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We have previously shown that impulsivity in rats is linked to decreased dopamine D2/3receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D2/3receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D2/3ligand [18F]fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [18F]fallypride PET scan. Before MPH treatment, we found that D2/3receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D2/3receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D2/3receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D2/3receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D2/3receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D2/3receptor availability through independent mechanisms.

Five different methods for the estimation of the binding potential, a measure of Bmax/Kd, of [11C]raclopride in human striatum were compared using data from a dose ranging study of the neuroleptic CP-88,059-01. Binding potential was estimated indirectly, from distribution volumes in striatum and cerebellum, using both single- and two-tissue compartment models with a metabolite-corrected plasma curve as input function. The two-tissue compartment model was also used for a direct estimate of the binding potential. In addition, a direct estimate was obtained from the reference tissue compartment model using the cerebellum as indirect input function. Finally, an estimate of binding potential was calculated from the ratio of striatum over cerebellum counts at late times after injection. The estimates of striatum binding potential from all methods, except the direct determination using a two-tissue compartment model with metabolite-corrected plasma input function, correlated with each other. Use of an average metabolite correction resulted in only a small reduction in accuracy in this series of normal subjects. The reference tissue model provided estimates of the binding potential with the same sensitivity for detecting changes as those methods that required a metabolite-corrected plasma input function. This indicates that for routine analysis of clinical [11C]raclopride studies, no arterial cannulation is required. The range of normal values was significantly less variable with the reference tissue method than when simple striatum-to-cerebellum ratios were used.

Intrastriatal injection of botulinum neurotoxin A (BoNT-A) results in improved motor behavior of hemiparkinsonian (hemi-PD) rats, an animal model for Parkinson’s disease. The caudate–putamen (CPu), as the main input nucleus of the basal ganglia loop, is fundamentally involved in motor function and directly interacts with the dopaminergic system. To determine receptor-mediated explanations for the BoNT-A effect, we analyzed the dopamine D2/D3 receptor (D2/D3R) in the CPu of 6-hydroxydopamine (6-OHDA)-induced hemi-PD rats by [18F]fallypride-PET/CT scans one, three, and six months post-BoNT-A or -sham-BoNT-A injection. Male Wistar rats were assigned to three different groups: controls, sham-injected hemi-PD rats, and BoNT-A-injected hemi-PD rats. Disease-specific motor impairment was verified by apomorphine and amphetamine rotation testing. Animal-specific magnetic resonance imaging was performed for co-registration and anatomical reference. PET quantification was achieved using PMOD software with the simplified reference tissue model 2. Hemi-PD rats exhibited a constant increase of 23% in D2/D3R availability in the CPu, which was almost normalized by intrastriatal application of BoNT-A. Importantly, the BoNT-A effect on striatal D2/D3R significantly correlated with behavioral results in the apomorphine rotation test. Our results suggest a therapeutic effect of BoNT-A on the impaired motor behavior of hemi-PD rats by reducing interhemispheric changes of striatal D2/D3R.

Introduction The development of clinically useful tracers for PET imaging is enormously challenging and expensive. The intranasal (IN) route of administration is purported to be a viable route for delivering drugs to the brain but has, as yet, not been investigated for the delivery of PET tracers. If the intranasal (IN) pathway presents a viable option, it extends the PET imaging field by increasing the number of tracers available for human use. Here we report the results of a rodent study testing the feasibility of the IN route to administer radiotracers for brain PET imaging. Methods We used two different, well characterised, brain penetrant radiotracers, [ 18 F]fluorodeoxyglucose ([ 18 F]FDG) and [ 18 F]fallypride, and aimed to evaluate the pharmacokinetics after administration of the tracers via the intranasal route, and contrast this to intravenous administration. Image acquisition was carried out after tracer administration and arterial blood samples were collected at different time intervals, centrifuged to extract plasma and gamma counted. We hypothesised that [brain region]:[plasma] ratios would be higher via the intranasal route as there are two inputs, one directly from the nose to the brain, and another from the peripheral circulation. To assess the feasibility of using this approach clinically, we used these data to estimate radiation dosimetry in humans. Results Contrary to our hypothesis, in case of both radiotracers, we did not see a higher ratio in the expected brain regions, except in the olfactory bulb, that is closest to the nose. It appears that the radiotracers move into the olfactory bulb region, but then do not progress further into other brain regions. Moreover, as the nasal cavity has a small surface area, the extrapolated dosimetry estimations for intranasal human imaging showed an unacceptably high level (15 mSv/MBq) of cumulative skin radiation exposure. Conclusions Therefore, although an attractive route for brain permeation, we conclude that the intranasal route would present difficulties due to non-specific signal and radiation dosimetry considerations for brain PET imaging.