Regulation of striatal nitric oxide synthesis by local dopamine and glutamate interactions

Nitric oxide (NO) is a key neuromodulator of corticostriatal synaptic transmission. We have shown previously that dopamine (DA) D1/5 receptor stimulation facilitates neuronal NO synthase (nNOS) activity in the intact striatum. To study the impact of local manipulations of D1/5 and glutamatergic NMDA receptors on striatal nNOS activity, we combined the techniques of in vivo amperometry and reverse microdialysis. Striatal NO efflux was monitored proximal to the microdialysis probe in urethane‐anesthetized rats during local infusion of vehicle or drug. NO efflux elicited by systemic administration of SKF‐81297 was blocked following intrastriatal infusion of: (i) the D1/5 receptor antagonist SCH‐23390, (ii) the nNOS inhibitor 7‐nitroindazole, (iii) the non‐specific ionotropic glutamate receptor antagonist kynurenic acid, and (iv) the selective NMDA receptor antagonist 3‐phosphonopropyl‐piperazine‐2‐carboxylic acid. Glycine co‐perfusion did not affect SKF‐81297‐induced NO efflux. Furthermore, intrastriatal infusion of SKF‐81297 potentiated NO efflux evoked during electrical stimulation of the motor cortex. The facilitatory effects of cortical stimulation and SKF‐81297 were both blocked by intrastriatal infusion of SCH‐23390, indicating that striatal D1/5 receptor activation is necessary for the activation of nNOS by corticostriatal afferents. These studies demonstrate for the first time that reciprocal DA‐glutamate interactions play a critical role in stimulating striatal nNOS activity.     

Frontal cortical afferents facilitate striatal nitric oxide transmission in vivo via a NMDA receptor and neuronal NOS-dependent mechanism

Striatal nitric oxide (NO) signaling plays a critical role in modulating neural processing and motor behavior. Nitrergic interneurons receive synaptic inputs from corticostriatal neurons and are activated via ionotropic glutamate receptor stimulation. However, the afferent regulation of NO signaling is poorly characterized. The role of frontal cortical afferents in regulating NO transmission was assessed in anesthetized rats using amperometric microsensor measurements of NO efflux and local field potential recordings. Low frequency (3 Hz) electrical stimulation of the ipsilateral cortex did not consistently evoke detectable changes in striatal NO efflux. In contrast, train stimulation (30 Hz) of frontal cortical afferents facilitated NO efflux in a stimulus intensity-dependent manner. Nitric oxide efflux evoked by train stimulation was transient, reproducible over time, and attenuated by systemic administration of either the NMDA receptor antagonist MK-801 or the neuronal NO synthase inhibitors 7-nitroindazole and NG-propyl-L-arginine. The interaction between NO efflux evoked via train stimulation and local striatal neuron activity was assessed using dual microsensor and local field potential recordings carried out concurrently in the contralateral and ipsilateral striatum, respectively. Systemic administration of the non-specific NO synthase inhibitor methylene blue attenuated both evoked NO efflux and the peak oscillation frequency (within the delta band) of local field potentials recorded immediately after train stimulation. Taken together, these observations indicate that feed-forward activation of neuronal NO signaling by phasic activation of frontal cortical afferents facilitates the synchronization of glutamate driven oscillations in striatal neurons. Thus, NO signaling may act to amplify coherent corticostriatal transmission and synchronize striatal output.     

γ—氨基丁酸在联合皮层抑制C类纤维皮层诱发电位效应中的作用

电刺激猫大脑皮层前外侧回联合区(ALA)对隐神经C类纤维传入引起的体感皮层(SI)诱发电位(C-CEP)有明显的抑制作用;侧脑室注射γ-氨基丁酸(GABA)能使C-CEP的幅值显著变小,潜伏期延长,表明GABA对C-CEP也有抑制作用;侧脑室注射GABA受体拮抗剂荷包牡丹硷后,电刺激ALA对C-CEP的抑制作用明显减弱,提示内源性GABA的释放可能参与大脑皮层联合区对C-CEP的调制过程。     

GABA参与兔杏仁体抑制内膝体神经元电活动

本文采用多管微电极胞外记录技术观察了短纯音引起兔内膝神经元的声反应及刺激杏仁体对声反应的影响,并在此基础上观察电泳ＧＡＢＡ及其拮抗剂Ｂｉｃｕｃｕｌｌｉｎｅ的效应。实验结果表明：ＧＡＢＡ可以抑制ＭＧＢ神经元的声反应及自发放电活动,而ＧＡＢＡＡ拮抗剂Ｂｉｃｕｃｕｌｌｉｎｅ的作用则相反;电泳ＧＡＢＡ对ＭＧＢ神经元产生同刺激杏仁体一样的抑制产应,并且这种影响可被Ｂｉｃｕｃｕｌｌｉｎｅ翻转;嗅鼻沟后缘听区农     

