Cognition-induced modulation of serotonin in the orbitofrontal cortex: A controlled cross-over PET study of a delayed match-to-sample task using the 5-HT2a receptor antagonist [ 18 F]altanserin

Behavioral and cellular studies indicate that serotonin interacting with the 5-HT2a receptor (5-HT2aR) is involved in cognitive processes supporting working memory (WM). However, 5-HT receptor neuroimaging studies directly relating WM-induced neuronal activations to concomitant changes in the availability of 5-HT receptors as a functional measure for serotonin release are lacking. This controlled cross-over PET study aimed to identify brain regions with WM-induced changes in the binding potential (BP _nd ) of the 5-HT2aR antagonist [ ¹⁸ F]altanserin. Ten young males underwent a delayed match-to-sample task using photographs of faces and a control task. The BP _nd s for both conditions were calculated by applying Ichise's noninvasive plot. Statistics were performed with the SPM toolbox statistical nonparametric mapping (SnPM3) particularly suited for analyzing whole-brain PET data in an exploratory way.A higher BP _nd for [ ¹⁸ F]altanserin during WM versus control was found in the orbitofrontal cortex (OFC) pointing towards an increased [ ¹⁸ F]altanserin/5-HT2aR interaction in OFC while BP _nd decreases during WM were not found. Furthermore, no BP _nd changes in regions known from functional neuroimaging studies to be more specifically involved in WM were identified. These findings may suggest that the increased [ ¹⁸ F]altanserin BP _nd under WM challenge and hence the increased availability of 5-HT2aR reflects a decrease in local OFC serotonin. As the OFC plays a prominent role in decision-making and supports cognitive processes related to the central executive functions of WM it might be modulated by the serotoninergic system via the 5-HT2aR in order to support and optimize basic cognitive functions.