Striatal binding of the PET ligand11C-raclopride is altered by drugs that modify synaptic dopamine levels (original) (raw)
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Quantitation of Carbon11-labeled raclopride in rat striatum using positron emission tomography
Synapse, 1992
Using conventional autoradiographic and tissue counting techniques, the experimental quantitation of in vivo kinetics of prospective or established radioligands for PET is animal and labour intensive. The present study tested the feasibility of using PET itself to quantitate the specific binding of [11C] raclopride to rat striatum and to study the effects of experimental manipulation of endogenous dopamine on binding parameters.Carbon-11-labeled raclopride was given i. v. to anaesthetised rats, positioned in a PET camera and dynamic emission scans acquired over 60 min. Time-activity curves were generated for selected regions of interest, representing striatum and cerebellum and the striatal data fitted to a compartmental model, using cerebellum as the input function, thus circumventing the need for individual metabolite-corrected plasma curves. In control rats, the binding potential (BP), defined as the ratio of the rate constants for transfer from “free to bound” and “bound to free” compartments, was of the order of 0.6. This was reduced threefold by predosing with nonraioactive raclopride. Increasing extracellular dopamine levels by predosing with d -amphetamine resulted in a significant decrease in BP whereas reducing extracellular dopamine by predosing with γ-butyrolactone caused a significant increase.Thus, despite the limitation in spatial resolution of PET, specific binding of raclopride could be assessed from regional time-activity curves from individual rats. The system was sufficiently sensitive that changes in BP could be detected following modulation of endogenous dopamine levels, a finding of potential relevance to the interpretation of clinical PET data.
PET analysis of human dopamine receptor subtypes using 11C-SCH 23390 and 11C-raclopride
Psychopharmacology, 1987
Tracer doses of HC-SCH 23390 and HC-raclopride, selective Dl-dopamine and D2-dopamine receptor antagonists, respectively, were injected intravenously into three healthy male volunteers and two drug-treated schizophrenic patients. Regional radioactivity in brain and plasma was followed during 1 h by positron emission tomography (PET). After injection of both ligands a high accumulation of radioactivity was observed in the dopamine-rich caudate putamen. Experiments with 11C-SCH 23390, but not ~ aC-raclopride, showed a conspicuous accumulation of radioactivity also in the neocortex. None of the ligands accumulated in the dopamine-poor cerebellum. Specific binding of 11C-raclopride in the putamen was reduced by more than 80% in schizophrenic patients treated with antipsychotic doses of sulpiride or eis(Z)-flupentixol decanoate.
NeuroImage, 2008
We investigated an imaging strategy that provides simultaneous measurements of radiotracer binding and behavior in awake, freely moving animals. In this strategy, animals are injected intravenously (i.v.) through a catheterized line and permitted to move freely for 30 min during uptake of the imaging agent, in this case 11 C-raclopride. After this Awake Uptake period, animals are anesthetized and scanned for 25 min. We tested the utility of this strategy for measuring changes in striatal 11 C-raclopride binding under control conditions (awake and freely moving in the home cage) and with several drug challenges: a loading dose of unlabeled raclopride, pretreatment with methamphetamine (METH) or pretreatment with γ-vinyl-GABA [S(+)-GVG] followed by METH. An additional group of animals underwent a stress paradigm that we have previously shown increases brain dopamine. For drug challenge experiments, the change in 11 C-raclopride binding was compared to data from animals that were anesthetized for the uptake period ("Anesthetized Uptake") and full time activity curves were used to calculate 11 C-raclopride binding. Regardless of the drug treatment protocol, there was no difference in 11 C-raclopride striatum to cerebellum ratio between the Awake versus the Anesthetized Uptake conditions. Awake and Anesthetized groups demonstrated over 90% occupancy of dopamine receptors with a loading dose of cold raclopride, both groups demonstrated a~30% reduction in 11 C-raclopride binding from METH pretreatment and this effect was modulated to the same degree by GVG under both uptake conditions. Restraint during Awake Uptake decreased 11 C-raclopride binding by 29%. These studies support a unique molecular imaging strategy in which radiotracer uptake occurs in freely moving animals, after which they are anesthetized and scanned. This imaging strategy extends the applicability of small animal PET to include functional neurotransmitter imaging and the neurochemical correlates of behavioral tasks.
