Effects Of AMPA Receptor Antagonists Research Articles

PTEN Is Required for The Anti-Epileptic Effects of AMPA Receptor Antagonists in Chronic Epileptic Rats.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) is one of the ligand-gated ion channels for glutamate, which is an important player in the generation and spread of seizures. The efficacy of AMPAR functionality is regulated by the trafficking, synaptic targeting, and phosphorylation. Paradoxically, AMPAR expression and its phosphorylation level are decreased in the epileptic hippocampus. Therefore, the roles of AMPAR in seizure onset and neuronal hyperexcitability in ictogenesis remain to be elucidated. In the present study, we found that AMPAR antagonists (perampanel and GYKI 52466) decreased glutamate ionotropic receptor AMPA type subunit 1 (GRIA1) surface expression in the epileptic rat hippocampus. They also upregulated phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expression and restored to basal levels the upregulated phosphoinositide 3-kinase (PI3K)/AKT1 phosphorylations. Dipotassium bisperoxovanadium(pic) dihydrate (BpV(pic), a PTEN inhibitor) co-treatment abolished the anti-epileptic effects of perampanel and GYKI 52466. Therefore, our findings suggest that PTEN may be required for the anti-epileptic effects of AMPAR antagonists.

Effects of AMPA receptor antagonist, NBQX, and extrasynaptic GABAA agonist, THIP, on social behavior of adolescent and adult rats.

Adolescence is characterized by high significance of social interactions, along with a propensity to exhibit social facilitating effects of ethanol while being less sensitive than adults to the inhibition of social behavior that emerges at higher doses of ethanol. Among the neural characteristics of adolescence are generally enhanced levels of glutamatergic (especially NMDA receptor) activity relative to adults, whereas the GABA system is still developmentally immature. Activation of NMDA receptors likely plays a role in modulation of social behavior in adolescent animals as well as in socially facilitating and suppressing effects of ethanol. For instance, adolescent and adult rats differ in their sensitivities to the effects of NMDA antagonists and ethanol on social behavior, with adolescents but not adults demonstrating social facilitation at lower doses of both drugs and adults being more sensitive to the socially suppressing effects evident at higher doses of each. The roles of AMPA and extrasynaptic GABAA receptors in modulation of social behavior during adolescence and in adulthood are still unknown. The present study was designed to assess whether pharmacological blockade of AMPA receptors and/or activation of extrasynaptic GABAA receptors results in age-dependent alterations of social behavior. Adolescent and adult male and female Sprague-Dawley rats were injected with an assigned dose of either a selective AMPA antagonist, NBQX (Experiment 1) or extrasynaptic GABAA agonist, THIP (Experiment 2) and placed into a modified social interaction chamber for a 30-min habituation period prior to a 10-min social interaction test with a novel age- and sex-matched partner. Behaviors such as social investigation, contact behavior and play behavior were scored from video recordings of the interaction tests. In Experiment 1, NBQX produced similar social inhibition at higher doses in both age groups. In Experiment 2, THIP induced inhibition in adolescents, but not adults. No social facilitation was evident following low doses of either drug. Therefore, AMPA and extrasynaptic GABAA receptors appear to play little role if any in modulation of peer-directed social behavior in adolescence and adulthood and not likely to contribute to previously observed age differences in the social effects of acute ethanol.

Rewarding and incentive motivational effects of excitatory amino acid receptor antagonists into the median raphe and adjacent regions of the rat.

The motivational process that regulates approach behavior toward salient distal stimuli (i.e., incentive motivation) plays a key role in voluntary behavior and motivational disorders such as addiction. This process may be mediated by many neurotransmitter systems and a network of many brain structures, including the median and dorsal raphe regions (MR and DR, respectively). We sought to examine whether the blockade of excitatory amino acid receptors in the MR and DR is rewarding, using intracranial self-administration, and whether the self-administration effect can be explained by drug's effectiveness to enhance incentive motivation, using a visual sensation seeking procedure. Rats learned to self-administer the AMPA receptor antagonist ZK 200775 into the vicinity of the MR, DR, or medial oral pontine reticular regions, but not the ventral tegmental area. The NMDA receptor antagonist AP5 was also self-administered into the MR, while it was not readily self-administered into other regions. When ZK 200775 was noncontingently administered into the MR, rats markedly increased approach responses rewarded by brief illumination of a light stimulus. In addition, contingent administration of ZK 200775 into the MR induced a conditioning effect on approach responses. Rats self-administer excitatory amino acid receptor antagonists into the MR and adjacent regions. Self-administration effect of AMPA receptor antagonists into the MR can be largely explained by the manipulation's properties to invigorate ongoing approach behavior and induces conditioned approach. Glutamatergic afferents to the median raphe and adjacent regions appear to tonically suppress incentive-motivational processes.

