Autoradiographic Characterization of a 2C -Adrenoceptors in the Human Striatum VERONICA FAGERHOLM, 1 * JOHANNA ROKKA, 1 LEENA NYMAN, 2 JUKKA SALLINEN, 2 JARI TIIHONEN, 3 ERKKI TUPALA, 3y MERJA HAAPARANTA, 1 AND JARMO HIETALA 4 1 Turku PET Centre, Turku, Finland 2 Orion Corporation, Orion Pharma, Turku, Finland 3 Departments of Forensic Psychiatry and Clinical Physiology, University of Kuopio, Kuopio, Finland 4 Department of Psychiatry, University of Turku, Turku, Finland KEY WORDS a2-adrenergic; brain; autoradiography; JP-1302; pharmacology; RS 79948-197 ABSTRACT Indirect experimental evidence suggests that drugs acting on the a 2C - adrenoceptor could be useful in the treatment of neuropsychiatric disorders such as depression and schizophrenia. In rodent brain, the highest levels of a 2C -adrenoceptors are found in the striatum, with lower levels in cerebral cortex and hippocampus. In human brain, because of the poor subtype-selectivity of the available a 2 -adrenoceptor ligands, the localization of a 2C -adrenoceptors has remained unknown. Recently, a selective a 2C -adrenoceptor antagonist, JP-1302, was characterized, and to assess the presence of a 2C -adrenoceptors in human brain, we performed competition binding in vitro receptor autoradiography with JP-1302 and the a 2 -adrenoceptor subtype nonse- lective antagonist [ethyl- 3 H]RS79948-197 on rat and human postmortem brain sec- tions. In striatum of both species, JP-1302 vs. [ethyl- 3 H]RS79948-197 competition binding was biphasic, identifying high- and low-affinity binding sites, whereas in cor- tex and cerebellum, only low-affinity binding sites were detected. The results indicate that a significant portion of the a 2 -adrenoceptors in striatum is of the a 2C subtype, whereas non-a 2C -adreocneptors predominate in cortex and cerebellum. Because the a 2C -adrenoceptor subtype distribution pattern appears to be conserved between rodents and humans, results obtained from studies on the role of the a 2C -adrenoceptor in rodent models of neuropsychiatric disorders may be relevant also for human dis- eases. Synapse 62:508–515, 2008. V V C 2008 Wiley-Liss, Inc. INTRODUCTION a 2 -Adrenoceptors in the central nervous system modulate a wide variety of physiological functions including arousal, attention, learning and memory, neuroendocrine secretion, and sympathetic outflow. a 2 -Adrenoceptors inhibit the release of noradrenaline and other neurotransmitters such as dopamine, sero- tonin, histamine, acetylcholine, and glutamate (Dalley and Stanford, 1995; Gulat-Marnay et al., 1989; Hill and Straw, 1988; Maura et al., 1982; Moroni et al., 1983; Pralong and Magistretti, 1995; Tellez et al., 1999; Yavich et al., 1997). Three a 2 -adrenoceptor sub- types are expressed in mammals, namely a 2A , a 2B , and a 2C . Pharmacological studies employing a 2 -adre- noceptor subtype-preferring ligands, and studies on a 2 -adrenoceptor subtype deficient mice, have identi- fied the a 2A -adrenoceptor as the chief mediator of a 2 - adrenoceptor auto- and heteroinhibition in brain (Hein, 2001; Philipp et al., 2002; Starke, 2001). The a 2A -adrenoceptor is widely expressed, with high re- ceptor densities in noradrenergic nuclei and in the noradrenergic projection regions, in line with its auto- inhibitory function (MacDonald et al., 1997). In rodents, the highest levels of a 2B -adrenoceptor mRNA have been detected in the thalamus and cerebellum (Schambra et al., 2005; Scheinin et al., 1994; Tavares et al., 1996; Wang et al., 2002; Winzer-Serhan and Leslie, 1997), but a 2B -adrenoceptor protein localiza- tion maps have not been published so far, and the physiological functions of central a 2B -adrenoceptors have remained largely unknown. The highest den- sities of a 2C -adrenoceptors in rodents are found in the striatum and the olfactory tubercles, with lower levels y Deceased. *Correspondence to: Veronica Fagerholm, Turku PET Centre, MediCity Research Laboratory, Tykisto ¨katu 6A, FI-20520 Turku, Finland. E-mail: veronica.fagerholm@abo.fi Received 1 June 2007; Revised 30 December 2007; Accepted 8 January 2008 DOI 10.1002/syn.20520 Published online in Wiley InterScience (www.interscience.wiley.com). V V C 2008 WILEY-LISS, INC. SYNAPSE 62:508–515 (2008)