Kynurenic acid blocks suprachiasmatic nucleus responses to optic nerve stimulation

An in vitro slice preparation of the mouse hypothalamus was used to determine the effects of pharmacological agents on the field potentials that are evoked in the suprachiasmatic nucleus (SCN) by stimulation of the optic nerve. Postsynaptic components of these responses were identified by lowering the concentration of calcium in the superfusate. Bath application of kynurenate, an antagonist of excitatory amino acid neurotransmission, reversibly blocked postsynaptic responses in the SCN. The evoked responses in the SCN were not affected by the acetylcholinergic agents (+)-tubocurarine, scopolamine, physostigmine, or carbachol. These results suggest that excitatory amino acid receptors mediate responses of SCN neurons to retinal input, but do not support a role for acetylcholine.     

Some effects of excitatory amino acid receptor antagonists on synaptic transmission in the rat olfactory cortex slice

A study has been made of the effects of a series of excitatory amino acid receptor antagonists on the field potentials evoked on electrical stimulation of the lateral olfactory tracts of olfactory cortex slices perfused in vitro. The antagonists studied included (+/-)-2-amino-5-phosphonovaleric acid, a potent, specific antagonist of N-methyl-D-aspartate (NMDA) receptors, gamma-D-glutamylglycine, an antagonist of NMDA and kainate receptors and (+/-)-cis-2,3-piperidine dicarboxylic acid and 2-amino-4-phosphonobutyric acid, drugs which in addition to antagonizing NMDA and kainate receptors also block responses to quisqualic acid. From the patterns of effects of the drugs it is proposed that quisqualate and NMDA but not kainate receptors are involved in mediating excitatory transmission in the olfactory cortex; quisqualate receptors are located at the lateral olfactory tract - superficial pyramidal cell synapse whereas NMDA receptors are present at the synapses of the superficial pyramidal cell collaterals with the deep pyramidal cell dendrites and/or at the synapses of the pyramidal cell collaterals and inhibitory interneurones. The results are discussed in terms of possible presynaptic and/or postsynaptic sites of antagonist action.     

Excitatory amino acid-evoked membrane currents and excitatory synaptic transmission in lamprey reticulospinal neurons

The characteristics of excitatory amino acid-evoked currents and of excitatory synaptic events have been examined in lamprey Müller neurons using voltage clamp and current clamp recording techniques. Application of glutamate evoked depolarizations associated with a decrease in input resistance. The reversal potential of the responses was -35 mV. Under voltage clamp conditions, a series of excitatory amino acid agonists evoked inward currents associated with little or no increase in baseline current noise. The order of potency of the excitatory amino acid agonists was quisqualate greater than kainate greater than glutamate greater than aspartate, while N-methyl-D-aspartic acid (NMDA) was inactive. Inward currents evoked by glutamate, as well as by kainate and quisqualate were attenuated reversibly by 1 mM kynurenic acid (KYN). In contrast, glutamate-evoked currents were not affected by 100 microM D(-)-2-amino-5-phosphonovaleric acid (APV), a selective NMDA antagonist. Spontaneously occurring and stimulus-evoked excitatory postsynaptic events were antagonized reversibly by 1 mM KYN. At this concentration, KYN had no effect on membrane potential, input resistance, or excitability of the cells. In contrast, excitatory postsynaptic currents were unaffected by APV. It is concluded that both glutamate responses and excitatory synaptic transmission in lamprey Müller neurons are mediated by non-NMDA-type receptors and that these receptors are associated with ionic channels with a low elementary conductance. The combined pharmacological and biophysical characteristics of these responses are therefore different from those previously reported in other preparations. Spontaneous (but not stimulus-evoked) inhibitory synaptic events in Müller neurons were blocked reversibly by 1 mM KYN but not by 100 microM APV, suggesting that excitation of interneurons inhibitory to Müller cells was also mediated by non-NMDA receptors.     

Brain-derived neurotrophic factor regulation of N-methyl-D-aspartate receptor-mediated synaptic currents in suprachiasmatic nucleus neurons

Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells. Previous work raises the possibility that brain-derived neurotrophic factor (BDNF) and its high-affinity receptor TrkB may be important as modulators of this excitatory input into the SCN. To test this possibility, we used whole-cell patch-clamp methods to measure excitatory currents in rat SCN neurons. These currents were evoked by electrical stimulation of the optic nerve. We found that the amplitude of the N-methyl-D-aspartate (NMDA) component of the evoked excitatory postsynaptic currents (NMDA-EPSC) was increased by application of BDNF. The neurotrophin also increased the magnitude of NMDA-evoked currents in SCN neurons. The BDNF enhancement of the NMDA-EPSC was blocked by treatment with the neurotrophin receptor antagonist K252a as well as treatment with the soluble form of the TrkB receptor engineered as an immunoadhesin (TrkB IgG). Finally, the BDNF enhancement was lost in brain slices treated with the NR2B antagonist ifenprodil. The results demonstrate that BDNF and TrkB receptors are important regulators of retinal glutamatergic synaptic transmission within the SCN.     

