Research reportMeasurement of d-amphetamine-induced effects on the binding of dopamine D-2/D-3 receptor radioligand, 18F-fallypride in extrastriatal brain regions in non-human primates using PET
Introduction
Dopaminergic neurotransmission in the striata (putamen and caudate) and in areas outside of the striata, such as the thalamus, amygdala and various regions in the cortex (collectively referred to as extrastriatal regions) have been implicated in a number of human behaviors and pathophysiologies [1], [30], [31]. Dopamine D-2/D-3 receptors are found in significant quantities in these brain areas outside the striata and are thought to play a major role in extrastriatal dopaminergic neurotransmission [6], [13], [21], [28]. Appreciable amounts of dopamine and its metabolites have also been found in extrastriatal brain regions in postmortem human brain tissue [12].
Alterations in endogenous dopamine levels can be assessed noninvasively by measuring competitive effects on the binding of dopamine D-2 receptor radioligands using positron emission tomography (PET) [15]. Various substance abuse drugs such as cocaine, methylphenidate and d-amphetamine (AMPH) have been used to increase levels of endogenous dopamine. These studies have focused exclusively on measuring changes in the striatum (putamen and caudate) using PET radiotracers such as 11C-raclopride. We and others have previously reported reduction in 18F-fallypride binding following the injection of AMPH in the striatal regions of rhesus monkeys [18], [24]. This suggested that 18F-fallypride binding is susceptible to dopamine competition in vivo. Improvements in PET scanner resolution have now enabled the study of extrastriatal regions in monkeys using high affinity agents such as 18F-fallypride [6]. Thus, in vivo dopamine competition studies in extrastriatal regions such as the thalamus and other dopamine containing brain regions are now possible.
Rodents do not offer a good model to examine the thalamus for dopamine D-2/D-3 receptor binding because of low receptor concentrations [19]. However, dopamine D-2/D-3 receptor concentrations are present in moderate concentrations in non-human primates and humans and exhibit a similar pattern of distribution [8], [6], [12], [21]. Little information on brain dopamine concentration data is available in non-human primates [17], although it may be expected to follow the pattern found in humans [12]. Since the concentration of dopaminergic neurons is significantly lower in extrastriatal regions compared to the striatum, a potential AMPH-induced effect on the binding of 18F-fallypride in areas such as the thalamus, amygdala, cortex and other brain areas was unclear. Using another high-affinity PET radiotracer, 11C-FLB 457, a small amphetamine-induced decrease in binding in the thalamus and neocortex has been reported in cynomolgous monkeys [5]. However, methamphetamine seemed to have little effect on the binding of 11C-FLB 457 in extrastriatal regions in rhesus monkeys [23].
Our goal in this work was to evaluate the ability of 18F-fallypride to measure AMPH-induced extrastriatal dopamine release [7]. Using male rhesus monkeys and the ECAT EXACT HR+scanner, we used two approaches: (1) demonstrate dopamine release in extrastriatal brain regions, particularly the thalamus by virtue of competition with 18F-fallypride by administering an intravenous bolus of AMPH after 18F-fallypride, and (2) carry out pre-injection studies with intravenous bolus AMPH in order to quantitatively measure the extent of reduction in 18F-fallypride binding in various brain regions. These experiments would assess the sensitivity of 18F-fallypride to AMPH-induced dopamine release in extrastriatal regions.
Section snippets
Radiopharmaceutical
The radioligand used in the study, 18F-fallypride, was made according to published methods with a specific activity of approx. 3000 Ci/mmol [21]. Briefly, the synthesis of 18F-fallypride was carried out in the chemical process control unit (CPCU) of the CTI RDS-112 cyclotron using modifications of previous methods [19]. Purification of 18F-fallypride was carried out by high performance liquid chromatography (HPLC) separation on a C-18 semi-prep column (Alltech Assoc., Deerfield, IL). Eluents
Control studies
Binding of 18F-fallypride in striatal and extrastriatal regions in the two monkeys was evident. Fig. 1 shows PET images of brain slices illustrating the striatal regions (putamen, caudate and ventral striatum) as well as extrastriatal regions (thalamus, amygdala and pituitary). Cerebellum contains little dopaminergic innervation and therefore serves as a reference region. Assignment of the extrastriatal regions were assisted by a T1-weigthed MR image of one of the monkeys. Representative
Discussion
Since dopamine concentrations in extrastriatal regions are small, it was uncertain if an AMPH effect on 18F-fallypride binding could be observed. Measurement of presynaptic dopamine concentration using 18F-FDOPA in extrastriatal regions is difficult due to the low signal-to-noise ratio of the tracer. However, one PET-18F-FDOPA human study indicates presence of significant uptake in regions such as the midbrain (ventral and dorsal), amygdala, hippocampus, prefrontal cortex and other regions [22]
Conclusions
Effects of AMPH on the binding of 18F-fallypride are noted in both striatal and extrastriatal regions. The effect in extrastriatal regions such as the thalamus is more pronounced than previously reported using other PET radiotracers such as 11C-FLB 457. Regional variations in the degree to which 18F-fallypride binding is reduced may be affected by methodological issues as well as several physiological factors. Nonetheless, the ability to measure dopamine release in extrastriatal brain regions
Acknowledgment
This research was supported by the Biological and Environmental Program (BER), U.S. Department of Energy, Grant No. DE-FG02-02ER63294. We thank Dr. Harold Stills and his staff for assistance with the non-human primates. The Wallace-Kettering Neuroscience Institute and the Air Force Research Laboratory under Cooperative Agreement No. F33615-98-2-6002 are acknowledged for use of the PET scanner.
