AMPA Antagonist Research Articles

Post-pubertal emergence of prefrontal cortical up states induced by D1-NMDA co-activation.

Dopamine-glutamate interactions may contribute to persistent electrical activity in the prefrontal cortex (PFC). We tested whether a D1 modulation of NMDA function can result in persistent depolarization in vitro. D1-NMDA co-activation yielded depolarizing plateaus resembling in vivo up states in PFC pyramidal neurons recorded in slices from adult (PD 45-65), but not pre-pubertal (PD 29-38) rats. These plateaus required intracellular Ca2+, activation of L-type Ca2+ channels and protein kinase A. These events were eliminated by intracellular administration of the voltage-gated Na+ channel blocker QX-314 or by interrupting synaptic activity with bath application of tetrodotoxin or the AMPA antagonist CNQX, suggesting that they require both intrinsic and synaptic mechanisms. These recurrent depolarizations could constitute important elements in cortical information processing, allowing synaptic plasticity and memory functions. Acquiring these PFC D1-NMDA interactions after puberty may be a critical element for developing mature cognitive abilities.

Glutamate Receptor Antagonists

GLUR5 Antagonists as Novel Migraine TherapiesBACKGROUND: L‐glutamate activates neurons in the trigeminal nucleus caudalis (TNC). Furthermore, non‐NMDA ionotropic glutamate receptors such as GluR5 are expressed in rat trigeminal ganglion (TG), and GluR5 receptors play an important role in central sensitization (CS). CS is implicated in, and the trigeminal system is at the core of, migraine. Therefore, we hypothesized that GluR5 receptor antagonists would be effective in preclinical models of migraine.OBJECTIVES: 1) To test the potency and efficacy of GluR5 antagonists with varying degrees of affinity and selectivity for the GluR5/kainate receptor in the dural plasma protein extravasation (PPE) and the c‐fos models of migraine. 2) To test these GluR5 receptor antagonists for their ability to contract the rabbit saphenous vein (RSV) in vitro.METHODS: GluR5 antagonists were synthesized in the Lilly Research Laboratories. Ligand binding studies using recombinant human non‐NMDA receptors expressed in HEK293 cell membranes were used to determine compound affinity. We evaluated parenterally administered compounds in the PPE and the c‐fos models induced by electrical stimulation of male rats TG. Fos protein in the TNC was measured in the c‐fos experiment. Ring preparations of RSV were suspended in tissue baths and isometric contractions were recorded following incremental increases in the concentration of the test compound. Sumatriptan was used as a positive control for the RSV studies.RESULTS: LY293558, LY382884 and LY435735 dose‐dependently blocked protein extravasation in the PPE model. The rank order of potency correlated with affinity for GluR5. In contrast, LY300168, a potent and selective AMPA antagonist, did not block protein extravasation, even at relatively high doses. LY293558 and LY435735 also blocked c‐fos expression in the TNC. LY293558 and LY382884 did not contract the tissue in the RSV assay at concentrations up to 100 mM.CONCLUSIONS: The inhibitory effects of GluR5 antagonists in the PPE and c‐fos preclinical models of migraine suggest a novel role for GluR5 antagonism in migraine therapy. The lack of efficacy of the selective AMPA antagonist LY300168 in PPE does not support a role for this mechanism in migraine. The lack of activity of these compounds in the RSV provides a therapeutic advantage of GluR5 antagonists over current vasoactive migraine therapies. These pharmacological properties of GluR5 antagonists suggest that they could be used in the treatment of acute migraine without a cardiovascular liability.

Rewarding effects of AMPA administration into the supramammillary or posterior hypothalamic nuclei but not the ventral tegmental area.

We examined whether injections of the excitatory amino acid AMPA are rewarding when injected into the posterior hypothalamus and ventral tegmental area. Rats quickly learned to lever-press for infusions of AMPA into the supramammillary or posterior hypothalamic nuclei but failed to learn to lever-press for similar injections into the ventral tegmental areas. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, induced conditioned place preference. The rewarding effects of AMPA appear to be mediated by AMPA receptors, because coadministration of the AMPA antagonist CNQX blocked the rewarding effects of AMPA, and administration of the enantiomer R-AMPA did not mimic the rewarding effects. AMPA injections into the supramammillary nucleus, but not the ventral tegmental area, also increased extracellular dopamine concentrations in the nucleus accumbens. Pretreatment with the D1 dopamine antagonist SCH 23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine] led to extinction of AMPA self-administration. These findings implicate posterior hypothalamic regions in reward function and suggest that reward mechanisms localized around the ventral tegmental area are more complex than has been assumed recently.

