Trait or state?
Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon, United StatesScience (Impact Factor: 33.61). 09/2007; 317(5841):1033-5; author reply 1033-5. DOI: 10.1126/science.317.5841.1033
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ABSTRACT: Drug addiction is a chronically relapsing brain disorder, which causes substantial harm to the addicted individual and society as a whole. Despite considerable research we still do not understand why some people appear particularly disposed to drug abuse and addiction, nor do we understand how frequently co-morbid brain disorders such as depression and attention-deficit hyperactivity disorder (ADHD) contribute causally to the emergence of addiction-like behaviour. In recent years positron emission tomography (PET) has come of age as a translational neuroimaging technique in the study of drug addiction, ADHD and other psychopathological states in humans. PET provides unparalleled quantitative assessment of the spatial distribution of radiolabelled molecules in the brain and because it is non-invasive permits longitudinal assessment of physiological parameters such as binding potential in the same subject over extended periods of time. However, whilst there are a burgeoning number of human PET experiments in ADHD and drug addiction there is presently a paucity of PET imaging studies in animals despite enormous advances in our understanding of the neurobiology of these disorders based on sophisticated animal models. This article highlights recent examples of successful cross-species convergence of findings from PET studies in the context of drug addiction and ADHD and identifies how small animal PET can more effectively be used to model complex psychiatric disorders involving at their core impaired behavioural self-control.
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ABSTRACT: [(18)F]Fallypride PET studies can be used to estimate the nondisplaceable binding potential (BP(ND)) in vivo of dopamine D2/D3 receptor-rich regions of the brain. These studies often take considerable time, up to >or=2 h, limiting the throughput. In this work, we investigated whether limited-duration scans performed subsequent to tracer administration yielded stable BP(ND) estimates. In particular, we applied a modified version of the Logan plot method on the last 60 min of 120-min data and compared the results to those from analysis of the full data set. Fourteen male Sprague-Dawley rats were injected with [(18)F]fallypride intravenously while under isoflurane anesthesia, and dynamic data were acquired on the microPET Focus 220 scanner for 120 min. The distribution volume ratio (DVR=BP(ND)+1) was calculated from a Logan plot using 120 min of data and from a modified version using only the last 60 min. Three of these rats were imaged again on a second day to test the reproducibility. A two-tissue compartment model also was used to fit the time-activity curves (TACs) of the 120-min scans to estimate the parameters K(1), k(2), k(on), k(4) and B(max). These parameters were then used to simulate similar TACs while changing k(on) to reflect changes in the dopaminergic system. The simulated TACs were used as a means for exploring the differences in DVR estimates between the last 60 min only and the full 120 min of simulated data. The average DVR from the full 120-min scans was 13.8+/-0.9, whereas the average DVR estimated from only the last 60 min of data (DVR') was 16.3+/-1.0. The DVR estimates showed good reproducibility in the three rats (mean DVR=13.8+/-1.5 on Day 1 and DVR=13.8+/-0.9 on Day 2). The simulations showed that the relationship between DVR' and DVR estimates follows a semilinear form with varying k(on). Although the BP(ND) estimates are slightly overestimated in a delayed scan mode (i.e., no initial radiotracer uptake measurements) compared to a full scan, this overestimation depends primarily on k(3) (approximately k(on) x B(max)) and has been evaluated in this work for a wide range of k(on) values using simulated TACs. In particular, the sensitivity of DVR' to changes in k(on) is similar to that of DVR. This method of delayed scans eliminates the necessity of imaging during the initial uptake of the radiotracer and, thus, can be used to increase the throughput of studies.
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ABSTRACT: In the previous work, we reported a method that utilized imaging data collected from 60 to 120 min following [(18) F]fallypride administration to estimate the distribution volume ratio DVR' (DVR' ∝ DVR; DVR = 1 + BP(ND) , where BP(ND) is a measure of receptor density, DA D2 in this case). In this work, we use this method to assess the effects of isoflurane anesthesia on [(18) F]fallypride DVR'. Rats were injected with [(18) F]fallypride either unconsciously under ∼1.5% isoflurane via the tail vein (Group 1) or consciously via a catheter inserted either in the jugular vein (Group 2) or the tail vein (Group 3). After about 1 h of free access to food and water the rats were anesthetized with 1.5% isoflurane and imaged in a microPET for 60 min. The rats that were injected consciously (Groups 2 and 3) were placed in a rat restrainer during [(18) F]fallypride injection. They were habituated in that restrainer for 3 days prior to the experiment day to minimize restraint-related stress. For comparison, a control group of rats was imaged for 120 min simultaneously with the administration of [(18) F]fallypride i.v. while under 1.5% isoflurane. The DVR' estimates from the 60 min acquisitions were compared with the DVR' from the last 60 min of the 120 min acquisitions (after neglecting the first 60 min). In addition, the striatal time-activity curves were fit with a 2-tissue + plasma compartment model using an arbitrary simulated plasma input function to obtain k(3) /k(4) (≈ BP(ND) ) for the 60 and 120 min acquisitions. Isoflurane anesthesia caused a significant reduction, up to 22%, in the DVR' estimates, which were 15.7 ± 0.3 (mean ± SE) for the controls, 17.7 ± 0.3 for Group 1, 19.2 ± 0.4 for Group 2, and 18.8 ± 0.7 for Group 3. The compartmental model fit produced similar results, ∼30% reduction in k(3) /k(4) for the 120-min acquisitions compared with the 60-min acquisitions (initial conscious uptake of the radiotracer). The results of this study demonstrate that isoflurane anesthesia significantly decreases striatal [(18) F]fallypride BP(ND) in rats. Of similar importance, this work demonstrates the effectiveness of delayed scans following radiotracer injection and the implication that different types of studies can be conducted simultaneously with this method, including studies of behavioral and environmental impact on brain receptors.
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