Ivermectin Interactions with Benzodiazepine Receptors in Rat Cortex and Cerebellum In Vitro

Abstract: The anthelmintic macrolide, ivermectin, enhances the binding of benzodiazepine agonist ([³H]-diazepam) and antagonist ([³H]β-carboline ethyl ester) ligands to rat cortical and cerebellar membrane preparations. Enhancement of benzodiazepine agonist binding is partially additive with that of γ-aminobutyric acid (GABA) and is inhibited by etazolate, bicuculline, and the steroid GABA antagonist R5135. Ivermectin-stimulated benzodiazepine antagonist binding is enhanced by bicuculline and inhibited by GABA and etazolate. The modulatory effects of bicuculline are chloride-dependent. The stimulatory effects of ivermectin, while quantitatively different in cortex and cerebellum, are qualitatively similar in both brain regions and are reduced in the presence of chloride. Ivermectin effects on benzodiazepine ligand binding to the benzodiazepine receptor complex and the differences in the effects of GABA, bicuculline, and R5135 on ivermectin-stimulated agonist and antagonist binding may provide evidence for distinct differences in the recognition sites for the two classes of benzodiazepine receptor ligand and their interactions with other components of the receptor complex.     

Imidazoleacetic acid-ribotide in the rodent striatum: a putative neurochemical link between motor and autonomic deficits in Parkinson's disease

We have previously demonstrated that imidazole-4-acetic acid-ribotide (IAA-RP) is present in the mammalian brain and is an endogenous ligand at imidazoline binding sites. In the present study, we used a polyclonal antiserum to visualize IAA-RP-containing neurons in the rat caudoputamen. We observe IAA-RP-immunostained neurons scattered throughout the dorsal and ventral striatum. Most of these cells co-localize GABA, but none are parvalbumin-immunoreactive. In contrast, approximately 50% of the calbindin D28k-immunopositive striatal neurons co-localize IAA-RP. Electrophysiological studies using corticostriatal slices demonstrated that bath application of IAA-RP reversibly depresses the synaptically mediated component of field potentials recorded in the striatum by stimulation of cortical axons. Addition of competitive glutamate receptor antagonists completely blocks the response, confirming its association with glutamatergic transmission. Using paired-pulse stimuli, IAA-RP was shown to exert, at least in part, a presynaptic effect, but blockade of GABAA receptor-mediated transmission did not alter the response. Lastly, we show that this effect is attributable to imidazoline-1 receptors, and not to α2 adrenergic receptors. Since IAA-RP is an endogenous central regulator of blood pressure, and cardiovascular dysfunction is a common symptom associated with Parkinson's disease (PD), we speculate that IAA-RP-related abnormalities may underlie some of the autonomic dysfunction that occurs in PD.     

GABA及荷包牡丹碱对金黄地鼠上丘视觉神经...

Visual response properties of single neurons in the superior colliculus of golden hamsters could be altered by iontophoretically applied gamma-aminobutyric acid (GABA) and its antagonist, bicuculline (Bicu). GABA decreased the responses of the superficial cells to stationary flashing stimuli, while Bicu increased the responses and suppressed the inhibition exerted by the surround. The number of spikes evoked by a moving bar/spot decreased after applying GABA in 76.6% of the cells (n = 60) and increased in 90.0% (n = 60) of the cells after Bicu. Similar effects on the spontaneous activities were observed. In addition, 65.0% of the 60 cells recorded have enlarged movement receptive fields after application of Bicu. GABA and Bicu have some effects on the orientation selectivity of the collicular cells too.     