Expression of behavioral sensitization to the cocaine-like fungicide triadimefon is blocked by pretreatment with AMPA, NMDA and DA D1 receptor antagonists

Triadimefon (TDF) is a triazole fungicide that blocks the reuptake of dopamine (DA), much like cocaine. A recent study in our laboratory found that intermittent injections of TDF led to robust locomotor sensitization in response to challenge TDF after a 2-week withdrawal period. The current study sought to determine whether the expression of TDF behavioral sensitization could be prevented by the DA D1-like receptor antagonist SCH 23390 (SCH), the DA D2-like receptor antagonist remoxipride (Rem), the competitive NMDA antagonist CPP, or the AMPA antagonist NBQX. Adult male C57/BL6 mice were injected with vehicle or 75 mg/kg TDF twice a week for 7 weeks, with locomotor activity measured periodically across the 14 doses. After a 2-week withdrawal period, mice were pretreated with SCH (0.015 mg/kg), Rem (0.3 mg/kg), CPP (2.5 mg/kg) or NBQX (10.0 mg/kg) followed 30 min later by vehicle or 75 mg/kg TDF and tested for the expression of TDF sensitization. Intermittent administration of TDF led to the development and robust expression of behavioral sensitization in terms of vertical activity. Pretreatment with SCH, NBQX and CPP successfully blocked the expression of vertical sensitization to TDF, while Rem pretreatment did not. All four antagonists, however, attenuated the neurochemical changes normally associated with TDF sensitization as measured 8 h after the 2-week TDF challenge. This paper reveals that NMDA, AMPA and DA D1-like receptors are necessary for the behavioral expression of sensitization to the fungicide triadimefon.

Two Loci of expression for long-term depression at hippocampal mossy fiber-interneuron synapses.

Two distinct forms of long-term depression (LTD) exist at mossy fiber synapses between dentate gyrus granule cells and hippocampal CA3 stratum lucidum interneurons. Although induction of each form of LTD requires an elevation of postsynaptic intracellular Ca2+, at Ca2+-impermeable AMPA receptor (CI-AMPAR) synapses, induction is NMDA receptor (NMDAR) dependent, whereas LTD at Ca2+-permeable AMPA receptor (CP-AMPAR) synapses is NMDAR independent. However, the expression locus of either form of LTD is not known. Using a number of criteria, including the coefficient of variation, paired-pulse ratio, AMPA-NMDA receptor activity, and the low-affinity AMPAR antagonist gamma-D-glutamyl-glycine, we demonstrate that LTD expression at CP-AMPAR synapses is presynaptic and results from reduced transmitter release, whereas LTD expression at CI-AMPAR synapses is postsynaptic. The N-ethylmaleimide-sensitive fusion protein-AP2-clathrin adaptor protein 2 inhibitory peptide pep2m occluded LTD expression at CI-AMPAR synapses but not at CP-AMPAR synapses, confirming that CI-AMPAR LTD involves postsynaptic AMPAR trafficking. Thus, mossy fiber innervation of CA3 stratum lucidum interneurons occurs via two parallel systems targeted to either Ca2+-permeable or Ca2+-impermeable AMPA receptors, each with a distinct expression locus for long-term synaptic plasticity.

Synthesis and structure-activity relationships of 4,10-dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine derivatives: highly potent and selective AMPA receptor antagonists with in vivo activity.

The excitatory neurotransmitter glutamate interacts with ionotropic and metabotropic receptors that mediate a variety of normal signalling processes in the brain. However, excessive stimulation of these receptors appears to be involved in neurodegenerative processes, at least in animal models. Ionotropic glutamate receptors can be divided into NMDA and non-NMDA (AMPA and KA) subtypes on the basis of t heir preferential affinities for the synthetic excitatory amino acids N-methyl-D-aspartic acid (NMDA) or 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA), respectively. Although most of the early evidence favoured a role for NMDA receptors in the excitotoxic processes, it has been recognised that AMPA receptors may also be significantly involved in neuronal death. As a consequence, the synthesis of specific AMPA antagonists has raised much interest as source of potential drugs for epilepsy and acute and chronic neurodegenerative diseases. The discovery of RPR117824, a potent and selective AMPA receptors antagonist endowed with anticonvulsant and neuroprotective properties, induced growing interest on dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine series. This review covers the main chemical course leading to the most promising compounds as well as the pharmacological properties of this original class of AMPA receptor antagonists.

