AMPA Receptor Antagonist NBQX Research Articles

The AMPA receptor antagonist NBQX prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis

α-Amino-3-hydroxy-5-methylisoxazole propionic acid (AMPA) receptor-mediated excitotoxicity has been implicated in the selective motor neuron loss in amyotrophic lateral sclerosis (ALS). The extent to which excitotoxicity contributes to motor neuron death remains incompletely understood. We therefore tested the potent and selective AMPA/kainate receptor antagonist 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[ f]quinoxaline-7-sulfonamide (NBQX) on motor neurons in culture and in the G93A mouse model for familial ALS. Kainate-induced currents and changes in intracellular Ca 2+ concentration were measured with the perforated patch clamp technique combined with Ca 2+ imaging, motor neuron death was quantified by counting experiments and G93A mice were treated with saline or 8 mg/kg NBQX. NBQX blocked kainate-induced currents and concomitant changes in intracellular Ca 2+, prevented the kainate-induced motor neuron death, and prolonged survival of G93A mice.

Ability of NMDA and non-NMDA receptor antagonists to inhibit cerebral ischemic damage in aged rats

Although stroke is a major cause of death and disability in the elderly, the inhibitory effects of neuroprotectants in acute stroke have been investigated using experimental cerebral ischemic models of young animals. Recent clinical trials have found that few neuroprotectants are effective. These observations indicate that effects in the clinical setting do not always reflect data from young animals. Thus, we compared the effects of the NMDA receptor antagonist MK-801 and of the AMPA receptor antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo( F)quinixaline] on ischemic cerebral damage in the photothrombosis model of aged and young rats. MK-801 administered immediately after MCA occlusion significantly ( P<0.05) reduced the extent of cerebral damage in young, but not in aged, rats and the effects of NBQX were similar. In separate experiments, we evaluated brain damage after microinjecting NMDA or kainic acid into the cortex using a stereotaxic apparatus. We found no significant differences in focal cerebral damage caused by NMDA between young and aged rats. On the other hand, kainic acid caused all of the aged rats tested to die, but none of the young rats. Our observations indicate that NMDA and AMPA receptor antagonists are less effective in aged, than in young, rats and that cerebral damage by receptor agonists depends on the type of receptor, such as NMDA and AMPA.

Behavioral analysis of anorexia produced by hindbrain injections of AMPA receptor antagonist NBQX in rats.

The caudal brain stem integrates short-term feedback signals from the oral cavity and the food-handling abdominal viscera, as well as long-term homeostatic, cognitive, and emotional signals from the forebrain, to control ingestive behavior. Glutamate, acting on various receptor subtypes, plays a prominent role in this integrative process. Fourth ventricular injection of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptor blocker 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[f]quinoxaline-7-sulfonamide (NBQX, 0.5-5 nmol/3 microl) dose dependently suppressed intake of 15% sucrose in food-deprived and non-food-deprived rats compared with saline injection. Two consecutive paired NBQX injections (5 nmol) into the fourth ventricle did not produce conditioned taste aversion to saccharin, but LiCl did. Intraburst lick rate and lick efficiency were not affected, but burst size and number and initial lick rate were significantly decreased by NBQX. Local injection of NBQX (2 nmol) into and near the nucleus tractus solitarius also suppressed sucrose intake. These results suggest a general role for non-N-methyl-D-aspartate receptors in the transmission of positive (feedforward) signals, but do not identify the exact processing step involved, such as taste input, sensory-motor processing, or descending facilitation. More localized injections and response measures will be necessary.

The non-NMDA receptor antagonist NBQX does not affect rats performance in the object recognition task

Though the AMPA receptor has been implicated in several neudegenerative processes (epilepsy, ischemia, spasticity), its role in cognition is yet to be clarified. The aim of this study was to assess in the rat the effects of the AMPA receptor antagonist NBQX (3.5, 7, 10, 20 and 30 mgkg−1, i.p.) on learning and memory. For this purpose, the object recognition task was chosen. NBQX, at the higher doses used (20 and 30mgkg−1 ) caused respectively, depression of motility and ataxia, while given at lower doses (3.5, 7 and 10 mgkg−1) it did not influence animals performance in the object recognition paradigm. All rats acquired similarly well the task. In conclusion, these results would support and broaden previous observations on the lack of major involvement of AMPA receptors in the rat working memory mechanisms.

