Dopamine receptor activation reveals a novel, kynurenate-sensitive component of striatal N-methyl-d-aspartate neurotoxicity

Abstract

The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors plays an important role in brain physiology, but excessive receptor stimulation results in seizures and excitotoxic nerve cell death. NMDA receptor-mediated neuronal excitation and injury can be prevented by high, nonphysiological concentrations of the neuroinhibitory tryptophan metabolite kynurenic acid (KYNA). Here we report that endogenous KYNA, which is formed in and released from astrocytes, controls NMDA receptors in vivo. This was revealed with the aid of the dopaminergic drugs d-amphetamine and apomorphine, which cause rapid, transient decreases in striatal KYNA levels in rats. Intrastriatal injections of the excitotoxins NMDA or quinolinate (but not the non-NMDA receptor agonist kainate) at the time of maximal KYNA reduction resulted in 2-3-fold increases in excitotoxic lesion size. Pretreatment with kynurenine 3-hydroxylase inhibitors or dopamine receptor antagonists, two classes of pharmacological agents that prevented the reduction in brain KYNA caused by dopaminergic stimulation, abolished the potentiation of neurotoxicity. Thus, the present study identifies a previously unappreciated role of KYNA as a functional link between dopamine receptor stimulation and NMDA neurotoxicity in the striatum. KeywordsAmphetamine; Astrocyte; Basal Ganglia; Dopamine; Kynurenine 3-hydroxylase; Quinolinic acid Glutamatergic neurotransmission mediated by N-methyl-D-aspartate (NMDA) receptors plays important roles in striatal physiology. Because of the discrete pre-and postsynaptic, and intraand extrasynaptic, localization of the various receptor subunits (Bernard and Bolam, 1998;Wang and Pickel, 2000;Dunah and Standaert, 2003;Galvan et al., 2006), striatal NMDA receptor stimulation has multiple and complex functional effects. Moderate activation of NMDA receptors controls, for example, monoaminergic, cholinergic, glutamatergic and peptidergic neurotransmission (Becquet et al., 1990;Young and Bradford, 1993;Knauber et al., 1999;Hathway et al., 2001;Radke et al., 2001;Marti et al., 2005) and, as a consequence, affects synaptic plasticity (Centonze et al., 2004;Dang et al., 2006), motor function (Hallett et al., 2005;Gardoni et al., 2006) and cellular bioenergetics (Moncada and Bolanos, 2006 Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. stimulation of striatal NMDA receptors, on the other hand, triggers excitotoxicity, a mode of neuronal death that is believed to play a causative role in neurodegenerative diseases affecting the basal ganglia (Sonsalla et al., 1998;Waxman and Lynch, 2005;Fan and Raymond, 2006)....

Crystal Structure of Human Kynurenine Aminotransferase II, a Drug Target for the Treatment of Schizophrenia

“…Although the individual contribution of each of the two isozymes to the synthesis of KYNA still needs to be precisely quantified, hKAT II is currently the primary target for the development of pharmacological tools aimed at lowering KYNA concentration in the brain. However, such a therapeutic intervention needs to take into account the possible pro-neurotoxic effects resulting from an excessive reduction of brain KYNA concentration (6,12). Therefore, the identification of the molecular determinants driving substrate recognition and catalysis in human kynurenine aminotransferases is of primary importance for the rational design of potent, specific hKAT II inhibitors.…”

“…Neurochemical studies show that KYNA-induced inhibition of ␣7-nAChRs causes a reduction in glutamate release and, secondarily, a decrease in extracellular dopamine levels (10). Inhibition of KYNA formation, on the other hand, results in an elevation in striatal dopamine levels, indicating a bi-directional modulation of dopaminergic neurotransmission by KYNA (11,12). Taken together, these and other supportive data from animals and humans (13)(14)(15)(16) suggest that KYNA may play a pathophysiologically significant role in the onset and progression of catastrophic brain diseases that are linked to a dysfunction of classic neurotransmitter systems.…”

Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder

“…Thus KYN metabolites can influence glutamatergic (Muller and Schwarz, 2007), dopaminergic (Amori, 2009; Poeggeler, 2007), and cholinergic (Schwarcz and Pellicciari, 2002) tone. Elevated KA causes impairments of spatial working memory (Chess, 2007) and contextual learning (Chess, 2009) in animals and could plausibly play a role in executive functioning deficits associated with suicidal behavior (Keilp, 2001; Marzuk, 2005).…”

Cognitive and Behavioral Consequences of Impaired Immunoregulation in Aging

“…It is hypothesized that IDO activation in microglia and macrophages by inflammatory cytokines (i.e. IL-1β, TNFα, IFNγ) is a key mechanism underlying mood and depressive complications because it alters serotonergic, dopaminergic, and noradrenergic neurotransmission (Raison et al 2006;Muller and Schwarz 2007;Poeggeler et al 2007;Dantzer et al 2008). Active IDO converts tryptophan (TRP) into kynurenine (L-KYN) which is then processed into neuroactive mediators, including 3′hydroxy-kynurenine (3′HK) and quinolinic acid (QUIN) (Stone and Darlington 2002).…”