Effects of the group I metabotropic glutamate receptor agonist, DHPG, and injection stress on striatal cell signaling in food-restricted and ad libitum fed rats

BackgroundChronic food restriction augments the rewarding effect of centrally administered psychostimulant drugs and this effect may involve a previously documented upregulation of D-1 dopamine receptor-mediated MAP kinase signaling in nucleus accumbens (NAc) and caudate-putamen (CPu). Psychostimulants are known to induce striatal glutamate release, and group I metabotropic glutamate receptors (mGluR) have been implicated in the cellular and behavioral responses to amphetamine. The purpose of the present study was to evaluate whether chronic food restriction increases striatal MAP kinase signaling in response to the group I mGluR agonist, DHPG.ResultsWestern immunoblotting was used to demonstrate that intracerebroventricular (i.c.v.) injection of DHPG (500 nmol) produces greater activation of ERK1/2 and CREB in CPu and NAc of food-restricted as compared to ad libitum fed rats. Fos-immunostaining induced by DHPG was also stronger in CPu and NAc core of food-restricted relative to ad libitum fed rats. However, i.c.v. injection of saline-vehicle produced greater activation of ERK1/2 and CREB in CPu and NAc of food-restricted relative to ad libitum fed rats, and this difference was not seen when subjects received no i.c.v. injection prior to sacrifice. In addition, although DHPG activated Akt, there was no difference in Akt activation between feeding groups. To probe whether the augmented ERK1/2 and CREB activation in vehicle-injected food-restricted rats are mediated by one or more GluR types, effects of an NMDA antagonist (MK-801, 100 nmol), AMPA antagonist (DNQX, 10 nmol), and group I mGluR antagonist (AIDA, 100 nmol) were compared to saline-vehicle. Antagonist injections did not diminish activation of ERK1/2 or CREB.ConclusionsThese results indicate that a group I mGluR agonist induces phosphorylation of Akt, ERK1/2 and CREB in both CPu and NAc. However, group I mGluR-mediated signaling may not be upregulated in food-restricted rats. Rather, a physiological response to "i.c.v. injection stress" is augmented by food restriction and appears to summate with effects of the group I mGluR agonist in activating ERK1/2 and CREB. While the augmented cellular response of food-restricted rats to i.c.v. injection treatment represents additional evidence of enhanced CNS responsiveness in these subjects, the functional significance and underlying mechanism(s) of this effect remain to be elucidated.

Model of frequent, recurrent, and spontaneous seizures in the intact mouse hippocampus.

This study presents a model of chronic, recurrent, spontaneous seizures in the intact isolated hippocampal preparation from mice aged P8-P25. Field activity from the CA1 pyramidal cell layer was recorded and recurrent, spontaneous seizure-like events (SLEs) were observed in the presence of low Mg2+ (0.25 mM) artificial cerebrospinal fluid (ACSF). Hippocampi also showed interictal epileptiform discharges (IEDs) of 0.9-4.2 Hz occurring between seizures. No age-specific differences were found in SLE occurrence (2 SLEs per 10 min, on average), duration, and corresponding frequencies. After long exposure to low Mg2+ ACSF (>3 h), SLEs were completely reversible within minutes with the application of normal (2 mM Mg2+) ACSF. The AMPA antagonist, CNQX, blocked all epileptiform activity, whereas the NMDA antagonist, APV, did not. The gamma-aminobutyric acid (GABA)A antagonist, bicuculline, attenuated and fragmented SLEs, implicating interneurons in SLE generation. The L-type Ca2+ blocker, nifedipine, enhanced epileptiform activity. Analysis of dual site recordings along the septotemporal hippocampus demonstrated that epileptiform activity began first in the temporal pole of the hippocampus, as illustrated by disconnection experiments. Once an SLE had been established, however, the septal hippocampus was sometimes seen to lead the epileptiform activity. The whole hippocampus with intact local circuitry, treated with low Mg2+, provides a realistic model of recurrent spontaneous seizures, which may be used, in normal and genetically modified mice, to study the dynamics of seizures and seizure evolution, as well as the mechanisms of action of anti-epileptic drugs and other therapeutic modalities.

