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Key Points The essential amino acid tryptophan is degraded to several neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. These metabolites, collectively termed 'kynurenines', directly target important neurotransmitter receptors and affect redox processes, and thus influence brain physiology. In the mammalian brain, the catabolic cascade responsible for the neosynthesis of kynurenines — the kynurenine pathway — is physically segregated into two branches. One, leading to the neuroprotective agent kynurenic acid, is contained in astrocytes, whereas the other, leading to the neurotoxins 3-hydroxykynurenine and quinolinic acid, is present in microglial cells. Brain kynurenines are not autonomous but are linked to, and affected by, the peripheral kynurenine pathway. As the pathway is stimulated by a host of cytokines and other intercellular signalling molecules, both peripheral and central functions of kynurenines are influenced by infections and other inflammatory conditions. Dysregulations of the pathway, causing hyper- or hypofunction of active metabolites, are associated with neurodegenerative and other neurological disorders, as well as psychiatric diseases such as depression and schizophrenia. Recently developed pharmacological agents make it increasingly possible to selectively influence the kynurenine pathway in the periphery and in the brain. Targeted interventions with such specific 'kynurenergic' drugs can now be used to influence brain physiology. This approach is also envisaged to normalize pathophysiologically relevant imbalances in cerebral kynurenines and thus provide novel treatments for a host of brain diseases. Tryptophan metabolism along the kynurenine pathway generates several neuroactive metabolites. Schwarcz and colleagues discuss the regulation of this pathway in the normal brain and in neurological and psychiatric disorders, and consider the potential therapeutic opportunities of targeting this pathway. The essential amino acid tryptophan is not only a precursor of serotonin but is also degraded to several other neuroactive compounds, including kynurenic acid, 3-hydroxykynurenine and quinolinic acid. The synthesis of these metabolites is regulated by an enzymatic cascade, known as the kynurenine pathway, that is tightly controlled by the immune system. Dysregulation of this pathway, resulting in hyper- or hypofunction of active metabolites, is associated with neurodegenerative and other neurological disorders, as well as with psychiatric diseases such as depression and schizophrenia. With recently developed pharmacological agents, it is now possible to restore metabolic equilibrium and envisage novel therapeutic interventions.

Kynurenic acid (KYNA), an astrocyte-derived metabolite, antagonizes the α7 nicotinic acetylcholine receptor (α7nAChR) and, possibly, the glycine co-agonist site of the NMDA receptor at endogenous brain concentrations. As both receptors are involved in cognitive processes, KYNA elevations may aggravate, whereas reductions may improve, cognitive functions. We tested this hypothesis in rats by examining the effects of acute up- or downregulation of endogenous KYNA on extracellular glutamate in the hippocampus and on performance in the Morris water maze (MWM). Applied directly by reverse dialysis, KYNA (30–300 nM) reduced, whereas the specific kynurenine aminotransferase-II inhibitor ( S )-4-(ethylsulfonyl)benzoylalanine (ESBA; 0.3–3 mM) raised, extracellular glutamate levels in the hippocampus. Co-application of KYNA (100 nM) with ESBA (1 mM) prevented the ESBA-induced glutamate increase. Comparable effects on hippocampal glutamate levels were seen after intra-cerebroventricular (i.c.v.) application of the KYNA precursor kynurenine (1 mM, 10 μl) or ESBA (10 mM, 10 μl), respectively. In separate animals, i.c.v. treatment with kynurenine impaired, whereas i.c.v. ESBA improved, performance in the MWM. I.c.v. co-application of KYNA (10 μM) eliminated the pro-cognitive effects of ESBA. Collectively, these studies show that KYNA serves as an endogenous modulator of extracellular glutamate in the hippocampus and regulates hippocampus-related cognitive function. Our results suggest that pharmacological interventions leading to acute reductions in hippocampal KYNA constitute an effective strategy for cognitive improvement. This approach might be especially useful in the treatment of cognitive deficits in neurological and psychiatric diseases that are associated with increased brain KYNA levels.