Modification of ionotropic glutamate receptor–mediated processes in the rat hippocampus following repeated, brief seizures

The seizure-induced molecular and functional alterations of glutamatergic transmission in the hippocampus have been investigated. Daily repeated epileptic seizures were induced for 12 days by intraperitoneal administration of 4-aminopyridine (4-AP; 4.5 mg/kg) in adult Wistar rats. The seizure symptoms were evaluated on the Racine's scale. One day after the last injection, the brains were removed for in vitro electrophysiological experiments and immunohistochemical analysis. The glutamate receptor subunits NR1, NR2A, NR2B, GluR1, GluR1flop, GluR2, and KA-2 were studied using the histoblotting method. The semi-quantitative analysis of subunit immunoreactivities in hippocampal layers was performed with densitometry. In the hippocampus, increase of GluR1, GluR1flop and NR2B immunostaining was observed in most of the areas and layers. The significant decrease of GluR2 staining intensity was observed in the CA1 and dentate gyrus. Calcium permeability of hippocampal neurons was tested by a cobalt uptake assay in hippocampal slices. The uptake of cobalt increased in the CA1 area and dentate gyrus, but not in the CA3 region following 4-AP treatment. Effects of AMPA and NMDA (N-methyl-d-aspartate) glutamate receptor antagonists (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride (GYKI 52466) and D-APV respectively) were measured in hippocampal slices using extracellular recording. Analysis of the population spikes revealed the reduced effectiveness of the AMPA receptor antagonist GYKI 52466, while the effect of the NMDA receptor antagonist d-(2R)-amino-5-phosphonovaleric acid was similar to controls. The results demonstrated that repeated convulsions induced structural and functional changes in AMPA receptor–mediated transmission, while NMDA and kainate receptor systems displayed only alterations in receptor subunit composition.

Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection

Neuronal cell death during fatal acute viral encephalomyelitis can result from damage caused by virus replication, glutamate excitotoxicity, and the immune response. A neurovirulent strain of the alphavirus Sindbis virus (NSV) causes fatal encephalomyelitis associated with motor neuron death in adult C57BL/6 mice that can be prevented by treatment with the prototypic noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor antagonist GYKI 52466 [Nargi-Aizenman J, et al. (2004) Ann Neurol 55:541-549]. To determine the mechanism of protection, NSV-infected mice were treated with 7-acetyl-5-(4-aminophenyl)-8(R)-methyl-8,9-dihydro-7H-1,3-dioxolo-(4,5-h)-benzodiazepine (talampanel), a potent, orally available member of the 2,3 benzodiazepine class of noncompetitive AMPA glutamate receptor antagonists. Talampanel-treated mice were protected from NSV-induced paralysis and death. Examination of the brain during infection showed significantly less mononuclear cell infiltration and no increase in astrocyte expression of glial fibrillary acidic protein in treated mice compared with untreated mice. Lack of CNS inflammation was attributable to failure of treated mice to induce activation and proliferation of lymphocytes in secondary lymphoid tissue in response to infection. Antibody responses to NSV were also suppressed by talampanel treatment, and virus clearance was delayed. These studies reveal a previously unrecognized effect of AMPA receptor antagonists on the immune response and suggest that prevention of immune-mediated damage, in addition to inhibition of excitotoxicity, is a mechanism by which these drugs protect from death of motor neurons caused by viral infection.