Inhibition of neuronal Ca 2+ influx by gabapentin and pregabalin in the human neocortex

Gabapentin and pregabalin (S-(+)-3-isobutylgaba) produced concentration-dependent inhibitions of the K +-induced [Ca 2+] i increase in fura-2-loaded human neocortical synaptosomes (IC 50=17 μM for both compounds; respective maximal inhibitions of 37 and 35%). The weaker enantiomer of pregabalin, R-(−)-3-isobutylgaba, was inactive. These findings were consistent with the potency of these drugs to inhibit [ 3H]-gabapentin binding to human neocortical membranes. The inhibitory effect of gabapentin on the K +-induced [Ca 2+] i increase was prevented by the P/Q-type voltage-gated Ca 2+ channel blocker ω-agatoxin IVA. The α2 δ-1, α2 δ-2, and α2 δ-3 subunits of voltage-gated Ca 2+ channels, presumed sites of gabapentin and pregabalin action, were detected with immunoblots of human neocortical synaptosomes. The K +-evoked release of [ 3H]-noradrenaline from human neocortical slices was inhibited by gabapentin (maximal inhibition of 31%); this effect was prevented by the AMPA receptor antagonist NBQX (2,3-dioxo-6-nitro-1,2,3,4-tetrahydro[f]quinoxaline-7-sulphonamide). Gabapentin and pregabalin may bind to the Ca 2+ channel α2 δ subunit to selectively attenuate depolarization-induced Ca 2+ influx of presynaptic P/Q-type Ca 2+ channels; this results in decreased glutamate/aspartate release from excitatory amino acid nerve terminals leading to a reduced activation of AMPA heteroreceptors on noradrenergic nerve terminals.

Long-lasting synaptic modification in the rat hippocampus resulting from NMDA receptor blockade during development.

Recent reports have suggested that proper maturation of synapses in the hippocampus requires activation of NMDA receptors. We previously demonstrated that neonatal ethanol exposure results in a lasting reduction in synaptic strength in the hippocampus. To determine if this reduction was due to ethanol's effects on NMDA receptors, we investigated long-term changes in synaptic properties resulting from administration of NMDA receptor antagonists to neonatal animals. Rats were injected daily from PND 4-9 with either the noncompetitive NMDA receptor antagonist MK-801, the competitive NMDA receptor antagonist CPP, or the AMPA receptor antagonist NBQX. Control rats were either injected daily with physiological saline during the same period or left to develop normally. Hippocampal slices were prepared from nembutal-anesthetized animals between PND 35 and PND 40. The maximum pEPSP and PS values were not significantly different between controls and NMDA antagonist-treated animals. However, slices from animals injected with NMDA receptor antagonists required higher stimulus currents to attain comparable pEPSPs. The ratio of the slope of the pEPSP to the amplitude of the presynaptic volley was also reduced, as were pEPSP responses to specific stimulus currents. None of these effects were observed in slices prepared from animals treated with the AMPA receptor antagonist NBQX. Glutamate receptor antagonism did not produce lasting changes in long-term potentiation or paired-pulse facilitation. These results indicate activation of NMDA receptors during development is necessary for proper development of synapses.

Cortical Death Caused by Striatal Administration of AMPA and Interleukin-1 is Mediated by Activation of Cortical NMDA Receptors

Striatal coadministration of interleukin-1beta (IL-1beta) with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) in rats results in widespread cortical cell death not caused by either treatment alone. This cortical damage was unaffected by cortical infusion of the AMPA-receptor antagonist NBQX. Cortical infusion of an NMDA-receptor antagonist D-AP5 significantly inhibited (57%; P < 0.05) cortical death, but had no effect on the local striatal death. Thus, cortical neuronal death induced by striatal S-AMPA and human recombinant interleukin-1beta (hrIL-1beta) is mediated by activation of NMDA receptors in the cortex. The authors propose that IL-1beta actions on AMPA-receptor mediated cell death may involve the activation of polysynaptic pathways from the striatum to the cortex.

