Copyright @ Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Amygdala Activation Modulated by Levodopa During Emotional Recognition Processing in Healthy Volunteers A Double-Blind, Placebo-Controlled Study Pauline Delaveau, MSc, Pilar Salgado-Pineda, PhD, Joe ¨lle Micallef-Roll, PhD, and Olivier Blin, PhD Abstract: A critical role of dopaminergic systems in emotional processing has been revealed by several animal and clinical studies in Parkinson disease and schizophrenia. We conducted a study with functional magnetic resonance imaging (fMRI) in 13 healthy volunteers to test the dopaminergic modulation on amygdala response to emotional processing and to evaluate if it was the result of a direct action on amygdalar nuclei or indirect modulation via medial prefrontal cortex projecting on amygdala. A placebo-controlled crossover experimental design was used. Subjects received either levodopa (100 mg) or placebo in 2 fMRI sessions. Amygdala activation was evaluated during a facial emotion recognition test. The statistical comparison between placebo versus levodopa situations revealed a significant reduction in activation of right amygdala during the levodopa fMRI session. The functional connectivity analysis revealed only a change of correlated activa- tions between right and left amygdala, and not medial prefrontal cortex, after levodopa administration. Our results suggest that administration of levodopa to healthy volunteers impairs the amygdalar activation. It supports the hypothesis that amygdala activation follows an inverted U-shaped curve in relation to dopamine (DA) concentration. The results of the functional connectivity seem to suggest a dopaminergic action on amygdalar nuclei rather than a modulation of medial prefrontal cortex on amygdala. (J Clin Psychopharmacol 2007;27:692–697) A critical role of dopaminergic systems in emotional pro- cessing has been revealed by several animal 1,2 and clin- ical studies in Parkinson disease (PD), 3,4 schizophrenia, 5,6 and neuroimaging studies (in PD 7 ) (for review, see Salgado- Pineda et al 8 ). However, the specific role of dopaminergic system in regulation of emotional processing remains unclear. In healthy subjects, sulpiride (400 mg), an antagonist of D2 family receptors, impaired the recognition of anger but not of other emotions. 9 In a functional magnetic reso- nance imaging (fMRI) study, the administration of another antagonist of D2 family receptor, sultopride (25 mg) atten- uated amygdala activation relative to placebo during the per- ception of unpleasant picture. 10 Moreover, D-amphetamine administration (0.25 mg/kg body weight), enhancing mono- aminergic transmission, led to an increased amygdala activ- ity in healthy subjects during perceptual processing of angry and fearful facial expressions. 11 In an emotional recognition fMRI study achieved by our laboratory, we demonstrated a decreased amygdala activation in healthy subjects after levodopa administration (100 mg). 12 This apparently contradictory result with study of Hariri et al 11 could be explained by the different pharmacological action of the 2 compounds. The levodopa is directly converted to DA, whereas the D-amphetamine increases, at the same time with DA, noradrenalin, and sero- tonin transmissions. It has been suggested that amygdala activity is modulated by noradrenergic 13 and serotoninergic activities. 10 Conjointly with previous data, our findings have led us to postulate that amygdala activation would follow an inverted U-shaped curve in relation to DA concentration. 12 This decreased activation might result from a direct action on amygdalar nuclei or indirect action via other limbic areas receiving DA inputs and projecting on amygdala, such as medial prefrontal cortex (mPFC). 14 There are anatomical and functional interactions between amygdala and prefrontal cortex that have a mutual role in the regulation of emotional processing (ie, mPFC inhibition on amygdala neurons). 15,16 In this present study, we evaluated using fMRI the dopaminergic modulation on amygdala response to emo- tional processing. This work was carried out to answer several questions raised by contradictory results in literature and the principal limitation of our previous study—the subjects were instructed to look passively at all stimuli and thus the absence of a recording feedback of their perfor- mance and attention level. The study was also conducted to take into account several factors that could influence amygdalar activation Brief Report Journal of Clinical Psychopharmacology  Volume 27, Number 6, December 2007 692 Centre d’Investigation Clinique-Unite ´ de Pharmacologie Clinique et d’Evaluations The ´rapeutiques and Pharmacologie Clinique, Centre National de la Recherche Scientifique, Unite ´ Mixte de Recherche, Marseille, France. Received April 20, 2007; accepted after revision August 8, 2007. This study was supported by a grant from the Health Ministry, Hospital Protocol of Clinical Research (PHRC 2001). Address correspondence and reprint requests to Olivier Blin, PhD, Professeur des Universite ´s-Praticien Hospitalier, CIC-UPCET et Pharmacologie Clinique, Institut des Neurosciences Cognitives de la Me ´diterrane ´e, Faculte ´ de Me ´decine, UMR 6193CNRS Universite ´ de la Me ´diterrane ´e, Assistance Publique Ho ˆpitaux de Marseille–Ho ˆpital de la Timone, 13385 Marseille Cedex 5, France. E-mail: olivier.blin@ap-hm.fr. Copyright * 2007 by Lippincott Williams & Wilkins ISSN: 0271-0749/07/2706-0692 DOI: 10.1097/jcp.0b013e31815a444d