Glutamate-associated plasticity in the ventral tegmental area is necessary for conditioning environmental stimuli with morphine

We sought to determine if plasticity in the ventral tegmental area (VTA) of the midbrain is involved in learning to associate morphine exposure with a specific environment. For this, we tested whether activation of glutamate receptors and protein kinase A is needed for the acquisition and expression of a morphine-conditioned place preference (CPP). Rats received bilateral microinjections of either the NMDA antagonist AP5 (0.48 nmol/0.3 μl), the AMPA antagonist CNQX (0.21 nmol/0.3 μl), or vehicle into the VTA prior to each of three morphine-conditioning sessions. Both the AMPA and NMDA receptor antagonists blocked the development of morphine CPP when given into the VTA but not when given outside the VTA. In similar studies the protein kinase A (PKA) inhibitor, Rp-cAMPS (13 nmol/0.3 μl), blocked the acquisition of morphine CPP when given into the VTA immediately after morphine conditioning. In separate experiments, glutamate antagonists, or Rp-cAMPS, immediately prior to the preference test blocked the expression of morphine CPP when microinjected into the VTA. These data indicate that the VTA is an important site for synaptic modifications involved in the learning and memory of environmental cues predicting reward, and that glutamate input and PKA activation are crucial to this process.

Administration of a non-NMDA antagonist, gyki 52466, increases excitotoxic Purkinje cell degeneration caused by ibogaine

Ibogaine is a tremorigenic hallucinogen that has been proposed for clinical use in treating addiction. We previously reported that ibogaine, administered systemically, produces degeneration of a subset of Purkinje cells in the cerebellum, primarily within the vermis. Ablation of the inferior olive affords protection against ibogaine-induced neurotoxicity leading to the interpretation that ibogaine itself is not directly toxic to Purkinje cells. We postulated that ibogaine produces sustained excitation of inferior olivary neurons that leads to excessive glutamate release at climbing fiber terminals, causing subsequent excitotoxic injury to Purkinje cells. The neuronal degeneration induced by ibogaine provides an animal model for studying excitotoxic injury in order to analyze the contribution of glutamate receptors to this injury and to evaluate neuroprotective strategies. Since non- N-methyl- d-aspartate (NMDA) receptors mediate Purkinje cell excitation by climbing fibers, we hypothesized that 1-4-aminophenyl-methyl-7,8-methylenedioxy-5 H-2,3-benzodiazepine (GYKI-52466), which antagonizes non-NMDA receptors, may have a neuroprotective effect by blocking glutamatergic excitation at climbing fiber synapses. To test this hypothesis, rats were administered systemic ibogaine plus GYKI-52466 and the degree of neuronal injury was analyzed in cerebellar sections. The results indicate that the AMPA antagonist GYKI-52466 (10 mg/kg i.p.×3) does not protect against Purkinje cell injury at the doses used. Rather, co-administration of GYKI-52466 with ibogaine produces increased toxicity evidenced by more extensive Purkinje cell degeneration. Several hypotheses that may underlie this result are discussed. Although the reason for the increased toxicity found in this study is not fully explained, the present results show that a non-NMDA antagonist can produce increased excitotoxic injury under some conditions. Therefore, caution should be exercised before employing glutamate antagonists to reduce the risk of neuronal damage in human clinical disorders. Moreover, the contribution of different glutamate receptors to excitotoxic injury is complex and merits further analysis.