Both glutamate receptor antagonists and prefrontal cortex lesions prevent induction of cocaine sensitization and associated neuroadaptations

Behavioral sensitization to psychomotor stimulants is accompanied by a number of alterations in the mesoaccumbens dopamine (DA) system, including DA autoreceptor subsensitivity in the ventral tegmental area (VTA) and DA D1 receptor supersensitivity in the nucleus accumbens (NAc). We investigated the role of excitatory amino acid (EAA) transmission in the induction of cocaine sensitization and these accompanying DA receptor alterations. To do so, we used three glutamate receptor antagonists, the noncompetitive NMDA receptor antagonist MK-801 (0.1 mg/kg), the competitive NMDA receptor antagonist CGS 19755 (10.0 mg/kg), and the AMPA receptor antagonist NBQX (12.5 mg/kg). Rats received daily double injections of either one of these antagonists or saline with either cocaine (15.0 mg/kg) or saline for 5 days. Cocaine sensitization was defined as an increase in horizontal locomotor activity in response to cocaine challenge (7.5 mg/kg) on the third day of withdrawal. All three antagonists prevented the induction of cocaine sensitization. Extracellular single cell recordings revealed that these antagonists also prevented the induction of DA autoreceptor subsensitivity in the VTA and DA D1 receptor supersensitivity in the NAc. To determine whether the relevant glutamate receptors were under regulation by medial prefrontal cortex (mPFC) EAA efferents, we next lesioned the mPFC bilaterally with ibotenic acid at least 7 days before repeated cocaine treatment began. These lesions also prevented the induction of cocaine sensitization and the associated neuroadaptations. Our findings indicate that glutamate transmission from mPFC to the mesoaccumbens DA system is critical for the induction of cocaine sensitization and its cellular correlates.

Comparison of the Changes in Protein Kinase C Induced by Glutamate in Primary Cortical Neurons and by in Vivo Cerebral Ischaemia

Changes in protein kinase C (PKC) were compared in primary cortical neurons exposed to glutamate and in the CA-1 hippocampal region of rats subjected to transient cerebral ischaemia. After a 15-min exposure of cortical neurons to excitotoxic levels of glutamate, a 50–60% loss of membrane PKC activity but only about a 20 % loss in the amount of enzyme was observed, suggesting that in addition to enzyme loss other mechanisms also contributed to the overall loss of membrane PKC activity. Glutamate induced a 25–40% decrease in immunodetectable levels of PKC α, β, γ, and λ but no detectable changes in PCK ϵ and ζ. The loss of PKC activity coincided with a shift in electrophoretic mobility of PKC γ, ϵ, and λ, but not of PKC α, β, or ζ, suggesting post-translational modification of some PKC isoforms. By comparison, in rats subjected to transient (15-min) global ischaemia, a similar 50–60% decrease in membrane PKC activity, a 20–25 % loss in the amount of PKC, and a shift in PKC mobility were observed in CA-1 neurons 6 h post-reperfusion. In both the in vivo and the in vitro “ischaemic” models, administration of the AMPA receptor antagonist NBQX prevented the loss of PKC activity. These results indicate that the loss of PKC observed in in vivo ischaemia is likely to be due to excitotoxic damage and that this event can be closely mirrored in primary neuronal cultures damaged by glutamate.

Slow modulation of depolarizing afterpotentials through activation of CaM KII in pyramidal cells of rat frontal cortex

Inhibition of histone deacetylases (HDACs) is a promising approach for the treatment of mood disorders. However, the effects of HDAC inhibition on the serotonin (5-HT) system, a common target for psychiatric disorders, are poorly understood. Here, we show that a broad-spectrum HDAC inhibitor, trichostatin A (TSA), enhances the function of 5-HT neurons in organotypic raphe slice cultures. Sustained treatment with TSA (1 μM) for 2 or 4 days significantly increased the 5-HT tissue content and tryptophan hydroxylase 2 (TPH2) expression, which were accompanied by hyper-acetylation of histone H3 in the promoter region of the TPH2 gene. TSA treatment for 4 days increased the extracellular 5-HT level, which was significantly suppressed in the presence of the selective AMPA receptor (AMPAR) antagonist NBQX. Moreover, the expression of both the AMPAR subunit GluA2 and Ca2+/calmodulin-dependent kinase II α (CaMKIIα) mRNAs were significantly increased by TSA treatment. Co-treatment with the CaMKII inhibitors KN-62 and KN-93 prevented the TSA-induced increase in 5-HT release, but had no effect on the increases in 5-HT tissue content. These results suggest that inhibition of HDACs increases 5-HT synthesis and release by epigenetic mechanisms, and that 5-HT release is mediated by the enhancement of AMPAR-mediated excitatory inputs and CaMKII signaling.

