Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

Rassoulpour, Arash; Wu, Hui‐Qiu; Albuquerque, Edson X.; Schwarcz, Robert

doi:10.1038/sj.npp.1300583

Cited by 20 publications

(9 citation statements)

References 76 publications

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“…It has also been shown that common cyclooxygnease-2 (COX-2) inhibitors, such as parecoxib, decrease KYNA concentration. 63 Relatedly, there is evidence that nicotine can alter KYNA concentration 64 supporting the possibility that nicotine may be used by persons with schizophrenia to counter cognitive deficits induced by KYNA. Thus, the development of kynurenergic compounds as adjunctive therapies for psychosis may also be useful in combating co-occurring psychopathology and substance abuse.…”

Section: Discussionmentioning

confidence: 99%

Exposure to Kynurenic Acid During Adolescence Produces Memory Deficits in Adulthood

Akagbosu

Evans

Gulick³

et al. 2010

Schizophrenia Bulletin

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The glia-derived molecule kynurenic acid (KYNA) is an antagonist of a7 nicotinic acetylcholine receptors and the glycine B binding site on n-methyl-d-aspartateglutamate receptors, both of which have critical roles in neural plasticity as well as learning and memory. KYNA levels are increased in the brains and cerebral spinal fluid of persons with schizophrenia, leading to the notion that changes in KYNA concentration might contribute to cognitive dysfunction associated with this disorder. Indeed, recent studies indicate that increasing endogenous KYNA concentration by administering l-kynurenine (L-KYN, the precursor of KYNA) impairs spatial as well as contextual learning and memory in adult rats. In the present study, rats were treated with L-KYN (100 mg/ kg) throughout adolescence to increase endogenous KYNA concentration during this critical time in brain development. Rats were then tested drug-free as adults to test the hypothesis that exposure to elevated levels of KYNA during development may contribute to cognitive dysfunction later in life. Consistent with prior studies in which adult rats were treated acutely with L-KYN, juvenile rats exposed to increased KYNA concentration during adolescence exhibited deficits in contextual fear memory, but cue-specific fear memory was not impaired. In addition, rats treated with L-KYN as adolescents were impaired on a novel object recognition memory task when tested as adults. The memory deficits could not be explained by drug-induced changes in locomotor activity or shock sensitivity. Together, these findings add to the growing literature supporting the notion that exposure to increased concentration of KYNA may contribute to cognitive deficits typically observed in schizophrenia.

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Section: Discussionmentioning

confidence: 99%

Exposure to Kynurenic Acid During Adolescence Produces Memory Deficits in Adulthood

Akagbosu

Evans

Gulick³

et al. 2010

Schizophrenia Bulletin

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“…However, it is also controlled by the cortical glutamatergic input to the dopaminergic neurons in the VTA. Local infusion in the rat striatum of a kynurenine hydroxylase inhibitor has been shown to increase extracellular levels of dopamine, which were decreased by the addition of KYNA to the perfusate (390, 391). The association between low levels of KYNA and increased levels of dopamine has also been observed in mice with a null mutation in the gene that encodes the KATII enzyme (516).…”

Section: Figures and Tablesmentioning

confidence: 99%

Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function

Albuquerque¹,

Pereira²,

Alkondon³

et al. 2009

Physiological Reviews

1,510

1,525

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The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a “receptive substance,” from which the idea of a “receptor” came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of α-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer’s, Parkinson’s, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.

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“…KA, an endogenous antagonist for NMDA and α7 nicotinic acetylcholine receptor, is dramatically increased in rat hippocampus, striatum, and frontal cortex, but not in the serum by prolonged (for 10 days) subcutaneous injections or osmotic minipumps of nicotine. Nicotine has no effect on Kyn in brain or blood [87]. There is no report about the effect of smoking on KP and its function in CVD.…”

Section: Abnormal Kp and Risk Factors For Cvdmentioning

confidence: 99%

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

Song

Ramprasath

Wang

et al. 2017

Cell. Mol. Life Sci.

174

134

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Kynurenine pathway (KP) is the primary path of tryptophan (Trp) catabolism in most mammalian cells. The KP generates several bioactive catabolites, such as kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykynurenine (3-HK), xanthurenic acid (XA), and 3-hydroxyanthranilic acid (3-HAA). Increased catabolite concentrations in serum are associated with several cardiovascular diseases (CVD), including heart disease, atherosclerosis, and endothelial dysfunction, as well as their risk factors, including hypertension, diabetes, obesity, and aging. The first catabolic step in KP is primarily controlled by indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). Following this first step, the KP has two major branches, one branch is mediated by kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU) and is responsible for the formation of 3-HK, 3-HAA, and quinolinic acid (QA); and another branch is controlled by kynurenine aminotransferase (KAT), which generates KA. Uncontrolled Trp catabolism has been demonstrated in distinct CVD, thus, understanding the underlying mechanisms by which regulates KP enzyme expression and activity is paramount. This review highlights the recent advances on the effect of KP enzyme expression and activity in different tissues on the pathological mechanisms of specific CVD, KP is an inflammatory sensor and modulator in the cardiovascular system, and KP catabolites act as the potential biomarkers for CVD initiation and progression. Moreover, the biochemical features of critical KP enzymes and principles of enzyme inhibitor development are briefly summarized, as well as the therapeutic potential of KP-enzyme inhibitors against CVD is briefly discussed.

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Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

Cited by 20 publications

References 76 publications

Exposure to Kynurenic Acid During Adolescence Produces Memory Deficits in Adulthood

Exposure to Kynurenic Acid During Adolescence Produces Memory Deficits in Adulthood

Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function

Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases

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