DOPAMINERGIC MODULATION OF RAPID REALITY ADAPTATION IN THINKING A. SCHNIDER,* A. GUGGISBERG, L. NAHUM, D. GABRIEL AND S. MORAND 1 Laboratory of Cognitive Neurorehabilitation, Division of Neurorehabili- tation, Department of Clinical Neurosciences, University Hospitals and University of Geneva, Av. de Beau-Séjour 26, CH-1211 Geneva 14, Switzerland Abstract—Dopamine has long held a prominent role in the interpretation of schizophrenia and other psychoses. Clinical studies on confabulation and disorientation, disorders marked by a confusion of reality in thinking, indicated that the ability to keep thinking in phase with reality depends on a process suppressing the interference of upcoming memo- ries that do not refer to ongoing reality. A host of animal studies and a recent clinical study suggested that this sup- pression might correspond to the phasic inhibition of dopa- minergic neurons in response to the absence of expected outcomes. In this study, we tested healthy subjects with a difficult version of a memory paradigm on which confabulat- ing patients had failed. Subjects participated in three test sessions, in which they received in double-blind, randomized fashion L-dopa, risperidone, or placebo. We found that L- dopa, in comparison with risperidone, impaired performance in a highly specific way, which corresponded to the pattern of patients with reality confusion. Specifically, they had an in- crease of false positive responses, while overall memory performance and reaction times were unaffected. We con- clude that dopaminergic transmission influences the ability to rapidly adapt thinking to ongoing reality. © 2010 IBRO. Published by Elsevier Ltd. All rights reserved. Key words: reality monitoring, disorientation, confabulation, dopamine, L-dopa, psychosis, extinction. Dopaminergic transmission is increasingly recognized as an important modulator of human cognition, motivation, and behavioral adaptation (Tobler et al., 2005; Morris et al., 2006; Schultz, 2007). Abnormal dopaminergic trans- mission is considered a key element in the pathogenesis of mental disorders with disturbed sense of reality—schizo- phrenia and other psychoses (Davis et al., 1991; Howes and Kapur, 2009). Antagonists of the dopamine D2-recep- tors are particularly efficacious against positive symptoms of psychosis: hallucinations and delusions (Cooper et al., 2003; Howes and Kapur, 2009). Behaviorally spontaneous confabulation is a much rarer disorder with reality confusion, which emanates from lesions to the posterior medial orbitofrontal cortex (OFC) or regions directly connected with it (Schnider, 2003, 2008). The patients are amnesic, disoriented, confabulate about their recent doings, and act according to these false ideas. Using a specific experimental design, we found that this disorder reflects an inability to suppress the interference of memories that do not pertain to ongoing reality (Schnider et al., 1996a; Schnider and Ptak, 1999). Specifically, pa- tients performed repeated runs of a continuous recognition task, always composed of the same picture series. In each run, subjects had to recognize picture repetitions only within the ongoing run. Behaviorally spontaneous confab- ulators increasingly failed to distinguish between items’ previous occurrence in a previous rather than the ongoing run: they increased their false positive responses from run to run. The mechanism underlying this inability to suppress currently irrelevant memories has been mysterious. Based on the observation that the patients typically maintain their false concept of reality despite unequivocal evidence dis- proving it, we suggested that they have a deficit of extinc- tion: They fail to use the absence of anticipated outcomes to adapt their idea of reality (Schnider, 2008). In agreement with this hypothesis, we recently found that behaviorally spontaneous confabulation and disorientation are strongly associated with deficient extinction capacity as measured with a simple reversal learning task (Nahum et al., 2009). Processing the absence of anticipated reward out- comes in single extinction trials involves modulation of activity of dopaminergic neurons. Animal experiments have shown that the absence of anticipated rewards is signaled by briefly increased firing of select neurons in the posterior medial OFC (Rosenkilde et al., 1981) and tran- sient inhibition of dopaminergic neurons in the substantia nigra and ventral tegmental area (Schultz et al., 1997; Schultz and Dickinson, 2000). Phasic depression of dopa- minergic neurons in the mid-brain may thus constitute the neural signal indicating that an anticipation (expectation of an outcome, a thought) is not currently valid; hence, we suggest that it is the critical signal for keeping thinking in phase with reality (Schnider, 2008; Nahum et al., 2009). Based on these considerations, we conducted the present study to investigate the influence of dopaminergic modulation on the selection of currently relevant memo- ries—the memory capacity in which the patients fail. As the continuous recognition task used with patients had had a ceiling effect (virtually perfect recognition of repetitions; absence of false positives) in healthy subjects (Schnider et al., 2000b), we first developed a difficult version, inducing 1 Present address: Department of Psychology and Centre for Cogni- tive Neuroimaging (CCN), University of Glasgow, UK. *Corresponding author. Tel: +41-22-382-3700; fax: +41-22-382-3705. E-mail address: armin.schnider@hcuge.ch (A. Schnider). Abbreviation: OFC, orbitofrontal cortex. Neuroscience 167 (2010) 583–587 0306-4522/10 $ - see front matter © 2010 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2010.02.044 583