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Previous Article | Next Article
The Journal of Neuroscience, October 1, 2001, 21(19):7463-7473
The Brain Metabolite Kynurenic Acid Inhibits
7 Nicotinic Receptor Activity and Increases Non-
Corey Hilmas1, Edna F. R. Pereira1, Manickavasagom Alkondon1, Arash Rassoulpour2, Robert Schwarcz1, 2, and Edson X. Albuquerque1, 3 1 Department of Pharmacology and Experimental Therapeutics and 2 Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland 21201, and 3 Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ 21944, Brazil
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
The tryptophan metabolite kynurenic acid (KYNA) has long been recognized as an NMDA receptor antagonist. Here, interactions between KYNA and the nicotinic system in the brain were investigated using the patch-clamp technique and HPLC. In the electrophysiological studies, agonists were delivered via a U-shaped tube, and KYNA was applied in admixture with agonists and via the background perfusion. Exposure (
4 min) of cultured hippocampal neurons to KYNA (
7 nAChRs; the IC50 for KYNA was ~7 µM. The inhibition of
2 nAChR expression. Furthermore, as determined by HPLC with fluorescence detection, repeated systemic treatment of rats with nicotine caused a transient reduction followed by an increase in brain KYNA levels. These results demonstrate that nAChRs are targets for KYNA and suggest a functionally significant cross talk between the nicotinic cholinergic system and the kynurenine pathway in the brain.
Key words: nicotinic ACh receptors; NMDA receptors; hippocampus; kynurenic acid; electrophysiology; brain slices
INTRODUCTION
Kynurenic acid (KYNA), a product of tryptophan metabolism, has neuroprotective and neuroinhibitory properties that have been attributed to its action as a competitive antagonist at the glycine site on NMDA receptors (Stone, 1993
; Parsons et al., 1997
Interest in the neurobiology of KYNA has gained momentum because of reports of changes in its brain content in several diseases. Cerebral KYNA levels are increased in patients with Alzheimer's disease (AD) (Baran et al., 1999
The physiopathological consequences of relatively modest variations in brain levels of KYNA raised the possibility that KYNA might interact with high affinity with an as-of-yet unidentified target. Nicotinic receptors (nAChRs) were among the most likely candidates because (1) preliminary electrophysiological experiments revealed an exquisite sensitivity of
Although numerous types of neuronal nAChRs have been identified (Lindstrom, 1996
This study was designed to investigate the effects of KYNA on nAChRs in CNS neurons and to determine the effects of nicotine on KYNA levels in vivo. The results indicate that (1)
MATERIALS AND METHODS
Cultured hippocampal and cerebral cortical neurons. Primary cultures of cells dissociated from the hippocampi or cerebral cortex of 16- to 19-d-old rat fetuses (Sprague Dawley) were prepared according to the procedure described in Alkondon and Albuquerque (1993)
Rat hippocampal slices. Slices of 250 µm thickness were obtained using a Vibratome (Leica Microsystems, Wetzlar, Germany) from the hippocampi of 15- to 30-d-old Sprague Dawley rats and placed in a chamber containing artificial CSF (ACSF). The ACSF was bubbled continuously with a mixture of 95% O2 and 5% CO2 at room temperature (20-22°C) and had the following composition (in mM): NaCl 125, NaHCO3 25, KCl 2.5, NaH2PO4 1.25, CaCl2 · 2H2O 2, MgCl2 1, and glucose 25. Slices were allowed to equilibrate for at least 1 hr before they were transferred to the recording chamber (Alkondon et al., 1999
Electrophysiological recordings. Transmembrane macroscopic currents were recorded according to the whole-cell mode of the patch-clamp technique (Hamill et al., 1981
(for cultured neurons) and 3-5 M
15 M
Drug application. A standard U-shaped glass tube (U-tube) was used for drug delivery onto cultured neurons (Alkondon and Albuquerque, 1993
Hippocampal neurons cultured for 7-10 d were used in experiments designed to investigate the effects of 3 d exposure to KYNA on nicotinic sensitivity. In short, these experiments involved changing the culture medium with drug-containing medium on the first and last day before testing the nicotinic responsiveness of the neurons.