Stress-Induced Enhancement of Suppression of [3H]GABA Release from Striatal Slices by Presynaptic Autoreceptor

The effect of cold and immobilization stress on presynaptic GABAergic autoreceptors was examined using the release of [3H]GABA (gamma-aminobutyric acid) from slices of rat striatum. It was found that in vitro addition of delta-aminolevulinic acid, as well as GABA agonists such as muscimol and imidazoleacetic acid, exhibited a significant suppression of the striatal release of [3H]GABA evoked by the addition of high potassium, whereas delta-aminovaleric acid had no significant effects on the evoked release. These suppressive actions were antagonized invariably by the GABA antagonists, bicuculline and picrotoxin, but not by the glycine antagonist, strychnine. Cholinergic agonists, such as pilocarpine and tetramethylammonium, also attenuated significantly the evoked release of [3H]GABA from striatal slices, while none of its antagonists, including atropine, hexamethonium and d-tubocurarine, affected the release. On the other hand, in vitro addition of dopamine receptor agents such as dopamine, apomorphine, and haloperidol, or the inhibitory amino acids, glycine, beta-alanine, and taurine failed to influence the evoked release of [3H]GABA from striatal slices. Application of a cold and immobilization stress for 3 h was found to induce a significant enhancement of the suppressive effects by muscimol and delta-aminolevulinic acid on the evoked release of [3H]GABA, without affecting that by pilocarpine and tetramethylammonium. These results suggest that the release of GABA from striatal GABA neurons may be regulated by presynaptic autoreceptors for this neuroactive amino acid, and may play a significant functional role in the exhibition of various symptoms induced by stress.     

Pain and neurotransmitters

1. To study physiological roles of substance P (SP), gamma-aminobutyric acid (GABA), enkephalins and other endogenous substances, we developed several kinds of isolated spinal cord preparations of newborn rats. 2. In these preparations, various slow responses of spinal neurons evoked by stimulation of primary afferent C fibers were depressed by a tachykinin antagonist, spantide. These results together with many other lines of evidence suggest that SP and neurokinin A serve as pain transmitters in a subpopulation of primary afferent C fibers. 3. Some C-fiber responses in various isolated spinal cord preparations were depressed by GABA, muscimol, and opioid peptides. In contrast, bicuculline (GABA antagonist) and naloxone (opioid antagonist) potentiated the "tail pinch potential," i.e., a nociceptive response of the ventral root evoked by pinch stimulation of the tail in isolated spinal cord-tail preparation of the newborn rat. The latter results support the hypothesis that some primary afferents activate inhibitory spinal interneurons which release GABA and enkephalins as transmitters to modulate pain inputs.     

NR2A-containing NMDA receptors depress glutamatergic synaptic transmission and evoked-dopamine release in the mouse striatum

NMDA receptors play essential roles in the physiology and pathophysiology of the striatum, a brain nucleus involved in motor control and reward-motivated behaviors. NMDA receptors are composed of NR1 and NR2A–D subunits. Functional properties of NMDA receptors are determined by the type of NR2 subunit they contain. In this study, we have examined the involvement of NR2B and NR2A in the modulatory effect of NMDA on glutamatergic and dopaminergic synaptic transmission in the striatum. We found that bath application of NMDA decreased the amplitude of the field excitatory post-synaptic potential/population spike (fEPSP/PS) measured in corticostriatal mouse brain slices. This depression was not affected by the NR2B-selective antagonists Ifenprodil and Ro 25-6981, but was abolished by the NR2A antagonist NVP-AAM077. Activation of corticostriatal neurons by NMDA did not contribute to synaptic depression because similar results were obtained in decorticated striatal slices. Synaptic depression was not dependent on GABA release because the GABA_A receptor antagonist bicuculline did not affect NMDA-induced decrease of the fEPSP/PS. NMDA also depressed evoked-dopamine release through NR2A- but not NR2B-containing NMDA receptors. Our results identify an important role for NR2A-containing NMDA receptors intrinsic to the striatum in regulating glutamatergic synaptic transmission and evoked-dopamine release.     

GABAB receptors in the NTS mediate the inhibitory effect of trigeminal nociceptive inputs on parasympathetic reflex vasodilation in the rat masseter muscle

The present study was designed to examine whether trigeminal nociceptive inputs are involved in the modulation of parasympathetic reflex vasodilation in the jaw muscles. This was accomplished by investigating the effects of noxious stimulation to the orofacial area with capsaicin, and by microinjecting GABA(A) and GABA(B) receptor agonists or antagonists into the nucleus of the solitary tract (NTS), on masseter hemodynamics in urethane-anesthetized rats. Electrical stimulation of the central cut end of the cervical vagus nerve (cVN) in sympathectomized animals bilaterally increased blood flow in the masseter muscle (MBF). Increases in MBF evoked by cVN stimulation were markedly reduced following injection of capsaicin into the anterior tongue in the distribution of the lingual nerve or lower lip, but not when injected into the skin of the dorsum of the foot. Intravenous administration of either phentolamine or propranolol had no effect on the inhibitory effects of capsaicin injection on the increases of MBF evoked by cVN stimulation, which were largely abolished by microinjecting the GABA(B) receptor agonist baclofen into the NTS. Microinjection of the GABA(B) receptor antagonist CGP-35348 into the NTS markedly attenuated the capsaicin-induced inhibition of MBF increase evoked by cVN stimulation, while microinjection of the GABA(A) receptor antagonist bicuculline did not. Our results indicate that trigeminal nociceptive inputs inhibit vagal-parasympathetic reflex vasodilation in the masseter muscle and suggest that the activation of GABA(B) rather than GABA(A) receptors underlies the observed inhibition in the NTS.     

