Out of Context: NMDA Receptor Antagonism in the Avian “Prefrontal Cortex” Impairs Context Processing in a Conditional Discrimination Task Silke Lissek and Onur Gu ¨ntu ¨rku ¨n Ruhr-Universita ¨t Bochum Processing of context information is implicated in prefrontal functions as response selection or attention. N-methyl-D-aspartate (NMDA) receptors in the mammalian prefrontal cortex (PFC) and in the nidopal- lium caudolaterale (NCL) of birds, the avian functional equivalent of the PFC, are involved in learning, which also requires processing of context. The authors investigated the role of NMDA receptors in the pigeon (Columba livia) NCL for context processing and response selection in a simultaneous-matching- to-sample task with 2 trial types, requiring either processing of context information, delivered by a conditional stimulus (context dependent), or only recall of a stimulus–response association (fixed response). The competitive NMDA antagonist DL-2-amino-5-phosphonovaleric acid impaired perfor- mance only in context-dependent trials. Therefore, NMDA receptors in the avian PFC participate in response selection requiring context processing rather than in response selection per se. Keywords: NMDA receptor, context processing, avian, prefrontal, DL-AP5 A primary function of the prefrontal cortex (PFC) is integration of information from the external environment and internal states of the organism to initiate appropriate behavior in a given situation. Integration of information requires processing of the context de- livered by the actual situation, whereas initiation of appropriate behavior requires response selection. The function context pro- cessing therefore refers to the ability to actively hold relevant context information in mind in such a form that it can be used to mediate task-appropriate behavior (Cohen, Barch, Carter, & Servan-Schreiber, 1999). The function response selection refers to choosing an adequate response from two or more available alter- natives. There is evidence that the PFC is implicated in both functions. Deficits in PFC-related tasks exhibited by patients with schizo- phrenia or frontal lesions as well as by healthy older adults demonstrate a causal link between PFC hypofunction and impair- ments in context processing (Barch et al., 2001; Barch, Carter, MacDonald, Braver, & Cohen, 2003; Braver et al., 2001; Cohen et al., 1999; Kerns & Berenbaum, 2003; Metzler, 2001). Lesion studies in rats (Morgan & LeDoux, 1999) and single cell record- ings in monkeys (Watanabe, Hikosaka, Sakagami, & Shirakawa, 2002) also demonstrate the participation of the lateral PFC in integration of contextual information. Consequently, a model of PFC function (Cohen & Servan-Schreiber, 1992; Servan- Schreiber, Cohen, & Steingard, 1996) proposes a comprehensive context-processing function located in the PFC that is supposed to subserve various prefrontal functions that are usually treated and investigated independently, such as active memory, attention, and response inhibition. In many instances, the choice of an adequate behavioral re- sponse, that is, response selection, requires processing of relevant contextual information—for example, in a conditional discrimina- tion (Winocur & Eskes, 1998). Therefore, conditional discrimina- tion tasks are a useful behavioral paradigm for the investigation of context processing. In other instances, however, context informa- tion is negligible for response selection—for example, in unam- biguous stimulus–response associations that always require the same response to the same stimulus (Delatour & Gisquet-Verrier, 1996). Ventrolateral PFC lesions in rats and monkeys also cause def- icits in response selection, in particular during conditional asso- ciative learning (Bussey, Wise, & Murray, 2001; Petrides, 1982, 1987; Winocur & Eskes, 1998); thus, the ventral PFC is considered essential for conditional associative learning and response selec- tion, as information about stimulus, response, and response out- come is available only in this region (Passingham, Toni, & Rush- worth, 2000). N-methyl-D-aspartate (NMDA) receptors in prefrontal regions participate in reversal and extinction learning in rats (Bohn, Giertler, & Hauber, 2003) and pigeons (Lissek, Diekamp, & Gu ¨n- tu ¨rku ¨n, 2002; Lissek & Gu ¨ntu ¨rku ¨n, 2003), situations in which relevant external context must be considered to alter existing stimulus–response associations. These results hint at prefrontal NMDA receptor involvement in context processing during learn- ing. However, because NMDA receptor blockade in various brain regions does not impair performance of previously learned tasks Silke Lissek and Onur Gu ¨ntu ¨rku ¨n, Institute for Cognitive Neuroscience, Department of Biopsychology, Faculty of Psychology, Ruhr-Universita ¨t Bochum, Bochum, Germany. This work was supported by Deutsche Forschungsgemeinschaft Grant Gu 227/5. The methods used in this experiment comply with American Psychological Association ethical standards and the specifications of the German law for the prevention of cruelty to animals. We thank Dr. Jens-Uwe Buschmann for developing and providing the Skinner box con- trolling software Operant Learning Conditioning Unit System (Version 1.2.01, Frank Buschmann International, Bochum, Germany). Correspondence concerning this article should be addressed to Silke Lissek, Institute for Cognitive Neuroscience, Department of Biopsychol- ogy, Faculty of Psychology, Ruhr-Universita ¨t Bochum, Universita ¨tsstrasse 150, Bochum 44801, Germany. E-mail: silke.lissek@ruhr-uni-bochum.de Behavioral Neuroscience Copyright 2005 by the American Psychological Association 2005, Vol. 119, No. 3, 797– 805 0735-7044/05/$12.00 DOI: 10.1037/0735-7044.119.3.797 797