Rationale Cognitive deficits represent a core symptom cluster in schizophrenia (SZ) that is predictive of outcome but not effectively treated by current antipsychotics. Thus, there is a need for validated animal models for testing potential pro-cognitive drugs. Objective As kynurenic acid levels are increased in prefrontal cortex (PFC) of individuals with SZ, we acutely increased brain levels of this astrocyte-derived, negative modulator of alpha7 nicotinic acetylcholine receptors (α7nAChRs) by administration of its bioprecursor kynurenine and measured the effects on extracellular kynurenic acid and glutamate levels in PFC and also performance in a set-shifting task. Results Injections of kynurenine (100 mg/kg, i.p.) increased extracellular kynurenic acid (1,500%) and decreased glutamate levels (30%) in PFC. Kynurenine also produced selective deficits in set-shifting. Saline- and kynurenine-treated rats similarly acquired the compound discrimination and intra-dimensional shift (saline, 7.0 and 6.3 trials, respectively; kynurenine, 8.0 and 6.7). Both groups required more trials to acquire the initial reversal (saline, 15.3; kynurenine, 22.2). Only kynurenine-treated rats were impaired in acquiring the extra-dimensional shift (saline, 8.2; kynurenine, 21.3). These deficits were normalized by administering the α7nAChR positive allosteric modulator galantamine (3.0 mg/kg, i.p) prior to kynurenine, as trials were comparable between galantamine + kynurenine (7.8) and controls (8.2). Bilateral local perfusion of the PFC with galantamine (5.0 μM) also attenuated kynurenine-induced deficits. Conclusions These results validate the use of animals with elevated brain kynurenic acid levels in SZ research and support studies of drugs that normalize brain kynurenic acid levels and/or positively modulate α7nAChRs as pro-cognitive treatments for SZ.

At endogenous brain concentrations, the astrocyte-derived metabolite kynurenic acid (KYNA) antagonizes the α 7 nicotinic acetylcholine receptor and, possibly, the glycine co-agonist site of the NMDA receptor. The functions of these two receptors, which are intimately involved in synaptic plasticity and cognitive processes, may, therefore, be enhanced by reductions in brain KYNA levels. This concept was tested in mice with a targeted deletion of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of brain KYNA. At 21 days of age, KAT II knock-out mice had reduced hippocampal KYNA levels (−71%) and showed significantly increased performance in three cognitive paradigms that rely in part on the integrity of hippocampal function, namely object exploration and recognition, passive avoidance, and spatial discrimination. Moreover, compared with wild-type controls, hippocampal slices from KAT II-deficient mice showed a significant increase in the amplitude of long-term potentiation in vitro . These functional changes were accompanied by reduced extracellular KYNA (−66%) and increased extracellular glutamate (+51%) concentrations, measured by hippocampal microdialysis in vivo . Taken together, a picture emerges in which a reduction in the astrocytic formation of KYNA increases glutamatergic tone in the hippocampus and enhances cognitive abilities and synaptic plasticity. Our studies raise the prospect that interventions aimed specifically at reducing KYNA formation in the brain may constitute a promising molecular strategy for cognitive improvement in health and disease.

The cognitive deficits seen in schizophrenia patients are likely related to abnormal glutamatergic and cholinergic neurotransmission in the prefrontal cortex. We hypothesized that these impairments may be secondary to increased levels of the astrocyte-derived metabolite kynurenic acid (KYNA), which inhibits α7 nicotinic acetylcholine receptors (α7AChR) and may thereby reduce glutamate release. Using in vivo microdialysis in unanesthetized rats, we show here that nanomolar concentrations of KYNA, infused directly or produced in situ from its bioprecursor kynurenine, significantly decrease extracellular glutamate levels in the prefrontal cortex. This effect was prevented by the systemic administration of galantamine (3 mg/kg) but not by donepezil (2 mg/kg), indicating that KYNA blocks the allosteric potentiating site of the α7AChR, which recognizes galantamine but not donepezil as an agonist. In separate rats, reduction of prefrontal KYNA formation by ( S )-4-ethylsulfonyl benzoylalanine, a specific inhibitor of KYNA synthesis, caused a significant elevation in extracellular glutamate levels. Jointly, our results demonstrate that fluctuations in endogenous KYNA formation bidirectionally influence cortical glutamate concentrations. These findings suggest that selective attenuation of cerebral KYNA production, by increasing glutamatergic tone, might improve cognitive function in individuals with schizophrenia.