Topiramate attenuates exaggerated acoustic startle in an animal model of PTSD

Exaggerated acoustic startle is a prominent symptom of post-traumatic stress disorder (PTSD); however, its physiological basis is not well understood, and there are few available treatments. Neurobiological research has suggested that anti-kindling agents and/or glutamate antagonists can attenuate the acoustic startle response (ASR) in animal models. The anticonvulsant topiramate is an AMPA antagonist that also demonstrates potent anti-kindling effects and may, therefore, have promise in treating trauma-enhanced ASR. To evaluate the ability of topiramate to attenuate stress-induced increases in ASR in a previously validated animal model of PTSD. Male Sprague-Dawley rats ( n=36) served as controls or received single prolonged stress (SPS). SPS consisted of 2 h restraint, forced swim and ether anesthesia, then a 7-day "undisturbed" period. Animals then received vehicle, 10 mg/kg or 30 mg/kg of topiramate orally, twice daily for 7 days. ASR was assessed for all animals before and after the study, in light and dark environments. SPS produced a sustained increase in the ASR in both environments, an effect that was significantly reduced by topiramate. Meanwhile the ASR of control animals remained unaffected by topiramate. The current results provide one of the few demonstrations of a single stress episode producing sustained enhancement of ASR. In addition, topiramate demonstrates promise in treating exaggerated acoustic startle symptoms in PTSD or other stress-related disorders.

Distinct roles of the different ionotropic glutamate receptors within the nucleus accumbens in passive‐avoidance learning and memory in mice

Research on the role of the nucleus accumbens in behaviour has been largely focused on the functions of this structure in conditioning to appetitive stimuli. It has been suggested that a network comprising the nucleus accumbens and its convergent inputs might mediate dissociable functions in the acquisition, the consolidation and the retrieval of information. However, findings related to a role of this structure in aversive conditioning are somewhat contradictory, and its involvement in this form of learning is still under debate. Moreover, very little evidence is available on the step of information processing mediated by the accumbens. Thus the purpose of this study was to investigate the effects of the blockade of the AMPA and NMDA glutamate receptors, which have been suggested to mediate the transmission of information from the limbic system to this structure, on a classical aversive conditioning task - the one-trial step through inhibitory avoidance paradigm (24 h interval between training and testing). Intra-accumbens focal injections of AP-5 and DNQX (NMDA and AMPA antagonists, respectively) were performed immediately after training, before training and before testing in mice. The NMDA antagonist (37.5, 75 and 150 ng per side) impaired animal performance only if administered immediately after but not before training or before testing. Conversely, DNQX (0.5, 1.0 and 5.0 ng per side) reduced the step through latencies when administered before training and before testing. These findings suggest that NMDA receptor activation within the accumbens is necessary in formation but not expression of memory for inhibitory avoidance. AMPA receptors, instead, are necessary for the acquisition and the expression but not consolidation of inhibitory avoidance memory.

Glutamate and Amyloid β-Protein Rapidly Inhibit Fast Axonal Transport in Cultured Rat Hippocampal Neurons by Different Mechanisms

Impairment of axonal transport leads to neurodegeneration and synapse loss. Glutamate and amyloid beta-protein (Abeta) have critical roles in the pathogenesis of Alzheimer's disease (AD). Here we show that both agents rapidly inhibit fast axonal transport in cultured rat hippocampal neurons. The effect of glutamate (100 microm), but not of Abeta25-35 (20 microm), was reversible, was mimicked by NMDA or AMPA, and was blocked by NMDA and AMPA antagonists and by removal of extracellular Ca2+. The effect of Abeta25-35 was progressive and irreversible, was prevented by the actin-depolymerizing agent latrunculin B, and was mimicked by the actin-polymerizing agent jasplakinolide. Abeta25-35 induced intracellular actin aggregation, which was prevented by latrunculin B. Abeta31-35 but not Abeta15-20 exerted effects similar to those of Abeta25-35. Full-length Abeta1-42 incubated for 7 d, which specifically contained 30-100 kDa molecular weight assemblies, also caused an inhibition of axonal transport associated with intracellular actin aggregation, whereas freshly dissolved Abeta1-40, incubated Abeta1-40, and fresh Abeta1-42 had no effect. These results suggest that glutamate inhibits axonal transport via activation of NMDA and AMPA receptors and Ca2+ influx, whereas Abeta exerts its inhibitory effect via actin polymerization and aggregation. The ability of Abeta to inhibit axonal transport seems to require active amino acid residues, which is probably present in the 31-35 sequence. Full-length Abeta may be effective when it represents a structure in which these active residues can access the cell membrane. Our results may provide insight into the early pathogenetic mechanisms of AD.

Differential involvement of NMDA and AMPA receptors within the nucleus accumbens in consolidation of information necessary for place navigation and guidance strategy of mice.

