While searching for a PET method to determine the density and occupancy of the dopamine D(3) receptor, we found evidence that suggested that the dopamine D(3) antagonist GR218231 could be a substrate ...of the P-glycoprotein efflux pump. P-glycoprotein protects the brain against toxic substances and xenobiotics, but it also hampers the delivery of various drugs into the brain. In this study, we aimed to explore whether radiolabeled GR218231 could be applied as a PET tracer for monitoring P-glycoprotein activity in the blood-brain barrier. Such an imaging technique could be useful for the development of new drugs and novel strategies to deliver drugs to the brain and for identification of undesirable drug-drug interactions.
As a potential PET tracer, GR218231 was labeled with (11)C by reaction of the newly synthesized desmethyl precursor with (11)C-methyl triflate. The biodistribution of (11)C-GR218231 was determined in rats. To assess specific binding to the dopamine D(3) receptor, blocking experiments with unlabeled GR218231 (0.2 and 2.5 mg/kg) were performed. To demonstrate the influence of P-glycoprotein on cerebral uptake of (11)C-GR218231, the efflux pump was modulated with 50 mg/kg cyclosporine A. The sensitivity of (11)C-GR218231 for P-glycoprotein modulation was assessed in dose-response studies, using escalating cyclosporine A dosages.
(11)C-GR218231 was prepared in 53% +/- 8% decay-corrected radiochemical yield and had a specific activity of 15 +/- 10 GBq/micromol (mean +/- SD). Biodistribution studies in rats revealed a low and homogeneous uptake in the brain. Pretreatment of the animals with unlabeled GR218231 did not demonstrate any specific binding. Modulation of P-glycoprotein with cyclosporine A caused a 12-fold higher (11)C-GR218231 uptake in the brain, indicating that the low cerebral tracer uptake was caused by the P-glycoprotein efflux pump in the blood-brain barrier. Cyclosporine A dose-escalation studies showed a dose-dependent sigmoidal increase in (11)C-GR218231 uptake in brain and spleen (median effective dose ED(50), 23.3 +/- 0.6 and 38.4 +/- 2.4 mg/kg, respectively), whereas a dose-dependent decrease was observed in the pancreas (ED(50), 36.0 +/- 4.4 mg/kg).
Although (11)C-GR218231 is unsuited for dopamine D(3) receptor imaging with PET, it appears to be an attractive PET tracer for visualization and quantification of P-glycoprotein activity in the blood-brain barrier.
Pleasure is fundamental to well-being and the quality of life, but until recently, was barely explored by science. Current research on pleasure has brought about ground-breaking developments on ...several fronts, and new data on pleasure and the brain have begun to converge from many disparate fields. The time is ripe to present these important findings in a single volume, and so Morten Kringelbach and Kent Berridge have brought together the leading researchers to provides a comprehensive review of our current scientific understanding of pleasure. The authors present their latest neuroscientific research into pleasure, describing studies on the brain’s role in pleasure and reward in animals and humans, including brain mechanisms, neuroimaging data, and psychological analyses, as well as how their findings have been applied to clinical problems, such as depression and other disorders of hedonic well-being. To clarify the differences between their views, the researchers also provide short answers to a set of fundamental questions about pleasure and its relation to the brain. This book is intended to serve as both a starting point for readers new to the field, and as a reference for more experienced graduate students and scientists from fields such as neuroscience, psychology, psychiatry, neurology, and neurosurgery.
Hippocampal theta activity is a large amplitude, sinusoidal wave that occurs during attentive immobility and exploratory behaviour in the rat, and it is thought to be involved in memory formation. ...Recent reports suggest that corticotropin-releasing hormone (CRH) has pro-mnemonic effects in rodents. Because memory-enhancing substances/manipulations generally alter either theta frequencies or amplitudes, these variables were monitored in urethane-anaesthetised rats following intra-hippocampal infusions of CRH. Adult male, Lister hooded rats were implanted with a hippocampal recording electrode and a guide cannula, both aimed at the dentate gyrus. When CRH was infused into the hippocampus, the main change in the hippocampal EEG was a slow onset increase in the amplitude of spontaneous theta and, paradoxically, a significant decrease in the amount of time spent displaying theta. These data suggest that CRH has the ability to modulate ongoing hippocampal theta, but, considering the slow effect, the involvement of hippocampal CRH receptors is suspect. Regardless of locus, the described electrophysiological changes suggest that hippocampal cholinergic systems may play a role in the memory-enhancing effects of CRH.
Every organism that is alive today is a direct descendant of one or two ancestors: one in the case of asexual reproduction and two in the case of sexual reproduction. This self-evident truth tells us ...two things about those ancestors: (i) they reached sexual maturity in a su0ciently healthy state and (ii) they actually replicated. These two achievements, individual survival and species survival, are essential for the continuity of life and, as a result, any trait that increases the ability to execute them is favored by natural selection. It is tempting to call these achievements the goals of life, but apparent goals is a safer term to use.