Data analysis. Peak amplitude, rise time, and decay-time constants (
decay) of whole-cell currents and postsynaptic currents (PSCs) were analyzed using the PCLAMP6 program. Rundown of whole-cell currents triggered by activation of
Binding assay. Primary cultures of rat cerebral cortex were used to assay nAChR binding. A solution of 0.02% EDTA was used to detach cells from the flasks, and mechanical scraping was performed to facilitate further detachment of cells. Four flasks of primary cerebral cortical cultures were combined for each control and treatment groups into separate culture tubes and centrifuged at 900 × g for 10 min at 8°C. The pellet was washed by resuspension in ice-cold Tris-HCl (20 mM, pH 7.4) and subsequently centrifuged again at 900 × g for 10 min at 8°C. The wash step was repeated twice. The final pellet was homogenized in 50 mM Tris-HCl buffer (pH 7.4) and kept on ice until assayed.
Binding of [3H] epibatidine (10 nM) to nAChRs was measured by vacuum filtration assay. Aliquots (25 µl) of the homogenized sample were added to the control and treatment tubes to begin the incubation. The preparation was then incubated for 60 min at 23°C with the radioactive ligand in a total volume of 250 µl buffer, in the absence and presence of its specific displacer. Bound radioactivity was separated from free ligand by vacuum filtration over Whatman GF/B polyethylenimine (0.05%)-treated filters and washed with 8 ml of ice-cold 0.9% saline solution. Radioactivity was determined by liquid scintillation spectroscopy. Nonspecific binding was determined using nonradioactive (+)epibatidine (100 µM). To determine the effect of prolonged exposure to KYNA on epibatidine binding, cultures of rat cerebral cortex were exposed for 3 d to 10 µM KYNA. The experiments consisted of changing the medium with drug-containing medium in the first and last day before the binding assay. KYNA was washed out during the preparation of the pellets. Epibatidine binding was assayed in untreated cultures and in age-matched, treated cultures. Protein measurements were done using the bicinchoninic acid assay (Pierce, Rockford, IL).
Nicotine treatment of rats. Adult male Sprague Dawley rats (180-200 gm) were used to evaluate the effect of repeated nicotine injections in vivo. Nicotine was dissolved in PBS and administered subcutaneously twice daily (every 12 hr) for 5 or 15 d. Control animals received identical PBS injections.
KYNA determination. One hour after the final nicotine or PBS injection, animals were decapitated, and the brain was rapidly removed from the skull and placed on ice. Brain regions of interest were dissected out, and the tissues were placed on dry ice and stored at
80°C. On the day of the assay, the tissue was thawed and homogenized (1:10, w/v) in ultra-pure water. A 300 µl aliquot of the homogenate was acidified with 75 µl of 6% perchloric acid. After centrifugation (10 min, 12,000 × g), an aliquot of the supernatant was diluted (1:1, v/v) with HPLC mobile phase containing 200 mM zinc acetate and 3.5% acetonitrile (pH 6.2). KYNA levels were then determined by HPLC with fluorescence detection (excitation wavelength 344 nm; emission wavelength 398 nm) as described by Wu et al. (1992)
Drugs used. Methyllycaconitine (MLA) citrate was a gift from Prof. M. H. Benn (Department of Chemistry, University of Calgary, Alberta, Canada). (+/
RESULTS
KYNA inhibits postsynaptic responses mediated by
In the presence of atropine (1 µM) and TTX (200 nM), application of ACh (1 mM) to ~80% of the cultured hippocampal neurons evoked whole-cell currents that had the characteristics of responses mediated by