Recent evidence now points to a role of glutamate transmission within the nucleus accumbens (Nacc) in spatial learning and memory. Unfortunately, the role of the distinct classes of glutamate receptors within this structure in mediating the different steps of the memorization process is not clear. The aim of this study therefore was to further investigate this issue, trying to assess the involvement of the two classes of glutamate receptors within the Nacc in consolidation of spatial information using an associative spatial task, the water maze. For this purpose, focal injections of the NMDA antagonist, AP-5, and of the AMPA antagonist, DNQX, have been performed immediately after the training phase, and mice have been tested for retention 24 h later. Two different versions of the water-maze task have been used: In the place version, animals could learn the position of the platform using visual distal cues, and in the cue version, the location of the platform was indicated by a single proximal cue. The results demonstrated that posttraining NMDA receptor blockade affects mice response in the place but not in the cue water-maze task. On the contrary, AMPA receptor blockade induced no effect in either version of the task. These data confirm a functional dissociation between glutamate receptors located in the Nacc in modulating spatial memory consolidation and indicate that they are specifically involved in consolidation of information necessary to acquire a place but not to a guidance strategy.

Multiple sclerosis and glutamate.

Experimental autoimmune encephalomyelitis reproduces in rodents the features of multiple sclerosis, an immune-mediated, disabling disorder of the human nervous system. No adequate therapy is available for multiple sclerosis, despite anti-inflammatory, immunosuppressive, and immunomodulatory measures. Increasingly glutamate is implicated in the pathogenesis of neurodegenerative diseases. Here we (1) review changes in the glutamatergic system in multiple sclerosis and (2) reveal the effects of glutamate AMPA antagonists in acute and chronic rodent models of multiple sclerosis. Administration of structurally diverse competitive and non-competitive AMPA antagonists reduces neurologic disability in rodents subjected to acute experimental autoimmune encephalomyelitis. In addition, AMPA antagonists are active in both the adoptive transfer and in chronic models of experimental autoimmune encephalomyelitis in rats and mice and affect both the acute and chronic relapsing phases. Moreover, short-term therapy with AMPA antagonists leads to sustained benefit well into the progressive phases. These results imply that therapeutic strategies for multiple sclerosis should be complemented by glutamate AMPA antagonists to reduce neurologic disability.

MAC reduction after intrathecal coadministration of GABA(A) agonist and glutamate antagonist in rats.

It has been reported that intrathecal coadministration of a GABA(A) agonist and a glutamate antagonist induces synergistic antinociceptive effects in rats. We hypothesized that this synergistic antinociceptive effect might induce a synergistic reduction in the minimum alveolar anesthetic concentration (MAC). The MAC for sevoflurane was determined before and after intrathecal administration of muscimol (GABA(A) agonist, 0.1-10 microg), AP-5 (N-methyl-D-aspartate [NMDA] antagonist, 0.1-10 microg), and YM872 (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] antagonist, 0.1-10 microg) in rats. The effects of coadministration of muscimol and AP-5 or YM872 on MAC reduction were also tested. Intrathecal administration of muscimol at doses of 1 and 10 microg significantly reduced the MAC by 34.5% +/- 3.3% and 46.9% +/- 4.4%, respectively (P < 0.01). Intrathecal administration of AP-5 at a dose of 10 microg and YM872 at a dose of 10 microg significantly reduced the MAC by 25.8% +/- 2.4% and 31.4% +/- 6.3%, respectively (P < 0.01). No additional reductions in MAC values were observed when a GABA(A) agonist was combined with either an NMDA or an AMPA antagonist. Intrathecal coadministration of a GABA(A) agonist and an NMDA or AMPA antagonist, which has been reported to produce a synergistic antinociceptive effect, did not induce a synergistic reduction in the MAC. The antinociceptive effect may not be the predominant factor in the reduction of the MAC induced by these drugs.

