Distribution of norepinephrine transporters in the non-human primate brain

Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Neuroscience (Impact Factor: 3.36). 02/2006; 138(2):703-14. DOI: 10.1016/j.neuroscience.2005.11.033
Source: PubMed


Noradrenergic terminals in the central nervous system are widespread; as such this system plays a role in varying functions such as stress responses, sympathetic regulation, attention, and memory processing, and its dysregulation has been linked to several pathologies. In particular, the norepinephrine transporter is a target in the brain of many therapeutic and abused drugs. We used the selective ligand [(3)H]nisoxetine, therefore, to describe autoradiographically the normal regional distribution of the norepinephrine transporter in the non-human primate central nervous system, thereby providing a baseline to which alterations due to pathological conditions can be compared. The norepinephrine transporter in the monkey brain was distributed heterogeneously, with highest levels occurring in the locus coeruleus complex and raphe nuclei, and moderate binding density in the hypothalamus, midline thalamic nuclei, bed nucleus of the stria terminalis, central nucleus of the amygdala, and brainstem nuclei such as the dorsal motor nucleus of the vagus and nucleus of the solitary tract. Low levels of binding to the norepinephrine transporter were measured in basolateral amygdala and cortical, hippocampal, and striatal regions. The distribution of the norepinephrine transporter in the non-human primate brain was comparable overall to that described in other species, however disparities exist between the rodent and the monkey in brain regions that play a role in such critical processes as memory and learning. The differences in such areas point to the possibility of important functional differences in noradrenergic information processing across species, and suggest the use of caution in applying findings made in the rodent to the human condition.

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Available from: Thomas J R Beveridge, Aug 20, 2014
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    • "Furthermore, the connectivity patterns of the prefrontal cortex as well as other brain regions of nonhuman primates are highly homologous to those of humans (Ongur et al., 2003). Other advantages of nonhuman primates include similarities in the anatomy and physiology of dopaminergic (Gonzalez-Hernandez et al., 2004; Sanchez-Gonzalez et al., 2005) and noradrenergic systems (Smith et al., 2006), as well as the hypothalamic–pituitary– adrenal axis (e.g. Morgan et al., 2000). "

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    • "One of the major prerequisites on these candidate tracers is their affinity towards NET, especially when considering the very low density of NET in cerebellum, striatum and human insular cortex [3] [4] [5] [6] [7] [8]. Visualization of NET-rich regions like LC, where NET density is 4–8-fold higher, can be also achieved using ligands with slightly lower affinity [4] [7] [9]. Besides, affinity of the candidate ligands correlates with their binding kinetics, i.e. longer equilibration times for high-affinity substances (e.g. "
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    ABSTRACT: In neurodegenerative diseases and neuropsychiatric disorders dysregulation of the norepinephrine transporter (NET) has been reported. For visualization of NET availability and occupancy in the human brain PET imaging can be used. Therefore, selective NET-PET tracers with high affinity are required. Amongst these, [(18)F]FMeNER-D2 is showing the best results so far. Furthermore, a reliable fully automated radiosynthesis is a prerequisite for successful application of PET-tracers. The aim of this work was the automation of [(18)F]FMeNER-D2 radiolabelling for subsequent clinical use. The presented study comprises 25 automated large-scale syntheses, which were directly applied to healthy volunteers and adult patients suffering from attention deficit hyperactivity disorder (ADHD). Procedures: Synthesis of [(18)F]FMeNER-D2 was automated within a Nuclear Interface Module. Starting from 20-30GBq [(18)F]fluoride, azeotropic drying, reaction with Br2CD2, distillation of 1-bromo-2-[(18)F]fluoromethane-D2 ([(18)F]BFM) and reaction of the pure [(18)F]BFM with unprotected precursor NER were optimized and completely automated. HPLC purification and SPE procedure were completed, formulation and sterile filtration were achieved on-line and full quality control was performed. Purified product was obtained in a fully automated synthesis in clinical scale allowing maximum radiation safety and routine production under GMP-like manner. So far, more than 25 fully automated syntheses were successfully performed, yielding 1.0-2.5GBq of formulated [(18)F]FMeNER-D2 with specific activities between 430 and 1707GBq/μmol within 95min total preparation time. A first fully automated [(18)F]FMeNER-D2 synthesis was established, allowing routine production of this NET-PET tracer under maximum radiation safety and standardization.
    Nuclear Medicine and Biology 10/2013; 40(8). DOI:10.1016/j.nucmedbio.2013.08.007 · 2.41 Impact Factor
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    • "More importantly, the distribution of corticotropinreleasing-factor (CRF) reactivity and that of corticoid receptors in the brain show great discrepancies in the amygdala (Bassett & Foote, 1992; Sanchez et al., 1999), hippocampus and pre-frontal cortex (PFC; Sanchez et al., 2000). The discrepancies in the amygdala and hippocampus are similar to the differences in the distribution of norepinephrine in those regions (Smith et al., 2006). These structures are important for learning and memory (McGaugh 2002; Tomaz et al., 1992) which, in turn, are also implicated in addictive behaviors (Garavan et al., 2000; Kilts et al., 2001; O'Brien et al., 1998). "

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