Elsevier

Brain Research

Volume 1032, Issues 1–2, 25 January 2005, Pages 77-84
Brain Research

Research report
Measurement 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

https://doi.org/10.1016/j.brainres.2004.11.005Get rights and content

Abstract

The ability to measure amphetamine-induced dopamine release in extrastriatal brain regions in the non-human primates was evaluated by using the dopamine D-2/D-3 receptor radioligand, 18F-fallypride. These regions included the thalamus, amygdala, pituitary, temporal cortex and frontal cortex as well as putamen, caudate and ventral striatum. The positron emission tomography (PET) studies involved control studies, which extended to 3 h, and the amphetamine-challenge studies, which involved administration of d-amphetamine (approx. 0.5–1 mg/kg, i.v.). PET data analysis employed the distribution volume ratio method (DVR) in which the cerebellum was used as a reference region. Our results show a substantial decrease in the binding potential of 18F-fallypride in extrastriatal regions: thalamus (−20%), amygdala (−39%) and pituitary (−14%). Putamen, caudate and ventral striatum also exhibited significant decreases (−20%). The decrease in 18F-fallypride binding in the extrastriatal regions points to the importance of dopaminergic neurotransmission in these brain regions. Furthermore, our findings support the use of 18F-fallypride to measure extrastriatal dopamine release.

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.

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