Expression of behavioral sensitization to ethanol by DBA/2J mice: the role of NMDA and non-NMDA glutamate receptors

Behavioral sensitization has been accorded a central role in contemporary theories of drug addiction. Accordingly, a substantial effort has been made to determine the processes mediating sensitization to psychostimulants. However, few studies have examined the mechanisms underlying sensitization to ethanol. Experiments were conducted to assess the role of N-methyl-D-aspartate (NMDA) and non-NMDA glutamate receptors in expression of sensitization to ethanol's locomotor stimulant effects. Sensitization was induced in DBA/2 J mice by administering ethanol (2 g/kg) intraperitoneally (i.p.) before four activity trials. Control groups were given saline (12.5 ml/kg i.p.) before each activity trial. Subsequently, the effects of two NMDA receptor antagonists, MK-801 and ifenprodil, and two non-NMDA glutamate receptor antagonists, DNQX and GYKI 52466, were assessed on expression of the sensitized locomotor response. MK-801 reduced the stimulant effects of ethanol and completely prevented expression of sensitization at doses exceeding 0.075 mg/kg. In contrast, although ifenprodil also reduced the stimulant effects of ethanol, the antagonist did not alter expression of sensitization. Non-NMDA glutamate antagonists were more consistent in their effects on sensitization. DNQX reduced the magnitude of the sensitized response at a low dose that did not alter the stimulant effects of ethanol. The more selective AMPA antagonist GYKI 52466 reduced the stimulant effects of ethanol and completely blocked expression of sensitization. The results provide initial evidence to suggest that both NMDA and non-NMDA glutamate receptors play a role in expression of sensitization to ethanol. Additional research will be required to elucidate the mechanisms underlying differences in the efficacy of glutamate antagonists.

Participation of AMPA- and NMDA-type excitatory amino acid receptors in the spinal reflex transmission, in rat

Classical in vitro and in vivo models and electrophysiological techniques were used to investigate the role of AMPA- and NMDA-type glutamate receptors in various components of spinal segmental reflex potentials. In the rat hemisected spinal cord preparation, the AMPA antagonists NBQX and GYKI 52466 abolished the monosynaptic reflex (MSR) potential but caused only partial inhibition of the motoneuronal population EPSP. NMDA antagonists had no noticeable effect on the MSR in normal medium, but markedly depressed the late part of EPSP. However, an NMDA receptor antagonist sensitive monosynaptic response was recorded in magnesium-free medium at complete blockade of the AMPA receptors. In spinalized rats, the AMPA antagonists completely blocked all components of the dorsal root stimulation evoked potential. MK-801 (2 mg/kg, i.v.) reduced monosynaptic responses in a frequency dependent way, with no effect at 0.03 Hz and 22% inhibition at 0.25 Hz. The reduction of the di- and polysynaptic reflex components was about 30% and did not depend on stimulation frequency. Long-latency reflex discharge responses, especially when evoked by train stimulation, were more sensitive to MK-801 than the polysynaptic reflex. These results suggest that glutamate activates MSR pathways through AMPA receptors. However, under certain conditions, NMDA receptors can modulate this transmission through plastic changes in the underlying neuronal circuits. AMPA and NMDA receptors play comparable roles in the mediation of longer latency reflex components.

Novel Quinolinone‐Phosphonic Acid AMPA Antagonists Devoid of Nephrotoxicity.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Neural Basis for Auditory Feedback Control of Vocal Pitch

Hearing one's own voice is essential for the production of correct vocalization patterns in many birds and mammals, including humans. Bats, for instance, adjust temporal, spectral, and intensity parameters of their echolocation calls by precisely monitoring the characteristics of the returning echo signals. However, neuronal substrates and mechanisms for auditory feedback control of vocalizations are still mostly unknown in any vertebrate. We used echolocating horseshoe bats to investigate the role of the midbrain and hindbrain tegmentum for the control of call frequencies in response to changing auditory feedback. These bats accurately control the frequency of their echolocation calls through auditory feedback both when the bat is at rest [resting frequency (RF)] and when it is flying and compensating for changes in echo frequency caused by flight-induced Doppler shifts [Doppler shift compensation (DSC)]. We iontophoretically injected various GABAergic and glutamatergic transmitter agonists and antagonists into the brainstem tegmentum. We found that within the parabrachial nuclei and the immediately adjacent tegmentum, excitatory effects caused by application of the glutamate agonist AMPA or the GABA(A) antagonist bicuculline raised RF and the frequency of calls emitted during DSC. Bicuculline application routinely blocked DSC altogether. Alternately, inhibitory effects caused by application of either the GABA(A) agonist muscimol or the AMPA antagonist CNQX lowered call frequencies emitted at rest and during DSC. Such an audio-vocal feedback mechanism might share basic aspects with audio-vocal feedback controlling the pitch of vocalizations in other mammals, including the involuntary response to "pitch-shifted feedback" in humans.