α7-nicotinic acetylcholine receptors (α7nAChRs) modulate the effects of the main psychoactive ingredient of marijuana, Δ 9 -tetrahydrocannabinol (THC), in the brain. Here the authors show that pharmacologically enhancing kynurenic acid, an endogenous modulator of α7nAChRs, attenuated the rewarding properties of THC and prevented drug relapse in monkeys and rats. In the reward circuitry of the brain, α-7-nicotinic acetylcholine receptors (α7nAChRs) modulate effects of Δ 9 -tetrahydrocannabinol (THC), marijuana's main psychoactive ingredient. Kynurenic acid (KYNA) is an endogenous negative allosteric modulator of α7nAChRs. Here we report that the kynurenine 3-monooxygenase (KMO) inhibitor Ro 61-8048 increases brain KYNA levels and attenuates cannabinoid-induced increases in extracellular dopamine in reward-related brain areas. In the self-administration model of drug abuse, Ro 61-8048 reduced the rewarding effects of THC and the synthetic cannabinoid WIN 55,212-2 in squirrel monkeys and rats, respectively, and it also prevented relapse to drug-seeking induced by reexposure to cannabinoids or cannabinoid-associated cues. The effects of enhancing endogenous KYNA levels with Ro 61-8048 were prevented by positive allosteric modulators of α7nAChRs. Despite a clear need, there are no medications approved for treatment of marijuana dependence. Modulation of KYNA offers a pharmacological strategy for achieving abstinence from marijuana and preventing relapse.

The content of the endogenous NMDA and alpha7 nicotinic acetylcholine receptor antagonist kynurenate (KYNA) is increased in the cerebral cortex and cerebrospinal fluid of patients with schizophrenia. In view of the very high incidence of smoking in schizophrenic individuals, a study was designed to examine the effect of acute and prolonged nicotine administration on brain KYNA levels in experimental animals. Adult male rats received subcutaneous nicotine injections twice daily for up to 10 days, and animals were routinely killed 1 h after the last injection. Neither acute treatment nor a 2-day regimen with 1 mg/kg nicotine (= 0.35 mg/kg pure base) caused changes in cerebral KYNA levels. Four- or 6 day-treatment with this dose resulted in 20-40% decreases in cerebral KYNA content. Animals treated with 1 or 10 mg/kg nicotine for 10 days showed dose-dependent, significant increases in KYNA in hippocampus, striatum, and cortex, but not in the serum. Discontinuation of nicotine treatment for 7 days restored brain KYNA to control levels. Separate animals, implanted with osmotic minipumps delivering 2 mg/kg of nicotine/day for 10 days also showed significant elevations in brain KYNA. Hippocampal microdialysis, performed in animals receiving nicotine (1 mg/kg) for 10 days, revealed a significant increase in basal extracellular KYNA levels compared to controls, whereas acute treatment with this dose produced no such change. Measurements of KYNA's bioprecursor kynurenine in brain or blood did not reveal any nicotine-induced changes. These results indicate that nicotine has a brain-specific, biphasic effect on the transamination of kynurenine to KYNA. Such nicotine-induced fluctuations in brain KYNA may cause functional changes in processes that regulate glutamatergic and cholinergic neurotransmission in the normal and diseased brain.

This study was designed to examine the effects of d-amphetamine (D-AMPH) and D1- and D2-selective dopaminergic drugs on the concentration of the broad-spectrum excitatory amino acid receptor antagonist kynurenic acid (KYNA) in the striatum of developing and adult rats. At all ages, KYNA levels were significantly reduced 1 h after the systemic administration of D-AMPH (5 mg/kg). SKF 38393 (5 mg/kg) and quinpirole (2 mg/kg) also caused a rapid decrease in striatal KYNA, but only in postnatal day (PND) 7 and 14 rats. All these effects were readily prevented by specific dopamine receptor antagonists. The possible functional significance of the reduction in KYNA levels was tested in PND 14 animals. When pretreated with D-AMPH (5 mg/kg), these rats showed markedly increased vulnerability to an intrastriatal injection of the excitotoxin NMDA. These data suggest that KYNA plays a role as a mediator of dopamine-glutamate interactions in the rat striatum.