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S.28.04 Endogenous kynurenate regulates dopaminergic activity: implications for schizophrenia research
S.28 Kynurenic acid: a new player in the pathophysiology of schizophrenia [2] Rassoulpour A, Wu HQ, Ferre S, Schwarcz R, 2005, Nanomolar concentrations of kynurenic acid reduce extracellular dopamine levels in the striatum. J Neurochem 93, 762–765.
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S.28.05 Manipulation of brain kynurenic acid levels: a possible treatment for psychiatric symptoms?
S.28.04 Endogenous kynurenate regulates dopaminergic activity: implications for schizophrenia research
Y. Kajii ° , A. Maruyama, J. Maeda, K. Yamagami, K. Saito. Mitsubishi Pharma Corporation, Research Laboratory I, Kanagawa, Japan
S. Erhardt ° , L. Schwieler, L.K. Nilsson, L.A. Andersson, K.R. Linderholm, M. Holtze, E. Olsson, S.K. Olsson, G. Engberg. Karolinska Institute, Dept. of Physiology & Pharmacology, Stockholm, Sweden
The tryptophan metabolite kynurenic acid (KYNA) can act as an endogenous inhibitor of NMDA and alpha 7 nicotinic receptors in the brain. Abnormalities in these receptors are likely involved in the pathogenesis of schizophrenia. In patients, endogenous sensitization to amphetamine is closely related to the psychotic state [1], and studies of amphetamine- or methamphetamine (MAP)-induced locomotor activity in rats can be used as a surrogate of vulnerability to stress. Since the levels of KYNA are elevated in brain and CSF of individuals with schizophrenia [2,3], we now investigated the effect of elevated brain KYNA on the responsiveness to MAP in rats. Extracellular brain KYNA levels were increased in rats by pharmacological means. To achieve sensitization, animals received 1.6 mg/kg of MAP daily for 10 days. This was followed by a 20day MAP-free period. During the first 10 days of this period, rats were treated daily with haloperidol or ondansetron to attenuate the establishment of behavioral sensitization. In each case, rats were pre-exposed to the test environment and then challenged with low dose of MAP. The behavioral responsiveness to MAP was augmented when brain KYNA levels were elevated. Neuroleptic-induced blockade of the establishment of behavioral sensitization caused altered expression of a gene, which can be predicted to reduce KYNA production. These results suggest that a decrease in brain KYNA may benefit patients by attenuating the recurrence of psychosis. Agents capable of reducing brain KYNA formation therefore hold promise as a novel treatment for schizophrenia.
In recent years progress in the field of schizophrenia research has led to the suggestion that dopamine (DA) only plays an intermediary role in the pathophysiology of the disease and that the main abnormalities lie elsewhere. In particular, deficits in brain glutamatergic systems are suggested to play a prominent role. Kynurenic acid (KYNA) is an endogenous nicotinic and N-methyl-D-aspartate (NMDA)-receptor antagonist. Mounting evidence indicate that KYNA is significantly involved in basal neurophysiological processes in the brain. Thus, pharmacologically elevated levels of KYNA, in similarity to systemic administration of NMDA receptor antagonists (e.g. PCP), are associated with increased neuronal activity of midbrain DA neurons (Schwieler et al., 2006). In addition, lowering of brain KYNA is associated with a reduced firing, suggesting that midbrain DA neurons are tonically driven by endogenous KYNA (Schwieler et al., 2006). Furthermore, elevated levels of rat brain KYNA disrupt prepulse inhibition (PPI; Erhardt et al., 2004), in similarity to administration of PCP or MK 801, thus mimicking the same deficits as observed in schizophrenic patients. In a large cohort of patients with schizophrenia, we recently confirmed elevated levels of KYNA in the cerebrospinal fluid (CSF) from first-episode, drug-na¨ıve patients as well as from patients on antipsychotic treatment (Nilsson et al., 2005). Finally, a relationship between brain KYNA concentration and the response of midbrain DA neurons by the antipsychotic drug clozapine is described. In summary, our results suggest that KYNA modulates glutamatergic mechanisms, serves as an endogenous modulator of PPI and contributes to the pathogenesis of schizophrenia. References [1] Erhardt S, Schwieler L, Emanuelsson C, Geyer M, 2004, Endogenous kynurenic acid disrupts prepulse inhibition. Biol Psychiatry 56, 255−60. [2] Nilsson LK, Linderholm KR, Engberg G, Paulson L, Blennow K, Lindstrom LH, Nordin C, Karanti A, Persson P, Erhardt S, 2005, Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res 80, 315−22. [3] Schwieler L, Erhardt S, Nilsson L, Linderholm K, Engberg G, 2006, Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons – possible involvement of endogenous kynurenic acid. Synapse 59, 290−8.
References [1] Laruelle M, 2000, The role of endogenous sensitization in the pathophysiology of schizophrenia: Implications from recent brain imaging studies. Brain Res Rev 31, 371–384. [2] Schwarcz R, et al, 2001, Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50, 521–530. [3] Erhardt S, et al, 2001, Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett 313, 96−98.
