DISTRIBUTION OF NOREPINEPHRINE TRANSPORTERS IN THE NON-HUMAN PRIMATE BRAIN H. R. SMITH, T. J. R. BEVERIDGE AND L. J. PORRINO* Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA Abstract—Noradrenergic terminals in the central nervous sys- tem 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 norepi- nephrine 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 com- pared. The norepinephrine transporter in the monkey brain was distributed heterogeneously, with highest levels occur- ring in the locus coeruleus complex and raphe nuclei, and moderate binding density in the hypothalamus, midline tha- lamic nuclei, bed nucleus of the stria terminalis, central nu- cleus 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, hip- pocampal, and striatal regions. The distribution of the nor- epinephrine transporter in the non-human primate brain was comparable overall to that described in other species, how- ever 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 norad- renergic information processing across species, and suggest the use of caution in applying findings made in the rodent to the human condition. © 2005 Published by Elsevier Ltd on behalf of IBRO. Key words: norepinephrine transporter, [ 3 H]nisoxetine, rhe- sus monkey, autoradiography. Studies of the central noradrenergic system have demon- strated its broad involvement in widely varying functions such as responses to stress and sympathetic regulation, as well as higher cognitive processing such as attention and memory retrieval. In addition it has been shown that dysregulation of this system may in part underlie such pathological states as depression and anxiety, and studies have demonstrated an emerging role for the norepineph- rine (NE) system in the pathogenesis of drug addiction and withdrawal (Farfel et al., 1992; Harris and Aston-Jones, 1993; McDougle et al., 1994; Aston-Jones et al., 1999; Delfs et al., 2000; Macey et al., 2003; Mash et al., 2005). The norepinephrine transporter (NET) is a member of the Na + /Cl - -dependent neurotransmitter transporter gene family, and is critical for limiting extracellular NE concen- trations. The NET is a molecular target site of many current anti-depressant and anti-anxiety therapies (Zhu and Ordway, 1997; Zavosh et al., 1999; Owens et al., 2000; Rubin, 2000; Roubert et al., 2001; Weinshenker et al., 2002; Richelson, 2003), as well as the abused stimulants cocaine and amphetamine (Koe, 1976; Heikkila et al., 1979; Reith et al., 1983; Ritz et al., 1990; Florin et al., 1994; Pifl et al., 1999; Haughey et al., 2000). In addition, genetic studies in hu- man populations have linked specific polymorphisms of the NET gene to such pathologies as depression and anorexia nervosa (Urwin et al., 2002; Inoue et al., 2004; Ryu et al., 2004) and to sensitivity to pharmacotherapies targeted to the monoamine transporters (Tellioglu and Robertson, 2001; Yoshida et al., 2004). Consequently, the NET has been the focus of countless molecular studies which have described in detail its structural and functional character- istics (for reviews see Blakely et al., 1994; Olivier et al., 2000; Norregaard and Gether, 2001; Gainetdinov and Ca- ron, 2003; Glatt and Reus, 2003; Torres et al., 2003). Despite the diverse functions of the NE system in both normal and pathological processes, the widespread clini- cal use of NET blockers to treat mood-related disorders, and recent interest in the development of NET ligands for positron emission tomography imaging (Ding et al., 2003; Schou et al., 2004), our understanding of the normal dis- tribution of the primate NET remains far from complete. Numerous anatomical studies have described the brain- stem noradrenergic cell groups and their projection fields in rodents (Loughlin et al., 1982; McKellar and Loewy, 1982; Foote et al., 1983; Loughlin et al., 1986a,b; Woulfe et al., 1988, 1990; Grzanna and Fritschy, 1991; Terenzi and In- gram, 1995) and monkeys (Gatter and Powell, 1977; Bowden et al., 1978; Felten and Sladek, 1983). In addition the distri- bution of the NET protein has been depicted autoradio- graphically in rodents (Biegon and Rainbow, 1983; Javitch et al., 1985; Tejani-Butt, 1992; Schroeter et al., 2000; Kung et al., 2004; Ghose et al., 2005; Sanders et al., 2005), cats (Charnay et al., 1995), and humans (Gross-Isseroff et al., 1988; Donnan et al., 1991; Tejani-Butt et al., 1993; Ordway et al., 1997), however prior to the characterization by Tejani-Butt (1992) of [ 3 H]nisoxetine as a selective ligand for autoradiographic description of the NET, such studies utilized relatively non-selective ligands such as [ 3 H]mazin- dol and [ 3 H]desmethylimipramine. The reports by Ordway *Corresponding author. Tel: +1-336-716-8575; fax: +1-336-716-8689. E-mail address: lporrino@wfubmc.edu (L. J. Porrino). Abbreviations: BNST, bed nucleus of the stria terminalis; DR, dorsal raphe; LC, locus coeruleus; NAcc, nucleus accumbens; NE, norepi- nephrine; NET, norepinephrine transporter. Neuroscience 138 (2006) 703–714 0306-4522/06$30.00+0.00 © 2005 Published by Elsevier Ltd on behalf of IBRO. doi:10.1016/j.neuroscience.2005.11.033 703