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Figure 1. KYNA-induced blockade of type IA currents in cultured hippocampal neurons. A, Fast desensitizing currents that were evoked by U-tube application of ACh to cultured hippocampal neurons were blocked after 10 min perfusion of the neurons with MLA (2 nM)-containing external solution. The effect of MLA was fully reversible after 15 min washing of the neurons. B, Sample recordings of ACh-evoked type IA currents obtained from hippocampal neurons before their exposure to KYNA (left traces), after 4-10 min perfusion with KYNA-containing external solution (middle traces), and after 10 min washing with KYNA-free external solution (right traces). Different neurons were exposed to each KYNA concentration. C, Concentration-response relationship for KYNA-induced blockade of ACh (1 mM)-evoked type IA currents. The rundown-corrected amplitude of type IA currents (see Materials and Methods) was taken as 1 and used to normalize the amplitude of type IA currents evoked by ACh in the presence of KYNA (0.1 µM to 1 mM). Each point and bar represent mean and SEM, respectively, of results obtained from 5-18 neurons. All experiments were performed in neurons perfused continuously with external solution containing atropine (1 µM) and TTX (200 nM). Membrane potential (A-C),
The amplitudes of ACh (1 mM)-evoked type IA currents were reduced after perfusion of cultured hippocampal neurons with external solution containing KYNA (0.1 µM to 1 mM) (Fig. 1B). At the lowest test concentration, i.e., 0.1 µM, KYNA reduced by ~20% the amplitude of type IA currents. On average, it took 4 min to observe the onset of the inhibitory effect of KYNA on
The inhibitory effect of KYNA on
The decay phase of type IA currents evoked by ACh in the absence and presence of KYNA (0.1 µM to 1 mM) was best fitted by a single exponential. The
7-Chloro-KYNA, a derivative of KYNA that is more potent as an NMDA receptor antagonist than the parent compound (Leeson and Iversen, 1994
KYNA inhibits presynaptic responses mediated by
In the absence of TTX, and in the continuous presence of atropine (1 µM) and the glutamate receptor antagonists APV (50 µM) and CNQX (10 µM), bursts of postsynaptic currents could be recorded from cultured hippocampal neurons that were exposed for 5 sec to choline (10 mM) (Fig. 2). These currents were sensitive to blockade by picrotoxin (100 µM; data not shown) and are herein referred to as IPSCs. They were the result of GABA released by choline-induced activation of
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Figure 2. KYNA-induced blockade of IPSCs evoked by choline in cultured hippocampal neurons. Sample recordings of choline (10 mM)-evoked IPSCs obtained before (Control), after 10 min perfusion of the hippocampal neurons with external solution containing KYNA (100 µM), and after 20 min washing of the neuron with external solution (Wash) are shown. Recordings were obtained in the presence of atropine (1 µM), CNQX (10 µM), and APV (50 µM). Membrane potential, +40 mV. Graph shows quantification of the effect of KYNA on choline-triggered IPSCs. Total charge carried by IPSCs triggered by choline was estimated by the area under the curve during the 5 sec pulse application of choline. The total charge of choline-evoked IPSCs recorded before exposure of the neurons to KYNA was taken as 100% and used to normalize the responses recorded in the presence of KYNA and after washing of the neurons. Each graph bar and error bar represent mean and SEM, respectively, of results obtained from three neurons. **p < 0.01 (paired Student's t test).