Neuropsychopharmacology, 1998
Subanesthetic doses of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist ketamine exacerbate psychosis in schizophrenic patients, and ketamine has significant abuse liability. These observations indicate that a secondary effect of ketamine may be to increase dopamine concentrations. The present study was undertaken using positron emission tomography (PET) and the dopamine (D 2 ) radiotracer 11 C-raclopride to determine whether ketamine would decrease D 2 receptor availability, indicative of an increase in dopamine concentrations. Two scans were performed in seven male control subjects before and after administration of ketamine (0.5 mg/kg, IV infused over 20 min). Ketamine significantly increased cortisol levels and decreased dopamine receptor availability in the striatum (specific binding), but not in the cerebellum (nonspecific binding). In addition, the cerebellar binding subtracted from the striatal binding (to account for changes in nonspecific binding) was significantly decreased after ketamine administration. These results provide in vivo evidence for the ability of ketamine to increase striatal dopamine concentrations, consistent with the role of the NMDA receptor in modulating dopamine function.
Neuroimage, 2007
The performance of small animal PET for neuroreceptor studies in a psychopharmacological challenge paradigm is not yet well-described. Therefore, we used microPET and [ 11 C]raclopride to map the availability of dopamine D 2/3 receptors in brain of anesthetized rats, first in a baseline condition, and again after challenge with saline or D-amphetamine. Parametric maps of the specific binding (binding potential, pB) were calculated using a reference tissue input from cerebellum, and spatially normalized to a digitized stereotaxic coordinate system for rat brain. In volumes of interest (VOIs), the mean baseline pB (n = 6) was 2.05 in dorsal striatum (caudate-putamen), and 1.34 in ventral striatum (nucleus accumbens), and did not significantly differ upon retest 2 h later. The availability of [ 11 C]raclopride binding sites at baseline was 8% higher in the right striatum. Challenge with amphetamine sulfate (1 mg/kg, i.v., n = 4) decreased pB by 19% in both ventral and dorsal striatum. We have earlier predicted that blockade of monoamine oxidase (MAO) should potentiate the amphetamine-evoked dopamine release, thus enhancing the displacement of [ 11 C]raclopride binding in vivo. However, pretreatment of rats with pargyline hydrochloride (4 mg/kg, n =4; 20 mg/kg, n = 4) 1 day prior to PET did not potentiate the amphetamine-evoked reduction in dopamine receptor availability within the extended striatum. We conclude that small animal PET can be used to investigate stimulantinduced dopamine release, but that the spatial resolution is insufficient to detect differences between relative changes in dorsal vs. ventral divisions of the rat striatum. Furthermore, the present results do not reveal potentiation of the amphetamine-evoked release of dopamine in rats with MAO inhibition.
A Comparative Evaluation of the Dopamine D2/3 Agonist Radiotracer 11C-N-Propyl-norapomorphine and Antagonist [11C]Raclopride to Measure Amphetamine-Induced Dopamine Release in the Human Striatum
Journal of Pharmacology and Experimental Therapeutics, 2010
Ϫ)-N-Propyl-norapomorphine (NPA) is a full dopamine D 2/3 receptor agonist, and [ 11 C]NPA is a suitable radiotracer to image D 2/3 receptors configured in a state of high affinity for agonists with positron emission tomography (PET). In this study, the vulnerability of the in vivo binding of [ 11 C]NPA to acute fluctuation in synaptic dopamine was assessed with PET in healthy humans and compared with that of the reference D 2/3 receptor antagonist radiotracer [ 11 C]raclopride. Ten subjects (eight females and two males) were studied on two separate days, a minimum of 1 week apart, both with [ 11 C]raclopride and [ 11 C]NPA at baseline and after the administration of 0.5 mg ⅐ kg Ϫ1 oral d-amphetamine. Kinetic modeling with an arterial input function was used to derive the binding potential relative to nonspecific uptake (BP ND ) in the ventral striatum (VST), cau-ABBREVIATIONS: PET, positron emission tomography; NPA, (Ϫ)-N-propyl-norapomorphine; PHNO, (ϩ)-4-propyl-3,4,4a,5,6,10b-hexahydro-2Hnaphtho[1,2-b][1,4]oxazin-9-ol; C L , plasma clearance; f P , plasma free fraction; VST, ventral striatum; CAD, caudate; PUT, putamen; STR, whole striatum; V ND , tissue distribution volume; BP P , binding potential relative to plasma concentration; BP ND , binding potential relative to nonspecific uptake; V T , distribution volume; RM ANOVA, repeated measures analysis of variance; DA, dopamine; f ND , nondisplaceable free fraction in the brain.
