 2C -Adrenoceptor-Overexpressing Mice Are Impaired in Executing Nonspatial and Spatial Escape Strategies MARKUS BJ ¨ ORKLUND, JOUNI SIRVI ¨ O, JUKKA PUOLIV ¨ ALI, JUKKA SALLINEN, PEKKA J ¨ AK ¨ AL ¨ A, MIKA SCHEININ, BRIAN K. KOBILKA, and PAAVO RIEKKINEN, JR. Department of Neurology and Neuroscience, University of Kuopio, Kuopio, FIN-70211, Finland (M.B., J.P., P.J., P.R.), A. I. Virtanen Institute, FIN-70211 Kuopio, Finland (J. Si.), Department of Pharmacology and Clinical Pharmacology, University of Turku, FIN-20520 Turku, Finland (J. Sa., M.S.), Kuopio University Hospital, FIN-70211 Kuopio, Finland (P.J., P.R.), and Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute and Division of Cardiovascular Medicine, Stanford University, Stanford, California 94305 (R.K.K.) Received October 13, 1997; Accepted May 27, 1998 This paper is available online at http://www.molpharm.org ABSTRACT Drugs acting via  2 -adrenoceptors modulate cognitive func- tions mediated via frontostriatothalamic feedback loops. The  2C -adrenoceptor subtype is expressed in the basal ganglia, hippocampus, and neocortex, areas that are involved in mem- ory and other cognitive functions.  2C -Overexpressing (OE) mice were impaired in spatial or nonspatial water maze (WM) tests, and  2 antagonist treatment fully reversed the WM es- cape defect in OE mice. However,  2C -overexpression did not influence open field and passive avoidance behaviors or corti- cal EEG arousal or the actions of  2 agonist or antagonist drugs on these functions. Our results suggest that  2C -adrenoceptors can modulate navigation to a hidden or visible escape platform, whereas many other actions of  2 -adrenergic agents, such as sedation, are not mediated via  2C -adrenoceptors. Therefore,  2 -agonists lacking  2C -AR affinity or  2C -AR subtype-selec- tive  2 antagonists could modulate functioning of frontostria- tothalamic feedback loops more effectively than the current subtype-nonselective drugs. LC norepinephrine neurons send noradrenergic fibers into different forebrain structures (Fillenz, 1990) and modulate different cognitive functions, such as arousal, attention, and planning (Crow, 1968; Kety, 1970; Arnsten and Goldman- Rakic, 1985; Arnsten and Leslie, 1991; Riekkinen et al., 1992; Sahakian et al., 1994; Arnsten et al., 1996; Coull et al., 1996). Because ARs are located both presynaptically and postsyn- aptically, it is not surprising that pharmacological studies have found that noradrenergic  2 -AR agonists and antago- nists can affect many behaviors mediated by different neural systems.  2 -ARs are divided into three different subtypes, termed  2A -,  2B -, and  2C -ARs (Kobilka et al., 1987; Regan et al., 1988; Lomasney et al., 1990; Link et al., 1992), and all these subtypes have distinct anatomic distributions in brain areas involved in separate functional systems (Nicholas et al., 1993, 1996; Aoki et al., 1994; Scheinin et al., 1994; Mac- Donald and Scheinin, 1995; Rosin et al., 1996; Talley et al., 1996).  2A -ARs are located in the LC, elsewhere in the brain- stem, and throughout the cerebral cortex and many deeper forebrain structures;  2B -ARs are found nearly exclusively in the thalamic nuclei; and  2C -ARs are located in the hip- pocampus, cerebral cortex, and striatum. Importantly, in the caudate and accumbens nuclei,  2C -ARs predominate, sug- gesting that this receptor subtype may mediate effects of  2 agonists and antagonists on modulation of cognitive func- tions via frontostriatothalamic feedback loops. The behavioral functions of different subtypes of  2 -ARs have been difficult to study because there are no ligands that selectively activate or block only one of the three subtypes. Therefore, to study the role of different  2 -ARs in behavioral functions and to better evaluate the potential for cognition- enhancement by subtype-selective  2 -AR active drugs, we have started to investigate the effects of overexpression and knockout of  2 -AR subtype genes on different behaviors in mice and how these manipulations affect reactions to sub- type-nonselective  2 -AR agonists and antagonists (Mac- Donald et al., 1997). Sallinen et al. (1997) found that spon- taneous locomotor activity and the effects of an  2 -agonist or -antagonist on brain monoamine turnover and on motor ac- tivity were not influenced by altered  2C -AR expression. However, mice with tissue-specific overexpression of  2C -AR were slightly more sensitive and KO mice were less sensitive to the hypothermic effects of the agonist DEX than their controls. The OE mice have 3-fold elevated densities of  2C -AR in regions that normally express this subtype (the This study was supported by Academy of Finland, Orion Corporation Farmos, R & D Pharmaceuticals (Turku, Finland), Research and Science Foundation of Farmos, and The Finnish Medical Foundation. ABBREVIATIONS: AR, adrenoceptor; ATI, atipamezole; CKO, wild-type control mice for  2C -knockout mice; DEX, dexmedetomidine; EEG, electroencephalogram; KO,  2C -knockout; LC, locus ceruleus; OE,  2C -overexpressing; OF, open field; PA, passive avoidance; WM; water maze; WT, wild-type control mice for  2C -overexpressing mice 0026-895X/98/030569-08$3.00/0 Copyright © by The American Society for Pharmacology and Experimental Therapeutics All rights of reproduction in any form reserved. MOLECULAR PHARMACOLOGY, 54:569 –576 (1998). 569 at ASPET Journals on July 22, 2018 molpharm.aspetjournals.org Downloaded from