GABA介导杏仁外侧核对皮层A Ⅰ区神经元声反应的抑制:在体微电泳研究

在SD大鼠上应用多顺利完成微电极方法,观察微电泳CABA及其受体的拮抗剂或激动剂对杏仁外侧核（LA）抑制皮层AⅠ神经元声反应效应的影响。结果显示,电泳GABA能抑制皮层AⅠ区神经元的电活动,电泳GABAA受体拮抗剂bicuculline（BIC）则能易化其反应;电刺激LA能抑制皮层AⅠ区听神经元声反应,电泳GABA产生类拟于刺激LA的抑制效应;LA对皮层AⅠ区神经的抑制效应能被BIC所翻转,而不能被什氨酸受体拮抗剂strychnine所翻转,电泳GABAB型受体例激动剂baclofen对神经元声反应无影响。上术结果表明,GABA可能是介民LA抑制皮层AⅠ区神经元声反应的最终递质,并且是通过GABAA受体作用的。     

Dizocilpine Inhibits Amphetamine-Induced Formation of Nitric Oxide and Amphetamine-Induced Release of Amino Acids and Acetylcholine in the Rat Brain

Glutamate receptor activation participates in mediation of neurotoxic effects in the striatum induced by the psychomotor stimulant amphetamine. The effects of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) on amphetamine-induced toxicity and formation of nitric oxide (NO) in both striatum and cortex and on induced transmitter release in the nucleus accumbens were investigated. Repeated, systemic application of amphetamine elevated striatal and cortical lipid peroxidation and NO production. Moreover, amphetamine caused an immediate release of acetylcholine and aspartate and a delayed release of GABA in the nucleus accumbens. Surprisingly, glutamate release was not affected. Dizocilpine abolished the amphetamine-induced lipid peroxidation and NO production in striatum and cortex and diminished the elevation of neurotransmitter release. These findings suggest that amphetamine evokes neurotoxic effects in both striatal and cortical brain areas that are prevented by inhibiting NMDA receptor activation. The amphetamine-induced acetylcholine, aspartate and GABA release in the nucleus accumbens is also mediated through NMDA receptor-dependent mechanisms. Interestingly, the enhanced aspartate release might contribute to NMDA receptor activation in the nucleus accumbens, while glutamate does not seem to mediate amphetamine-evoked transmitter release in this striatal brain area.     

Central integration of muscle reflex and arterial baroreflex in midbrain periaqueductal gray: roles of GABA and NO

It has been suggested that the midbrain periaqueductal gray (PAG) is a neural integrating site for the interaction between the muscle pressor reflex and the arterial baroreceptor reflex. The underlying mechanisms are poorly understood. The purpose of this study was to examine the roles of GABA and nitric oxide (NO) in modulating the PAG integration of both reflexes. To activate muscle afferents, static contraction of the triceps surae muscle was evoked by electrical stimulation of the L7 and S1 ventral roots of 18 anesthetized cats. In the first group of experiments (n = 6), the pressor response to muscle contraction was attenuated by bilateral microinjection of muscimol (a GABA receptor agonist) into the lateral PAG [change in mean arterial pressure (DeltaMAP) = 24 +/- 5 vs. 46 +/- 8 mmHg in control]. Conversely, the pressor response was significantly augmented by 0.1 mM bicuculline, a GABAA receptor antagonist (DeltaMAP = 65 +/- 10 mmHg). In addition, the effect of GABAA receptor blockade on the reflex response was significantly blunted after sinoaortic denervation and vagotomy (n = 4). In the second group of experiments (n = 8), the pressor response to contraction was significantly attenuated by microinjection of L-arginine into the lateral PAG (DeltaMAP = 26 +/- 4 mmHg after L-arginine injection vs. 45 +/- 7 mmHg in control). The effect of NO attenuation was antagonized by bicuculline and was reduced after denervation. These data demonstrate that GABA and NO within the PAG modulate the pressor response to muscle contraction and that NO attenuation of the muscle pressor reflex is mediated via arterial baroreflex-engaged GABA increase. The results suggest that the PAG plays an important role in modulating cardiovascular responses when muscle afferents are activated.     

