β-¹¹C]DOPA PET

Regional L-[β-¹¹C]DOPA uptake in schizophrenia and control subjects

D₂ dopamine receptors in neuroleptic-naive schizophrenic patients. A positron emission tomography study with [¹¹C]raclopride