Glutamate and dopamine receptors contribute to the lateral spread of epileptiform discharges in rat neocortical slices

The effects of AMPA-type glutamate receptor as well as dopamine D1 and D2 receptors on the lateral propagation of epileptiform field potentials (EFP) were studied across adjacent areas of rat neocortical tissues. Epileptiform burst discharges were induced by superfusion of Mg(2+)-free artificial cerebrospinal fluid. Simultaneous field potential recordings of EFP were obtained from four microelectrodes placed 2-3 mm apart across coronal slices in the third layer of the neocortex. The effects of AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), dopamine D1 receptor agonist SKF 81297, and dopamine D2 receptor agonist quinpirole on lateral propagation of burst discharges were investigated. CNQX, applied focally between recording sites, blocked rapid propagation across treated areas and resulted in the emergence of spatially separate, independent pacemakers. Focal application of SKF 81297 between recording sites increased the repetition rate of EFP, but reduced the amplitude as well as the duration of epileptic discharges. However, addition of SKF 81297 to the bath medium abolished EFP. Both local and systemic applications of quinpirole irreversibly enhanced repetition rate of epileptiform burst discharges. The results indicate the prerequisite of AMPA synaptic transmission for synchronized lateral propagation of Mg(2+)-free ACSF-induced epileptic activity and the modulatory effects of dopamine D1 and D2 receptors on both EFP initiation and propagation in epileptic tissues.

Acute effects of AMPA-type glutamate receptor antagonists on intermale social behavior in two mouse lines bidirectionally selected for offensive aggression

Involvement of AMPA-type glutamate receptors in the regulation of social behavior has been suggested by experiments with mice deficient for the GluR-A subunit-containing AMPA receptors showing reduced intermale aggression. In the present study, effects of AMPA receptor antagonists on mouse social behavior towards unfamiliar Swiss–Webster males on a neutral territory were tested using male subjects from the Turku Aggressive (TA) and Turku Non-Aggressive (TNA) mouse lines bidirectionally selected for high and low levels of offensive aggression. The drugs were the competitive antagonists 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), and the non-competitive antagonist 4-(8-methyl-9 H-1,3-dioxolo[4,5- h][2,3]benzodiazepin-5-yl)-benzenamine (GYKI 52466). In TA mice, CNQX and NBQX decreased the biting component of aggressive structure, while GYKI 52466 suppressed all aggressive manifestations. All drugs increased anxiety-like behavior towards the partner. In TNA mice, NBQX activated mouse social behavior and ambivalent aggression, while CNQX and GYKI 52466 only increased anxiety. Thus, AMPA receptor antagonists affect aggressive behaviors in TA mice supporting the idea that AMPA receptors are involved in the modulation of agonistic impulsive behavioral pattern. GYKI 52466 appeared to be the most selective and efficacious in suppressing the aggression.

Atypical antipsychotic-like effect of AMPA receptor antagonists in the rat.

Systemic administration of two chemically different AMPA receptor antagonists, GYKI52466, 20mg/kg, and LY326325, 18mg/kg, given subcutaneously, caused a selective suppression of conditioned avoidance response in the rat with preservation of escape behavior. The number of intertrial crosses was not affected and no catalepsy was observed. These experimental results indicate, in principle, an antipsychotic effect of AMPA receptor antagonists with a low liability for extrapyramidal side effects and, consequently, a pharmacological profile consonant with atypical antipsychotic drugs.

Antipsychotic-like effect of the AMPA receptor antagonist LY326325 as indicated by suppression of conditioned avoidance response in the rat.

The effect of LY326325, a novel AMPA receptor antagonist, on the conditioned avoidance response and catalepsy was investigated in the rat. The conditioned avoidance response is a behavioral methodology which is regarded to predict potential antipsychotic efficacy of experimental drugs. Catalepsy ratings were utilized to assess the putative propensity of LY325326 to induce extrapyramidal side effects. Systemic administration of LY326325, 18 mg/kg subcutaneously, caused a selective suppression of conditioned avoidance response, without effect on escape behavior or intertrial crosses. In addition, no catalepsy was observed. Our present and previous results support an antipsychotic effect of AMPA receptor antagonists with a low liability for extrapyramidal side effects, i.e. pharmacological effects consonant with an atypical antipsychotic profile.