Comparative electrophysiological characteristics of afferent representation in the cortical and striatal divisions of the turtle forebrain

In experiments on immobilized, lightly anesthetized turtles the presence of visual and somatic representation was established in the subcortical striatal division of the forebrain — the pallial thickening, the dorsal ventricular ridge, and the putamen. In their physiological characteristics they are similar to the corresponding representation in the general cortex. The absence of significant differences between the latent periods of cortical and striatal evoked potentials to flashes and to stimulation of the dorsal thalamus indicates that visual projection fibers (from the lateral geniculate body) terminate at both cortical and striatal levels. Differences in the distribution of latent periods of unit responses in the cortex to visual and thalamic stimulation are due to the presence of a rotundo-telencephalic visual channel, with direct connections with the striatal and polysynaptic connections with the general cortex, as well as the geniculo-telencephalic tract. Considerable differences between the latent periods of the evoked potentials and also between unit responses to electrodermal stimulation in the cortical and striatal structures indicate that somatic projection fibers relay in the striatum on their path to the general cortex. Consequently, the somatosensory system of turtles is less corticalized than the visual system. Comparison of the results described with those obtained by workers studying other vertebrates suggests that the afferent supply of the striatum may be reorganized in the transition from premammals to mammals.I. M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Academy of Sciences of the USSR, Leningrad. Translated from Neirofiziologiya, Vol. 7, No. 2, pp. 184–193, March–April, 1973.     

GABAergic Modulation of Striatal Cholinergic Interneurons: An In Vivo Microdialysis Study

Abstract: Striatal cholinergic interneurons have been shown to receive input from Striatal γ-aminobutyric acid (GABA)-containing cell elements. GABA is known to act on two different types of receptors, the GABA_A and the GABA₆ receptor. Using in vivo microdialysis, we have studied the effect of intrastriatal application of the GABA_A-selective compounds muscimol and bicuculline and the GA- BA_B-selective compounds baclofen and 2-hydroxysaclofen, agonists and antagonists, respectively, at GABA receptors, on the output of Striatal acetylcholine (ACh). Intrastriatal infusion of 1 and 10 μmol/L concentrations of the GABA_A antagonist bicuculline resulted in a significant increase in Striatal ACh output, whereas infusion of 1 and 10 /μmol/L concentrations of the GABA_A agonist muscimol significantly decreased the output of Striatal ACh. Both compounds were ineffective in changing the output of Striatal ACh at lower concentrations. Infusion of concentrations up to 100 μmol/L of the GABA_B-selective antagonist 2-hydroxy-saclofen failed to affect Striatal ACh output, whereas infusion of 10 and 100 μmol/L baclofen, but not 0.1 and 1 μmol/L baclofen, significantly decreased the output of Striatal ACh. Thus, agonist-stimulation of GABAA and GABA_B receptors decreases the output of striatal ACh in a dose-dependent fashion, whereas the GABAergic system appears to inhibit tonically the output of striatal ACh via GABA_A receptors, but not via GABA_B receptors. We hypothesize that although GABA_A mediated regulation of striatal ACh occurs via GABA receptors on the cholinergic neuron, the GABA_B mediated effects may be explained by presynaptic inhibition of the glutamatergic input of the striatal cholinergic neuron.     

N-甲基-D-天冬氨酸和γ-氨基丁酸对蝙蝠下丘薄片诱发电活动的影响

在47只不同年龄的蝙蝠的86张中脑下丘的冠状薄片上 ,电刺激外侧丘系 ,记录到149例下丘中央核的诱发场电位。分别观察了微电泳N -甲基 -D -天冬氨酸 (NMDA)、2 -氨基 -5 -磷酸戊酸 (2 -APV)、γ -氨基丁酸 (GABA)、荷包牡丹碱 (bicuculline)等对下丘中央核诱发场电位幅度的影响。实验结果表明 ,外侧丘系对蝙蝠中脑下丘中央核的传入影响可能主要由GABA、Glu以及GABAA 、NMDA受体所介导 ;在不同的年龄组 ,对NMDA及GABA等反应的诱发单位比例基本一致、反应幅度无显著差异。鉴于蝙蝠整体实验的结果表明 ,中脑下丘中央核听反应神经元的GA BA能输入在出生后早期存在显著的发育过程。根据对诱发电位幅度的分析结果 ,推测这种GABA能输入在出生后早期的增长可能源于高位中枢的下行投射。     