S219
S.28.05 Manipulation of brain kynurenic acid levels: a possible treatment for psychiatric symptoms?
S.28.04 Endogenous kynurenate regulates dopaminergic activity: implications for schizophrenia research
Y. Kajii ° , A. Maruyama, J. Maeda, K. Yamagami, K. Saito. Mitsubishi Pharma Corporation, Research Laboratory I, Kanagawa, Japan
S. Erhardt ° , L. Schwieler, L.K. Nilsson, L.A. Andersson, K.R. Linderholm, M. Holtze, E. Olsson, S.K. Olsson, G. Engberg. Karolinska Institute, Dept. of Physiology & Pharmacology, Stockholm, Sweden
The tryptophan metabolite kynurenic acid (KYNA) can act as an endogenous inhibitor of NMDA and alpha 7 nicotinic receptors in the brain. Abnormalities in these receptors are likely involved in the pathogenesis of schizophrenia. In patients, endogenous sensitization to amphetamine is closely related to the psychotic state [1], and studies of amphetamine- or methamphetamine (MAP)-induced locomotor activity in rats can be used as a surrogate of vulnerability to stress. Since the levels of KYNA are elevated in brain and CSF of individuals with schizophrenia [2,3], we now investigated the effect of elevated brain KYNA on the responsiveness to MAP in rats. Extracellular brain KYNA levels were increased in rats by pharmacological means. To achieve sensitization, animals received 1.6 mg/kg of MAP daily for 10 days. This was followed by a 20day MAP-free period. During the first 10 days of this period, rats were treated daily with haloperidol or ondansetron to attenuate the establishment of behavioral sensitization. In each case, rats were pre-exposed to the test environment and then challenged with low dose of MAP. The behavioral responsiveness to MAP was augmented when brain KYNA levels were elevated. Neuroleptic-induced blockade of the establishment of behavioral sensitization caused altered expression of a gene, which can be predicted to reduce KYNA production. These results suggest that a decrease in brain KYNA may benefit patients by attenuating the recurrence of psychosis. Agents capable of reducing brain KYNA formation therefore hold promise as a novel treatment for schizophrenia.
In recent years progress in the field of schizophrenia research has led to the suggestion that dopamine (DA) only plays an intermediary role in the pathophysiology of the disease and that the main abnormalities lie elsewhere. In particular, deficits in brain glutamatergic systems are suggested to play a prominent role. Kynurenic acid (KYNA) is an endogenous nicotinic and N-methyl-D-aspartate (NMDA)-receptor antagonist. Mounting evidence indicate that KYNA is significantly involved in basal neurophysiological processes in the brain. Thus, pharmacologically elevated levels of KYNA, in similarity to systemic administration of NMDA receptor antagonists (e.g. PCP), are associated with increased neuronal activity of midbrain DA neurons (Schwieler et al., 2006). In addition, lowering of brain KYNA is associated with a reduced firing, suggesting that midbrain DA neurons are tonically driven by endogenous KYNA (Schwieler et al., 2006). Furthermore, elevated levels of rat brain KYNA disrupt prepulse inhibition (PPI; Erhardt et al., 2004), in similarity to administration of PCP or MK 801, thus mimicking the same deficits as observed in schizophrenic patients. In a large cohort of patients with schizophrenia, we recently confirmed elevated levels of KYNA in the cerebrospinal fluid (CSF) from first-episode, drug-na¨ıve patients as well as from patients on antipsychotic treatment (Nilsson et al., 2005). Finally, a relationship between brain KYNA concentration and the response of midbrain DA neurons by the antipsychotic drug clozapine is described. In summary, our results suggest that KYNA modulates glutamatergic mechanisms, serves as an endogenous modulator of PPI and contributes to the pathogenesis of schizophrenia. References [1] Erhardt S, Schwieler L, Emanuelsson C, Geyer M, 2004, Endogenous kynurenic acid disrupts prepulse inhibition. Biol Psychiatry 56, 255−60. [2] Nilsson LK, Linderholm KR, Engberg G, Paulson L, Blennow K, Lindstrom LH, Nordin C, Karanti A, Persson P, Erhardt S, 2005, Elevated levels of kynurenic acid in the cerebrospinal fluid of male patients with schizophrenia. Schizophr Res 80, 315−22. [3] Schwieler L, Erhardt S, Nilsson L, Linderholm K, Engberg G, 2006, Effects of COX-1 and COX-2 inhibitors on the firing of rat midbrain dopaminergic neurons – possible involvement of endogenous kynurenic acid. Synapse 59, 290−8.
References [1] Laruelle M, 2000, The role of endogenous sensitization in the pathophysiology of schizophrenia: Implications from recent brain imaging studies. Brain Res Rev 31, 371–384. [2] Schwarcz R, et al, 2001, Increased cortical kynurenate content in schizophrenia. Biol Psychiatry 50, 521–530. [3] Erhardt S, et al, 2001, Kynurenic acid levels are elevated in the cerebrospinal fluid of patients with schizophrenia. Neurosci Lett 313, 96−98.