Glutamate-evoked currents in acutely dissociated neurons from the rat medial preoptic nucleus

Membrane currents evoked by glutamate were investigated in acutely dissociated neurons from the medial preoptic nucleus (MPN) of rat. Rapid application of glutamate induced a fast current component in all neurons studied. In addition, in >50% of the neurons, a slow current component was elicited. The fast and the slow current components were selectively blocked by the AMPA-receptor antagonist NBQX and by the NMDA-receptor channel blocker MK-801, respectively. Rapid application of AMPA induced, in all neurons tested, currents with properties similar to the fast component of the glutamate-evoked currents whereas rapid application of NMDA induced, in ≈75% of the neurons, currents similar to the slow component of the glutamate-evoked currents. The NMDA-evoked currents showed a marked outward rectification that was attributed to a potential-dependent block by extracellular Mg 2+. The NMDA-evoked currents also required the presence of extracellular glycine in the micromolar range. In conclusion, the results show that MPN neurons respond to glutamate with currents that can be attributed to activation of ionotropic glutamate receptors of the AMPA-receptor type as well as of the NMDA-receptor type.

Release of β-endorphin immunoreactivity into ventriculo-cisternal perfusate by lumbar intrathecal capsaicin in the rat

A model employing perfusion of artificial cerebrospinal fluid from the lateral ventricle to the cisterna magna in the halothane anesthetized rat was used to study β-endorphin release in the brain. Injection of 75 μg capsaicin into the lumbar intrathecal space released β-endorphin immunoreactivity into perfusate. The release was blocked by intrathecal pretreatment with 1.25 mg lidocaine and the capsaicin receptor antagonist capsazepine (92 μg), showing that the release is caused by binding of capsaicin to a spinal receptor. The release was also blocked by intrathecal pretreatment with the NMDA antagonist MK-801 (3 μg) and the NK-1 receptor antagonist CP96,345 (200 μg) , whereas the AMPA receptor antagonist NBQX (6 μg) yielded no significant inhibition. Surprisingly, morphine (30 μg) and sufentanil (1.5 μg) did not prevent release of β-endorphin immunoreactivity, although blocking the cardiovascular responses to a noxious heat stimulus. High performance liquid chromatography characterization of perfusates collected after capsaicin injection showed that all β-endorphin immunoreactivity coeluted with authentic β-endorphin 1–31. β-Endorphin immunoreactivity in plasma was increased 10 min, but not 25 min, after capsaicin injection. Capsaicin injection abolished the motor and cardiovascular responses to tail immersion in 52.5°C water. Addition of MK-801 (10 −4 mol/1) to the lateral ventricle-cisterna magna perfusate blocked the capsaicin-induced β-endorphin release, showing that our previous demonstration of an NMDA receptor regulating arcuate nucleus β-endorphin neuron activity has functional significance. We conclude that in this in vivo, anesthetized preparation including three hot water tail immersions, β-endorphin can be released into a ventriculo-cisternal perfusate, by activation of the central axons of small primary afferent neurons by capsaicin. These data support the idea that central β-endorphin may be released in response to prolonged, intense noxious stimulation.

Amphetamine induction of c- fos in the nucleus accumbens is not inhibited by glutamate antagonists

Systemic administration of relatively high doses of amphetamine or cocaine induces expression of c- fos in the rat striatum and nucleus accumbens. The doses of drugs used in such experiments are substantially higher than those needed to produce reward or sensitization. Therefore, it was determined if low doses of amphetamine capable of eliciting reward and sensitization increase levels of c-Fos protein in the nucleus accumbens. Amphetamine, 1 mg/kg, stimulated locomotor activity and increased the number of nucleus accumbens cells immunohistochemically positive for c-Fos protein to approximately 800 cells per section from a control of approximately 100 cells per section. Since glutamate antagonists modify various responses to amphetamine, it was then determined whether activation of glutamate receptors is involved in the induction of c-Fos protein by low doses of amphetamine. The NMDA receptor antagonist MK-801 by itself stimulated locomotr activity but did not alter baseline levels of c-Fos protein. When given before amphetamine, both locomotor activity and extent of c- fos induction were greater than from amphetamine alone. The AMPA receptor antagonist NBQX by itself had no effect on locomotor activity but increased slightly the number of cells positive for c-Fos protein in the nucleus accumbens. When given before amphetamine, locomotor activity was completely attenuated, and the extent of c- fos induction was greater than from amphetamine alone. We conclude that low doses of amphetamine do increase abundance of c-Fos protein in the nucleus accumbens. This action does not correlate with locomotor activity and is independent of activation of glutamate receptors.