Choline-evoked IPSCs were blocked after 5 min perfusion of the hippocampal neurons with the external solution containing KYNA. At 100 µM, KYNA reduced by ~60% the net charge carried by choline-evoked IPSCs (Fig. 2). The effect of KYNA was reversed after washing of the neurons with KYNA-free external solution. At 1 mM, a concentration sufficient to block >90% of the
KYNA inhibits the activity of
Choline (10 mM, 6 sec) applied to CA1 interneurons of the stratum radiatum of rat hippocampal slices had effects that could be distinguished at different membrane potentials. At 0 mV, it triggered bursts of PSCs (Fig. 3). The events recorded at 0 mV were GABAergic in nature because the reversal potential for nicotinic and glutamatergic currents is close to 0 mV. As in the experiments performed in cultured neurons, choline-evoked GABAergic PSCs were the result of GABA released by activation of
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Figure 3. KYNA-induced blockade of choline-evoked IPSCs recorded from CA1 interneurons in rat hippocampal slices. Representative sample traces of choline (10 mM)-evoked GABAergic PSCs recorded before (Control) and after 25 min perfusion of the slices with ACSF containing KYNA (100 µM or 1 mM) are shown. Pairs of traces shown in the top and bottom panels were obtained from different neurons. Recordings were obtained in the presence of atropine (1 µM), CNQX (10 µM), and APV (50 µM). Methanesulfonate-based internal solution was used to fill the patch pipettes (see Materials and Methods). Membrane potential, 0 mV.
Perfusion of the slices with ACSF containing KYNA (100 µM or 1 mM) for 25 min resulted in the reduction of the total charge carried by choline-triggered GABAergic PSCs (Fig. 3). At 100 µM and 1 mM, KYNA reduced by 25-50 and 50-75%, respectively, the total charge carried by choline-triggered GABAergic PSCs (n = 3 for each concentration of KYNA). The magnitude of the effect of KYNA was time dependent. For instance, after 8 min perfusion of hippocampal slices with KYNA (1 mM), the total charge carried by choline-triggered GABAergic PSCs was reduced by only 30 ± 5% (n = 3 neurons). KYNA seemed less effective in inhibiting
Mechanism of action of KYNA on
Considering the slow onset of KYNA-induced inhibition of
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Figure 4. KYNA applied intracellularly has no effect on ACh-evoked type IA currents. Rundown of the peak amplitude of ACh (1 mM)-evoked type IA currents recorded from cultured hippocampal neurons using pipette solution without (Control) or with KYNA (1 mM) is shown. The amplitude of the currents evoked by the first ACh pulse in each neuron was taken as 1 and used to normalize the amplitude of currents recorded subsequently from that same neuron. Each symbol and bar represent mean and SEM, respectively, of results obtained from 54 neurons in the control group and 4 neurons in the test group. All recordings were obtained in the presence of TTX (200 nM) and atropine (1 µM). Membrane potential,
To investigate the nature of the blockade of
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Figure 5. KYNA-induced blockade of ) or presence of KYNA (30 µM;
). Under the control condition, rundown-corrected amplitudes of ACh (1 mM)-evoked currents recorded from neurons voltage clamped at
To determine the voltage dependence of KYNA-induced blockade of
KYNA on NMDA receptors in cultured hippocampal neurons: the effect of added glycine
A straightforward comparison of the sensitivity of nAChRs and NMDA receptors to blockade by KYNA would be made possible if the effects of the metabolite on both receptors were examined under the same experimental conditions. Thus, two sets of experiments were designed to determine the effects of KYNA on NMDA receptors. In one set, glycine was not added to the agonist solution. In the other set, the agonist solution consisted of NMDA (100 µM) plus glycine (10 µM).
