S218 S.28 Kynurenic acid: a new player in the pathophysiology of schizophrenia derivatives and nicotinamide adenine dinucleotides. In a variety of cells, IDO is inducible by the Th1-type cytokine interferon-Y and some other pro-inflammatory stimuli and represents an anti- proliferative defense strategy. Accelerated tryptophan degradation is observed in diseases and disorders concomitant with cellular immune activation, e.g. infec- tious, autoimmune, and malignant diseases, but also in coronary heart disease and even in normal aging. Especially in states of persistent immune activation, the availability of free tryptophan is significantly diminished. Thereby, decreased tryptophan levels and higher kynurenine to tryptophan ratios coincide with im- mune activation. Since tryptophan is precursor of neurotransmit- ter 5-hydroxytryptamine (serotonin), cytokine-induced tryptophan degradation could be of particular importance in the pathogenesis of depression and cognitive decline in patients. The accumulation of neurotoxic tryptophan catabolites can be of additional rele- vance. Also in neurodegenerative disorders like Alzheimer’s demen- tia, vascular dementia and Huntington’s disease and also in Parkinson’s disease, accelerated tryptophan catabolism has been described, and it correlates with, e.g. the degree of cognitive impairment and/or the course of disease. Interestingly, a decline of tryptophan and a concomitant increase of kynurenine is apparent in the cerebrospinal fluid and in the blood of these patients. Surprisingly no such observations were made in patients with schizophrenia, rather decreased Th1-type immune activation and tryptophan degradation is common in such patients. IDO could represent a link between the immunological network and neuroendocrine functions with far reaching consequences in regard to the psychological status of patients. Observations provide a basis for the better understanding of mood disorders and related symptoms in chronic diseases. References [1] Schroecksnadel K, Wirleitner B, Winkler C, Fuchs D, 2006, Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta 364, 82−90. [2] Widner B, Laich A, Sperner-Unterweger B, Ledochowski M, Fuchs D, 2002, Neopterin production tryptophan degradation and mental depres- sion: what is the link? Brain Behav Immun 16, 590–595. [3] Widner B, Leblhuber F, Walli J, Tilz GP, Demel U, Fuchs D, 2000, Tryptophan degradation and immune activation in Alzheimer’s disease. J Neural Transm 107, 343–353. S.28.02 Astrocytes, kynurenic acid and schizophrenia: multiple emerging links R. Schwarcz 1 ° , P. Guidetti 1 , H.Q. Wu 1 , R. Pellicciari 2 . 1 University of Maryland, Maryland Psychiatric Research Center Dept. of Psychiatry, Baltimore, USA; 2 University of Perugia, Dipartimento di Chimica e Tecnologia del Farmaco, Perugia, Italy At endogenous brain concentrations, kynurenic acid (KYNA), an astrocyte-derived metabolite of the kynurenine pathway of tryptophan degradation, is a preferential inhibitor of the a7 nicotinic acetylcholine receptor (a7nAChR) [1]. This, as well as the fact that KYNA levels are elevated in the brain of individuals with schizophrenia [2], suggests a possible role of KYNA in the pathophysiology of the disease. By microdialysis in unanesthetized adult rats, we now examined whether KYNA influences extracellular glutamate (Glu) and dopamine (DA) levels in the neostriatum and the prefrontal cortex [3]. Focal infusion of nanomolar concentrations of KYNA reduced basal extracellular Glu and DA levels in both brain areas. In the striatum, this effect was initiated by the KYNA-induced inhibition of a7nACh recep- tors, which are situated on glutamatergic afferents. Conversely, extracellular Glu and DA levels in both brain areas were enhanced when KYNA formation was compromised by specific inhibition of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of brain KYNA. Complementary studies in the striatum of mice with a targeted deletion of KAT II revealed that reductions in extracellular KYNA levels were accompanied by a significant increase in extracellular DA. Taken together, a picture emerges where fluctuations in the astrocytic formation of KYNA inversely regulate glutamatergic and dopaminergic tone in two brain areas involved in schizophrenia. In view of the suspected dysregulation of glutamatergic and dopaminergic neurotransmission in schizo- phrenia, these studies raise the prospect that interventions aimed at reducing brain KYNA function may constitute a promising new treatment strategy for the disease. References [1] Hilmas C, Pereira EFR, Alkondon M, Rassoulpour A, Schwarcz R, Albuquerque EX, 2001, The brain metabolite kynurenic acid inhibits a7 nicotinic receptor activity and increases non-a7 nicotinic receptor expression: physiopathological implications. J Neurosci 21, 7463–7473. [2] Schwarcz R, Rassoulpour A, Wu H-Q, Medoff D, Tamminga CA, Roberts RC, 2001, Increased cortical kynurenate content in schizo- phrenia. Biol Psychiatry 50, 521–530. [3] Rassoulpour A, Wu H-Q, Ferre S, Schwarcz R, 2005, Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J Neurochem 93, 762–765. S.28.03 Kynurenic acid actions in brain and periphery F. Moroni ° . University of Florence, Dept. of Pharmacology, Florence, Italy Kynurenic acid (KYNA) concentrations in rat brain extracellular spaces are approximately 10–100 nM and a modest increase of these concentrations is sufficient to reduce neuronal excitability, cause sedation and a decrease of post-ischemic brain damage. Since KYNA affinity for the glycine site of NMDA receptors is relatively low, these observation may suggest that KYNA actions in the brain are not exclusively mediated by this receptor site. Low micromolar concentrations (1−2 mM) of KYNA also antagonize the alpha 7 subtype of nicotine receptors and significantly reduce glutamate and dopamine release in the striatum (Carpenedo et al. 2001; Rassoulpour et al 2005). Although the mechanism of release inhibition and the cell type involved have not been fully clarified, it is possible that nicotinic cholinergic receptors are responsible of these effects. KYNA ability to interfere with the release of active compounds and its overall profile of action prompted us to study the effects of KYNA in primary glial cultures and in isolated macrophages. We noticed that KYNA reduces the LPS- induced expression and activation of pro-inflammatory genes and inhibits the release of high mobility group box 1 (HMGB1) protein. In mice treated with LPS (10 mg/kg), a septic shock model, KYNA administration significantly reduces the mortality rate possibly preventing macrophage activation. Thus KYNA may have receptors both in the nervous and peripheral tissues where it may play interesting regulatory role on cell activation and survival. References [1] Carpenedo R, Pittaluga A, Cozzi A, Attucci S, Galli A, Raiteri M, Moroni F, 2001, Presynaptic kynurenate receptors inhibit glutamate release. Eur J Neurosci 13, 2141–2147.