Comparison of glutamate antagonists in continuous multiple-trial and single-trial dark avoidance

NMDA receptor antagonists (MK-801, memantine, amantadine, CGP37849), and the AMPA receptor antagonist NBQX, were tested in a continuous multiple-trial two-choice dark avoidance paradigm. During training MK-801 (0.2mg/kg) and CGP-37849 (12mg/kg) increased the number of trials to criterion. Amantadine (92mg/kg) increased all parameters except the number of trials to criterion. CGP37849 (6 and 12mg/kg) increased the number of shocks per trial. Injection of MK-801 (0.2mg/kg), memantine (20mg/kg), amantadine (92mg/kg) or CGP37849 (6 or 12mg/kg) before training decreased the latency to enter the dark compartment in the retention test 24h later. NBQX affected neither training nor retention parameters. NMDA antagonists were also tested in a single-trial two-choice dark avoidance procedure. Pre-training but not pre-retention test injection of MK-801 (0.2mg/kg), memantine (20mg/kg), amantadine (92mg/kg) or CGP37849 (12mg/kg) decreased the latency to enter the dark compartment during retention; scopolamine had similar effects. Hence, NMDA receptor antagonists, but not the AMPA receptor antagonist NBQX, impair memory storage which is also seen in animals trained to criterion, indicating that interference with the acquisition processes is not solely responsible for the memory deficit. This deficit occurs at doses that do not appear to interfere with the recall and the performance of the previously learned response.

Over-additive anticonvulsant effect of memantine and NBQX in kindled rats

We investigate the anticonvulsant and adverse effects of various dose combinations of the AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo( F) quinoxaline) and the low-affinity, rapidly channel blocking NMDA receptor antagonist memantine in the kindling model of epilepsy. While memantine was ineffective when given alone, co-administration with NBQX markedly potentiated the increase in focal seizure threshold induced by NBQX alone. This synergistic (i.e. over-additive) interaction was seen at doses of both drugs which did not induce behavioural adverse effects. The data substantiate that combinations of AMPA and NMDA receptor antagonists provide a new strategy for the treatment of epileptic seizures.

Sensitive and rapid behavioral differentiation ofN-methyl-d-aspartate receptor antagonists

Behavioral effects of PCP-type noncompetitive antagonists of N-methyl-D-aspartate (NMDA) receptors overlap with those of a host of other centrally acting compounds. In the present experiment, locomotor activity and performance on an inverted screen test in untrained mice were used to differentiate PCP-type non-competitive NMDA antagonists from other drug classes. These uncompetitive NMDA antagonists [PCP, dizocilpine, (-)-MK-801, TCP, (+)-SKF 10,047, dextrorphan, ketamine] produced dose-related increases in locomotor activity and the percentage of mice falling off an inverted, elevated wire mesh screen. Both effects demonstrated stereoselectivity, occurred at comparable dose levels, and were within the range of doses producing other biological effects (e.g., anticonvulsant). The potencies of these drugs for producing behavioral effects were positively correlated with affinities for PCP ([3H]MK-801) but not sigma([3H]SKF 10,047) receptors. Although muscarinic antagonists (benactyzine, atropine) produced effects in the same direction, locomotor stimulation was small and occurred at lower doses than those inducing screen failures. Competitive NMDA antagonists (LY 274614, LY 233536, CPP, NPC 12626), sigma receptor ligands (DTG, dextromethorphan), postsynaptic dopamine agonists (quinpirole, SKF 38393) and antagonists (haloperidol, SCH 39166), and some depressant compounds (morphine, diazepam) increased failures on the screen test but decreased locomotor activity. Ligands of the polyamine regulatory site of the NMDA receptor (ifenprodil, SL 82.0715-10) and the AMPA receptor antagonist NBQX decreased locomotor activity without increasing screen failures. An antagonist of the strychnine-insensitive glycine receptor (7-chlorokynurenic acid) did not affect performance on either test. Psychomotor stimulants (cocaine and methamphetamine) stimulated locomotor activity without affecting screen performance. The only false positives occurred with barbiturates (pentobarbital, phenobarbital). Nonetheless, the present procedure demonstrates excellent sensitivity and power for rapid discrimination of uncompetitive NMDA antagonists.