In the absence of added glycine, 500 msec pulses of NMDA applied to the cultured hippocampal neurons elicited whole-cell currents that decayed much faster than currents evoked by the admixture of NMDA (100 µM) plus glycine (10 µM) (Figs. 6A, 7A). The
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Figure 6. KYNA-induced blockade of whole-cell currents evoked by NMDA in cultured hippocampal neurons. A, Traces are sample recordings of currents evoked by NMDA (100 µM) under control conditions (left traces), in the presence of KYNA (0.1 µM to 1 mM) after 4 min perfusion of the neurons with external solution containing KYNA (middle traces), and after 10 min washing of the neurons with KYNA-free external solution (right traces). B, Graph is the semi-logarithmic plot of the concentration-dependent inhibition of NMDA-evoked currents by KYNA. The amplitudes of currents evoked by NMDA under control condition were taken as 1 and used to normalize the amplitudes of currents recorded in the presence of KYNA. Each point and bar represent mean and SEM, respectively, of results obtained from 3-10 experiments. All recordings were obtained in the presence of TTX (200 nM). Membrane potential,
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Figure 7. KYNA-induced blockade of whole-cell currents evoked by NMDA-plus-glycine in cultured hippocampal neurons. A, Traces are sample recordings of whole-cell currents evoked by NMDA (100 µM)-plus-glycine (10 µM) under control conditions (left traces), in the presence of KYNA (30 µM to 1 mM) after 4 min perfusion of the neurons with external solution containing KYNA (middle traces), and after 10 min washing of the neurons with KYNA-free external solution (right traces). B, Graph is semi-logarithmic plot of the concentration-dependent effect of KYNA on whole-cell current evoked by NMDA-plus-glycine. The amplitudes of currents evoked by NMDA-plus-glycine under control condition were taken as 1 and used to normalize the amplitudes of currents recorded in the presence of KYNA. Each point and bar represent mean and SEM, respectively, of results obtained from four to seven experiments. All recordings were obtained in the presence of TTX (200 nM). Membrane potential,
In several experiments, the effects of KYNA on whole-cell currents evoked by either NMDA or NMDA-plus-glycine were analyzed. Currents elicited by NMDA or NMDA-plus-glycine were recorded from neurons before and during their exposure to KYNA (0.1 µM to 1 mM). After 4 min perfusion of the neurons with external solution containing KYNA, the amplitudes of currents induced by NMDA (or NMDA-plus-glycine) in the continuous presence of the drug were smaller than those of currents recorded under control conditions. The effect of KYNA on the amplitude of NMDA-elicited currents was fully reversible and concentration dependent: the higher the concentration of the drug, the lower the amplitude of the currents. Fitting the concentration-response relationship by the Hill equation revealed that, in the absence of added glycine, KYNA blocks NMDA receptors with an IC50 of 15.4 ± 2.6 µM and an nH of 0.48 ± 0.04 (Fig. 6B). In the presence of glycine (10 µM), the IC50 and the nH for KYNA in blocking NMDA receptors were 238.9 ± 5.8 µM and 0.93 ± 0.06, respectively (Fig. 7B).
Prolonged exposure of hippocampal and cerebral cortical neurons to KYNA increases expression of non-
It has been proposed that nAChR inhibition by some nicotinic antagonists leads to receptor upregulation (Dani and Heinemann, 1996
To examine changes in receptor function, nicotinic currents were evoked by ACh in 10 neurons of each treated culture dish and in 10 neurons of untreated dishes from the same batch. Three and four different cultures were treated with 1 and 10 µM KYNA, respectively. In this set of experiments, ACh was used as the agonist because, being a non-subtype selective nicotinic agonist, it could provide information regarding the function of different nAChR subtypes in the neurons. ACh-evoked currents were classified as type IA if they decayed to the baseline before the end of the agonist pulse and as non-type IA currents if they decayed to the baseline after the end of the agonist pulse. Most non-type IA currents had a rapidly decaying and a slowly decaying component, resembling type IB currents (Alkondon and Albuquerque, 1993
The average amplitude of ACh (1 mM)-evoked type IA currents recorded from neurons treated for 3 d with 1 or 10 µM KYNA was not statistically different from that of ACh-elicited currents recorded from batch-matched, untreated neurons (n = 30 or 40 neurons in each experimental group) (Table 1). However, after 3 d exposure of the hippocampal neurons to KYNA, there were changes in the pattern of nicotinic responsiveness. Of 40 neurons sampled from untreated cultures, 5 (12.5%) showed no response to ACh, 27 (67.5%) responded to ACh with fast-desensitizing, type IA currents, and 8 (20%) responded to ACh with non-type IA currents. In contrast, of 40 neurons that were sampled from cultures exposed to KYNA (10 µM), 2 (5%) showed no response to ACh, whereas 25 (62.5%) and 18 (45%) showed type IA and non-type IA currents in response to ACh, respectively (Table 1). Although the treatment with 10 µM KYNA increased significantly the non-
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Table 1. Effects of KYNA on nicotinic sensitivity of cultured hippocampal neurons Increased nicotinic sensitivity of hippocampal neurons exposed for 3 d to KYNA could be a result of enhanced expression or sensitization of non-
Nicotine induces biphasic changes in KYNA levels in rat brain
Adult male rats received injections of PBS or nicotine (1 mg/kg, s.c.) twice daily for 5 or 15 d. Animals were killed 1 hr after the last injection, and the tissue content of KYNA was measured in three areas of the rat brain: striatum, hippocampus, and frontal cortex. The levels of KYNA were substantially lower in all three brain regions of rats treated for 5 d with nicotine than in the same brain areas of control animals (Table 2). In contrast, KYNA content in all three brain areas of rats treated with nicotine for 15 d was significantly higher than that in the same areas of control animals (Table 2). Thus, these results indicate that nicotine can dynamically control the levels of KYNA in the mammalian brain.
