Changes in Dopamine D₂ Receptors and 6-[¹⁸F]Fluoro-<i>L</i>-3,4-Dihydroxyphenylalanine Uptake in the Brain of 6-Hydroxydopamine- Lesioned Rats

Abstract

We studied tracer distributions in positron emission tomography of ligands for dopamine D₁ receptors ([¹¹C]SCH23390) and D₂ receptors ([¹¹C]raclopride) and the dopamine precursor analog 6-[¹⁸F]fluoro-L-3,4-dihydroxyphenylalanine ([¹⁸F]FDOPA), as a measurement of presynaptic dopaminergic function, in the brain after 6-hydroxydopamine lesioning of the medial forebrain bundle in rats. The unilateral lesions were confirmed behaviorally by methamphetamine-induced rotation 2 weeks after lesioning, and the brains were analyzed by tissue dissection following an intravenous bolus of each tracer 3 weeks after lesioning. [¹¹C]Raclopride, but not [¹¹C]SCH23390, showed a higher accumulation in the striatum on the lesion side compared with that on the non-lesioned (intact) side. On the other hand, a lower accumulation of [¹⁸F]FDOPA was found in the striatum and cerebral cortex on the lesion side. Our studies demonstrate upregulation of dopamine D₂ receptors in the striatum and a decrease in FDOPA uptake in both the striatum and cerebral cortex ipsilateral to the 6-hydroxydopamine lesions. Therefore, the combination of a D₂ antagonist and FDOPA may provide a potentially useful method for assessing the effects of dopamine depletion in Parkinson’s disease.

Neurochemical changes in the striatum of dyskinetic rats after administration of the cannabinoid agonist WIN55,212-2

“…Although in our study levodopa administration did not increase DA output, we cannot rule out that levodopa-induced increase of DA turnover might have masked DA elevation, thus making the tonic stimulation of D 2 receptors still possible. Alternatively, levodopa may directly bind to D 2 receptors as postulated by Silva and colleagues in PD patients (Silva et al 2006), and confirmed by PET studies in 6-OHDA-treated rats (Ishida et al 2004). …”

“…In this study, however, the dose of levodopa was ~ 17 fold higher than ours, and the length of treatment almost double (21 vs 11 days). The decrease of GLU observed by us in the ipsi-lateral striatum may result from the stimulation of dopamine D 2 receptors, which are highly expressed in rat striatum (Graybiel et al 1994; Surmeier et al 2007), become supersensitive after DA denervation (Pierot et al 1988; Lisovoski et al 1992; Cai et al 2000; Ishida et al 2004) and negatively control GLU transmission. Indeed, (1) ex vivo studies show that stimulation of D 2 receptors reduces GLU release presynaptically (Bamford et al 2004); (2) dopaminergic and glutamatergic systems work antagonistically in the striatum to control cognitive and motor functions (Carlsson and Carlsson 1990; Riederer et al 1992; Amalric et al 1994).…”

“…This hypothesis fits with the pharmacological treatment received by dyskinetic rats; indeed, the concomitant stimulation of DA and CB 1 receptors by levodopa and WIN may change the coupling of CB 1 receptors and prevent in turn a further decrease of GLU efflux in the denervated striatum. This phenomenon, however, appears to be relevant only in this side, where D 2 receptors are supersensitive (Pierot et al 1988; Ishida et al 2004), have altered coupling (Hossain and Weiner 1993) and CB 1 receptors are over-expressed following chronic levodopa treatment (Zeng et al 1999). Nevertheless, we cannot rule out that other receptor systems in the striatum, i.e.…”

Interrogating Tumor Metabolism and Tumor Microenvironments Using Molecular Positron Emission Tomography Imaging. Theranostic Approaches to Improve Therapeutics

“…Some known radiotracers that have been used in the clinic for measuring different processes in the human body are [ 18 F]FDG (Jhanwar and Straus, 2006;Tafti et al, 2012), 39-deoxy-39-[ (Enslow et al, 2012;Kishino et al, 2012), and [ 11 C]choline (Gofrit et al, 2006;Rodari et al, 2011) for the measurements of energy, proliferation, and cell membrane metabolism, respectively; 13 N-NH 3 for perfusion imaging (Niemeyer et al, 1993;Fiechter et al, 2012Fiechter et al, , 2013; 15 O-H 2 O for cerebral blood flow (Ter-Pogossian and Herscovitch, 1985;Gruner et al, 2011;Komar et al, 2012); [ 11 C]raclopride (Montgomery et al, 2007;te Beek et al 2012;Urban et al, 2012); and [ (Ishida et al, 2004) for the measurements of dopamine system and 68 Ga-N-[ [4,7,10-tris (carboxymethyl)-1,4,7,10-tetraazacyclododec-1-yl] (hydroxymethyl)propyl]-, cyclic (2-7)-disulfide (DOTA-NOC) for the detection of neuroendocrine tumors (NETs) (Krausz et al, 2011).…”

PET Designated Flouride-18 Production and Chemistry

“…In order to be suitable for PET, the radiotracers required to have high affinity and selectivity towards the receptor, low nonspecific binding and optimal biological half-life. The most common radiotracers that are being used in the clinic for measurements of different processes in the human body are [ 18 F]-FDG [2] and [ 11 C]-Choline [3] for the measurements of energy and cell membrane metabolism, [ 13 N]-NH 3 for perfusion imaging [4], [ 15 O]-H 2 O for cerebral blood flow [5], [ 11 C]-raclopride [6] and [ 18 F]-FDOPA [7] for the measurements of dopamine system.…”