Hypoxia-Ischemia in the Neonatal Rat Brain: Histopathology after Post-Treatment with NMDA and Non NMDA Receptor Antagonists

In a model of perinatal hypoxic-ischemic brain damage, we examined the neuroprotective efficacy of posttreatment with the NMDA receptor antagonist MK-801 and the AMPA receptor antagonist NBQX. Unilateral brain damage developed in 95% of rat pups subjected to hypoxia-ischemia with a 27.8 +/- 1.2% weight deficit of the damaged hemisphere. MK-801 in doses of 0.3 and 0.5 mg/kg i.p. reduced the brain damage by 61% (p < 0.001) and 43% (p < 0.001), respectively. A higher dose of MK-801 (0.75 mg/kg) did not offer neuroprotection. Treatment with NBQX (40 mg/kg) reduced the hemispheric lesion by 28% (p < 0.05). In conclusion, posttreatment with both NBQX and low doses of MK-801 reduced perinatal brain damage. The NMDA receptor antagonist offered stronger neuroprotection which is in agreement with a proposed NMDA receptor hyperactivity around postnatal day 7 in rats.

Interaction of the competitive AMPA receptor antagonist NBQX with hexobarbital

IP administration of hexobarbital to rats caused a mean sleeping time of 93.6 min (SD 21.5). IV infusion of 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo( f)quinoxaline (NBQX) at a dose rate of 0.11 mg/kg/min starting 30 min after administration of hexobarbital prolonged the mean sleeping time to 132.2 min (SD 14.9). Dose rates of 0.33 and 1.10 mg/kg/min prolonged the mean sleeping times to 176.4 min (SD 33.3) and 444.1 min (SD 72.0), respectively. Measured 180 and 450 min after the start of the study, there were no differences in the plasma concentrations of hexobarbital in groups receiving hexobarbital alone compared to groups receiving the high-dose rate of NBQX starting 30 min after administration of hexobarbital. The present results demonstrate that by IV infusion NBQX dose dependently prolonged the sleeping time of hexobarbital. There were no indications of interactions on hexobarbital elimination of either isomer. It is therefore likely that NBQX acts synergistically with hexobarbital to depress the central nervous activity.

The AMPA receptor antagonist NBQX does not alter the motor response induced by selective dopamine agonists in MPTP-treated monkeys

We studied the motor response induced by theinistration of the AMPA receptor antagonist, NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline (1H,4H)dione sodium salt), in two parkinsonian monkeys and its interaction with the selective D-2 dopamine receptor agonist, (+)-PHNO [(+)-4-propyl-9-hydroxynaphthoxazine], and the partial dopamine D-1 receptor agonist, CY 208–243 [(−)-4,6,6a,7,8,12b-hexahydro-7-methyl-indolo[4,3a-b]phenanthyxidine]. NBNQX treatment did not reverse the parkinsonism or change the responses previously induced by dopamine agonists. These results do not support an antiparkinsonian effect of the AMPA receptor antagonist, NBQX. In addition they indicate that there is no functional interaction between AMPA and dopamine receptors in monkeys with a substantia nigra lesion.

The AMPA receptor antagonist NBQX exerts antidystonic effects in an animal model of idiopathic dystonia

The effects of the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) antagonist NBQX (2,3-dihydroxy-6-nitro-7- sulfamoyl-benzo(F)quinoxaline) were studied in an inbred line of Syrian golden hamsters with paroxysmal dystonia. The severity of dystonia in these mutant hamsters was significantly reduced by NBQX at doses of 10–20 mg/kg i.p. Coadministration of the transport inhibitor probenicid prolonged the antidystonic action of NBQX, indicating that NBQX may be rapidly eliminated by a process sensitive to probenecid. A similar potent and long-lasting antidystonic effect was obtained when NBQX was administered as an aqueous suspension rather than an aqueous solution, which may be explained by retarded absorption of NBQX after its injection as a suspension. The antidystonic activity of the AMPA antagonist NBQX may indicate that an overactivity of excitatory acidergic neurotransmission is involved in the pathophysiology of dystonia in genetically dystonic hamsters.