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Table 2. Effects of systemic nicotine treatment on KYNA levels in different areas of the rat brain
DISCUSSION
The present study demonstrates that KYNA inhibits noncompetitively
KYNA: an endogenous, noncompetitive antagonist of
Results obtained from the electrophysiological experiments performed in hippocampal neurons demonstrated that KYNA is a noncompetitive antagonist of
The slow onset of the effect of KYNA on
The slope of the concentration-response relationship for KYNA was shallower than one would have expected for a simple mass interaction with a single site. The Hill coefficient below unity can be interpreted as negative cooperativity between the binding sites for KYNA on the nAChRs, whereby binding of KYNA to one site lowers the drug affinities to other receptor site(s). Negative cooperativity has been observed in other systems, including the ryanodine receptor (Carroll et al., 1991
KYNA is more potent in inhibiting
It has been reported that KYNA binds with an apparent affinity of ~8 µM to the glycine site of the NMDA receptor (Parsons et al., 1997
At physiologically relevant concentrations (Moroni et al., 1988
The mechanism underlying the effects of endogenous KYNA on neuronal excitability and viability remains unclear (Schwarcz et al., 1992
KYNA enhances non-
Prolonged exposure to KYNA increased
Reciprocal functional interactions between the nicotinic system and KYNA in the brain
In agreement with data showing that cigarette smoking reduces levels of endogenous KYNA (Milart et al., 2000
Physiopathological considerations
KYNA levels are altered in numerous multifactorial neurological disorders in which dysfunctions of various neurotransmitter systems are also evident. On the basis of results presented herein, it is tempting to speculate that
Fluctuations in brain KYNA levels can also underlie the involvement of cigarette smoking in the pathophysiology of these and other brain disorders. For example, cigarette smoking is more prevalent among individuals with schizophrenia than in normal subjects; it appears to be a means by which schizophrenics try to correct auditory gating deficits, which are caused by reduced
In summary, this is the first study to demonstrate reciprocal functional interactions between nAChRs and KYNA in the CNS. KYNA should be considered a neuromodulator in the nicotinic cholinergic system; it inhibits
FOOTNOTES Received April 27, 2001; revised July 2, 2001; accepted July 19, 2001.
This study was supported by United States Public Health Service Grants NS25296 (E.X.A.) and NS16102 (R.S.). We are indebted to Dr. Mohyee Eldefrawi for allowing the use of his laboratory and Dr. Ahmed Elnabawi for his expert assistance with the binding assays. The technical assistance of Bhagavathy Alkondon, Barbara Marrow, and Mabel Zelle is also gratefully acknowledged.
Correspondence should be addressed to Dr. Edson X. Albuquerque, Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201. E-mail: ealbuque{at}umaryland.edu.
A preliminary account of this study was presented at the 30th Annual Meeting of the Society for Neuroscience (2000).
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