Synapse, 1996
Pharmacologically induced changes in synaptic levels of dopamine (DA) have been found, in some studies, to affect the in vivo binding of dopaminergic radioligands. In the present study we used a superfused brain slice preparation to examine the effect of synaptically released dopamine on the binding of some commonly used PET and SPECT radioligands under more controlled conditions than those present in vivo. The release of DA was evoked by electrical stimulation of striatal slices and the sensitivity of binding of the D, receptor ligand, [3H]SCH 23390, the Dz receptor ligands [3Hlraclopride and [lZ3I]epidepride, and the DA uptake transporter ligands, r3H]WIN 35,428 and [1231]RTI-55, to the frequency of stimulation examined. Most affected by stimulation was the specific binding of [3H]SCH 23390, which was fully inhibited at 2.5 Hz. This was followed by [3H]raclopride and [lZ3I]epidepride, respectively, the binding of the latter showing only a 50% reduction at the highest frequency of 10 Hz. [3H]WIN 35,428 and [1231]RTI-55 binding was unaffected by stimulation. The effects of stimulation on [3H]raclopride binding were prevented by reserpine pretreatment of the rat, when combined with inclusion of the dopamine synthesis inhibitor, a-methyl-p-tyrosine, in the superfusate medium. We conclude that, in brain slices, the binding of D, and D, receptor ligands but not that of DA uptake transporter ligands is readily inhibited by DA released into the synaptic cleft. Brain slices may prove to be a useful model system for the investigation of factors affecting competition between radioligand binding and endogenous neurotransmitters. 0 1996 Wiley-Liss, Inc.
Synapse, 1991
Competition by endogenous dopamine with the binding of D2 dopamine receptor ligands may be important in the interpretation of positron emission tomography (PET) neuroreceptor studies. PET studies with N-methylspiperone (NMSP) have revealed increased D, dopamine receptors in schizophrenia, whereas studies with raclopride (RAC) have not detected such differences. This may be due, at least in part, to differences in competition with endogenous dopamine for ligand binding. To determine effects of endogenous dopamine on in vivo receptor binding, adult male rats were preinjected with amphetamine and reserpine prior to 13H]NMSP or [3H]RAC. Striatal to cerebellar ratios of ligand binding were determined. To approximate the conditions of a PET study, a kinetic model was employed to examine effects of pharmacologically increasing brain dopamine levels (amphetamine pretreatment) on PET ligand binding. In these experiments, tail veins and arteries were cannulated and kinetic parameters determined from normalized integral plots in rats treated with amphetamine prior to radioligand injection. Both [3H]NMSP (43.5%) and [3H]RAC (41.5%) binding were significantly decreased after amphetamine pretreatment, whereas after reserpine pretreatment [3HlRAC binding was increased (52.7%). Kinetic studies revealed a marked resistance of C3]NMSP to competition with endogenous dopamine released by amphetamine. In contrast, kinetic parameters of I3H1RAC were markedly reduced at all time intervals. This suggests significant differences in competition with endogenous dopamine by I3H1NMSP and [3HIRAC, determined kinetically. These findings may have important implications for the interpretation of PET neuroreceptor studies.