N-甲基-D-天冬氨酸和γ-氨基丁酸对蝙蝠下丘薄片诱发电活动的影响

在４７只不同年龄的蝙蝠的８６张中脑下丘的冠状薄片上,电刺激外侧丘系,记录到１４９例下丘中央核的诱发场电位。分别观察了微电泳Ｎ－甲基－Ｄ－天冬氨酸（ＮＭＤＡ）、２－氨基－５－磷酸戊酸（２－ＡＰＶ）、γ－氨基丁酸（ＧＡＢＡ）、荷包牡丹碱（ｂｉｃｕｃｕｌｌｉｎｅ）等对下丘中央核诱发场电位幅度的影响。实验结果表明,外侧丘系对蝙蝠中脑下丘中央核的传入影响可能主要由由ＧＡＢＡ、Ｇｌｕ以及ＧＡＢＡＡ、ＮＭＤＡ受     

Activation of central adenosine A(2A) receptors enhances superior laryngeal nerve stimulation-induced apnea in piglets via a GABAergic pathway.

Activation of the laryngeal mucosa results in apnea that is mediated through, and can be elicited via electrical stimulation of, the superior laryngeal nerve (SLN). This potent inhibitory reflex has been suggested to play a role in the pathogenesis of apnea of prematurity and sudden infant death syndrome, and it is attenuated by theophylline and blockade of GABA(A) receptors. However, the interaction between GABA and adenosine in the production of SLN stimulation-induced apnea has not been previously examined. We hypothesized that activation of adenosine A(2A) receptors will enhance apnea induced by SLN stimulation while subsequent blockade of GABA(A) receptors will reverse the effect of A(2A) receptor activation. The phrenic nerve responses to increasing levels of SLN stimulation were measured before and after sequential intracisternal administration of the adenosine A(2A) receptor agonist CGS (n = 10) and GABA(A) receptor blocker bicuculline (n = 7) in ventilated, vagotomized, decerebrate, and paralyzed newborn piglets. Increasing levels of SLN stimulation caused progressive inhibition of phrenic activity and lead to apnea during higher levels of stimulation. CGS caused inhibition of baseline phrenic activity, hypotension, and enhancement of apnea induced by SLN stimulation. Subsequent bicuculline administration reversed the effects of CGS and prevented the production of apnea compared with control at higher SLN stimulation levels. We conclude that activation of adenosine A(2A) receptors enhances SLN stimulation-induced apnea probably via a GABAergic pathway. We speculate that SLN stimulation causes endogenous release of adenosine that activates A(2A) receptors on GABAergic neurons, resulting in the release of GABA at inspiratory neurons and subsequent respiratory inhibition.     

Chronic blockade of N-methyl-D-aspartate receptors alters gamma-aminobutyric acid type A receptor peptide expression and function in the rat

Chronic in vivo or in vitro application of GABA(A) receptor agonists alters GABA(A) receptor peptide expression and function. Furthermore, chronic in vitro application of N-methyl-D-aspartate (NMDA) agonists and antagonists alters GABA(A) receptor function and mRNA expression. However, it is unknown if chronic in vivo blockade of NMDA receptors alters GABA(A) receptor function and peptide expression in brain. Male Sprague-Dawley rats were chronically administered the noncompetitive NMDA receptor antagonist MK-801 (0.40 mg/kg, twice daily) for 14 days. Chronic blockade of NMDA receptors significantly increased hippocampal GABA(A) receptor alpha4 and gamma2 subunit expression while significantly decreasing hippocampal GABA(A) receptor alpha2 and beta2/3 subunit expression. Hippocampal GABA(A) receptor alpha1 subunit peptide expression was not altered. In contrast, no significant alterations in GABA(A) receptor subunit expression were found in cerebral cortex. Chronic MK-801 administration also significantly decreased GABA(A) receptor-mediated hippocampal Cl- uptake, whereas no change was found in GABA(A) receptor-mediated cerebral cortical Cl- uptake. Finally, chronic MK-801 administration did not alter NMDA receptor NR1, NR2A, or NR2B subunit peptide expression in either the cerebral cortex or the hippocampus. These data demonstrate heterogeneous regulation of GABA(A) receptors by glutamatergic activity in rat hippocampus but not cerebral cortex, suggesting a new mechanism of GABA(A) receptor regulation in brain.