Antipsychotics inhibit TREK but not TRAAK channels Susanne Thu ¨ mmler, Fabrice Duprat, Michel Lazdunski * Institut de Pharmacologie Mole ´culaire et Cellulaire, Centre National de la Recherche Scientifique, UMR 6097, Universite ´ de Nice-Sophia Antipolis, 660 Route des Lucioles, Sophia-Antipolis, 06560 Valbonne, France Received 27 December 2006 Available online 3 January 2007 Abstract Schizophrenia is a chronic mental illness affecting 0.4% of the population. Existing antipsychotic drugs are mainly used to treat posi- tive symptoms such as hallucinations but have only poor effects on negative symptoms such as cognitive deficits or depression. TREK and TRAAK channels are two P domain background potassium channels activated by polyunsaturated fatty acids and mechanical stress. TREK but not TRAAK channels are regulated by Gs- and Gq-coupled pathways. The inactivation of the TREK-1 but not the TRAAK channel in mice results in a depression-resistant phenotype. In addition, it has been shown that antidepressants such as fluoxetine or paroxetine directly inhibit TREK channel activity. Here we show that different antipsychotic drugs directly inhibit TREK currents with IC 50 values of 1 to 20 lM. No effect is seen on TRAAK channel activity. We conclude that TREK channels might be involved in the therapeutic action of antipsychotics or in their secondary effects. Furthermore, TREK channels could play a role in the pathophysiology of psychiatric disorders such as depression and schizophrenia. Ó 2007 Published by Elsevier Inc. Keywords: Two-pore domain background potassium channels; Mental disorders; Neuroleptics; Schizophrenia; Depression Schizophrenia is a chronic serious mental illness marked by episodes of exacerbated psychotic symptoms such as hallucination and delusion or chronic disability of mental and social functions. It affects 0.4% of the population [1]. Treatment of schizophrenia remains difficult and often inadequate in many patients despite the discovery of chlor- promazine as the first ‘typical’ antipsychotic in the 1950s and the development of ‘atypical’ antipsychotics like cloza- pine 20 years later. Existing antipsychotics are mainly used to treat positive symptoms of schizophrenia such as hallucination, delusion, and aggression, but have only a poor effect on negative symptoms such as cognitive deficits, depression or social disabilities. In addition, 30–60% of acutely ill patients fail to respond or respond inadequately to existing drugs [2,3]. A major side effect of ‘typical’ antipsychotics is extra- pyramidal symptoms such as parkinsonism, dystonia or tardive dyskinesia as a consequence of dopamine D2 recep- tor antagonism. Treatment with ‘atypical’ antipsychotics which interact in addition with serotonin, muscarinic, cho- linergic, and histamine receptors is complicated by weight gain, diabetes, cardiovascular, and hematological side effects [3]. Potassium channels constitute the biggest and most diversified family of ion channels. Mutations of K + chan- nels in humans are resulting in a number of channelopa- thies touching brain, muscle, heart, and other organs. TREK and TRAAK channels belong to the two P domain background potassium channel family (K 2P ) (for reviews, see [4–7]). They produce outwardly rectifying currents acti- vated by polyunsaturated fatty acids (PUFAs) such as ara- chidonic acid (AA), intracellular acidification, and mechanical stress. TREK and TRAAK channels are expressed throughout the central nervous system and are stimulated by volatile anesthetics [8] and by the neuropro- tective drug riluzole [9]. Furthermore, the TREK channel is 0006-291X/$ - see front matter Ó 2007 Published by Elsevier Inc. doi:10.1016/j.bbrc.2006.12.199 Abbreviations: AA, arachidonic acid; K + , potassium; K 2P , two P domain potassium channel; KO, knock-out; PUFA, polyunsaturated fatty acid; SSRI, selective serotonin reuptake inhibitor. * Corresponding author. Fax: +33 493537704. E-mail address: ipmc@ipmc.cnrs.fr (M. Lazdunski). www.elsevier.com/locate/ybbrc Biochemical and Biophysical Research Communications 354 (2007) 284–289