References (32)
- et al.
Identification of extrastriatal dopamine D-2 receptors in post mortem human brain with 125I-epidepride
Brain Res.
(1993) - et al.
Preliminary assessment of extrastriatal dopamine D-2 receptor binding in the rodent and non-human primate brains using the high affinity radioligand, [F-18]fallypride
Nucl. Med. Biol.
(1999) - et al.
Evaluation of dopamine D-2 receptor occupancy in vivo by clozapine, risperidone and haloperidol in rodents and non-human primates using 18F-fallypride
Neuropsychopharmacology
(2001) - et al.
Extrastriatal mean regional uptake of fluorine-18-FDOPA in the normal aged brain—an approach using MRI-aided spatial normalization
Neuroimage
(2000) Do we still believe in the dopamine hypothesis? New data bring new evidence
Int. J. Neuropsychopharmacol.
(2004)- et al.
Striatal dopamine release during unrewarded motor task in human volunteers
NeuroReport
(2003) - et al.
Performance evaluation of a whole body PET scanner using the NEMA protocol
J. Nucl. Med.
(1997) - et al.
18F-Fallypride binding in never-medicated patients with schizophrenia
Biol. Psychiatry
(2004) - et al.
Effect of amphetamine on extrastriatal D2 dopamine receptor binding in the primate brain
Synapse
(2000) - et al.
Quantitation of striatal and extrastriatal dopamine D-2 receptors using PET imaging of F-18 fallypride in nonhuman primates
Synapse
(2000)
Amphetamine-induced displacement of 18F-fallypride in the thalamus in monkey PET studies
Abstr.-Soc. Neurosci.
Measuring the in vivo binding parameters of 18F-fallypride in monkeys using a PET multiple-injection protocol
J. Cereb. Blood Flow Metab.
Dopamine release and uptake dynamics within nonhuman primate striatum in vitro
J. Neurosci.
Regional cerebral blood flow response to oral amphetamine challenge in healthy volunteers
J. Nucl. Med.
Assessment of dynamic neurotransmitter changes with bolus or infusion delivery of neuroreceptor ligands
J. Cereb. Blood Flow Metab.
Distribution of D1- and D2-dopamine receptors, and dopamine and its metabolites in the human brain
Neuropsychopharmacology
Cited by (54)
The influence of acute dopamine transporter inhibition on manic-, depressive-like phenotypes, and brain oxidative status in adult zebrafish
2024, Progress in Neuro-Psychopharmacology and Biological PsychiatryCross-sectional and longitudinal small animal PET shows pre and post-synaptic striatal dopaminergic deficits in an animal model of HIV
2017, Nuclear Medicine and BiologyCitation Excerpt :Our ultimate goal was to validate in vivo imaging biomarkers of dopaminergic dysfunction in this animal model that could potentially be used in the evaluation of neuroprotective therapies, prior to human translation. The synthesis of [18F]-Fallypride was performed as previously described [25]. Radiochemical purity was > 99%.
Positron emission tomography (PET) imaging of nicotine-induced dopamine release in squirrel monkeys using [<sup>18</sup>F]Fallypride
2017, Drug and Alcohol DependenceStriatal and extrastriatal dopamine release in the common marmoset brain measured by positron emission tomography and [<sup>18</sup>F]fallypride
2015, Neuroscience ResearchCitation Excerpt :In this study, the change of receptor occupancy by acute methylphenidate challenge (5 mg/kg) was thought to be detectable by [18F]fallypride. [ 18F]Fallypride has been used to estimate psychostimulant-induced dopamine release in mice, rats, rhesus monkeys, and humans (Mukherjee et al., 2005; Rominger et al., 2010; Slifstein et al., 2010; Ota et al., 2015), but not in the common marmosets. Our results established the effectiveness of [18F]fallypride for the calculation of psychostimulant-induced dopamine release in the common marmoset.
Quantitative, noninvasive, in vivo longitudinal monitoring of gene expression in the brain by co-AAV transduction with a PET reporter gene
2014, Molecular Therapy Methods and Clinical DevelopmentCitation Excerpt :The dual vector approach also allows the D2R80A gene to be injected into a single site for monitoring while the therapeutic gene can be distributed more widely as needed in each disease. The PET ligand [18F]-fallypride is widely used in animals and humans27–30,40 due to its high affinity for dopamine D2/D3 receptors. Most importantly, it crosses the blood–brain barrier after intravenous injection, making it suitable for imaging the brain of patients.
Imaging of Neurochemical Transmission in the Central Nervous System
2014, Imaging of the Human Brain in Health and Disease