Electrophysiology of optic nerve input to suprachiasmatic nucleus neurons in rats and degus

Neurons in the mammalian suprachiasmatic nucleus (SCN), the principal pacemaker of the circadian system, receive direct retinal input. Some SCN neurons respond to retinal illumination or optic nerve stimulation with changes in firing rates. In nocturnal rodents, retinal illumination increases firing rates of a large majority and decreases firing rates of a minority of responsive neurons. In two species of diurnal rodent, these proportions are altered or even reversed. Since retinal input to the SCN has been reported to involve release of the excitatory neurotransmitter glutamate, the mechanism mediating suppressions is unknown. We studied responses of neurons in SCN slices from diurnal degus and nocturnal rats to optic nerve stimulation. To test whether suppressions are mediated indirectly by release of the inhibitory neurotransmitter GABA from SCN neurons that are first activated by glutamate release, we attempted to block suppressions by adding to the bath either APV, an antagonist for excitatory glutamate receptors, or bicuculline, a GABA_A receptor antagonist. If glutamate is the only neurotransmitter released by optic nerves in the SCN, APV should prevent both activations and suppressions in response to optic nerve stimulation. We found that APV had little effect on suppressions although it effectively blocked activations. Bicuculline blocked most suppressions. These findings are inconsistent with a model in which the retina provides only excitatory glutamate input to the SCN via NMDA receptors. Since some retinal fibers in adult mammals contain GABA, it is possible that the retinal innervation of the SCN includes both glutamate- and GABA-containing axons.     

Antagonists of glutaminergic neurotransmission block retinotectal transmission in goldfish

The hypothesis that excitatory retinotectal transmission is mediated primarily by a glutamate or glutamate-related transmitter-receptor system was examined by recording extracellular field potentials in isolated sections of goldfish tectum while stimulating the optic tract and applying antagonists of excitatory amino acid (EAA) neurotransmission via the tissue bath. Three antagonists of EAA receptors produced greater than 90% reduction in the postsynaptic components of these evoked potentials. In order of potency, these were (with the concentrations that produced 50% block): kyurenic acid (0.15 mM), γ- -glutamyglycine (0.33 mM), and cis-2,3-piperidine dicarboxylic acid (0.47 mM). All 3 log concentration-effect curves were parallel, symmetrically sigmoidal, and somewhat steeper than non-cooperative single-site binding isotherms. All antagonist actions stabilized within 15 min and were completely reversible. An EAA antagonist potent and selective for the N-methyl- -aspartate (NMDA) subtype of receptor, 2-amino-5-phosphonovalerate, had little or no effect in either normal, low [Ca²⁺]/high [Mg²⁺], or Mg²⁺-free media. These data indicate that an excitatory amino acid receptor not of the NMDA subtype plays an essential role in fast excitatory retinotectal transmission, and would be most consistent with the mediation of most or all excitatory retinotectal transmission by a single class and subtype of glutamate receptor.     

The effects of electrical stimulation of the optic nerves and anterior optic chiasm on the circadian activity rhythm of the Syrian hamster: involvement of excitatory amino acids

The circadian pacemaker of the suprachiasmatic nuclei (SCN) is entrained to the environmental light-dark cycle via the retinohypothalamic tract (RHT). It is unknown whether light activates or suppresses firing of the retinal ganglion cells which mediate photic entrainment. We therefore electrically stimulated the optic nerves and the anterior optic chiasm of hamsters with free-running activity rhythms in continuous darkness. These electrical stimulations are thought to induce a release of neurotransmitter at the RHT terminals. Electrical stimulation mimicked the phase dependent shifts induced by light pulses. The phase shifts were significantly larger than the shifts induced by sham stimulation in the same animals or by electrical stimulation in animals with an electrode outside the optic nerves and chiasm. Our results indicate that the retinal ganglion cells which project to the SCN are activated by light. Intraperitoneal administration of MK-801, a non-competitive antagonist of the NMDA-receptor, attenuated the phase delays induced by electrical stimulation in the early subjective night. This suggests that an excitatory amino acid mediates the effects of light upon the circadian pacemaker.     

Responses of the suprachiasmatic nucleus to retinohypothalamic tract volleys in a slice preparation of the mouse hypothalamus

The electrophysiological responses of the mouse suprachiasmatic nucleus (SCN) to stimulated synaptic input from the retinohypothalamic tract (RHT) were investigated using a hypothalamic slice preparation that includes the entire SCN, optic chiasm and optic nerves. Extracellular recordings of single-unit activity reveal a population of neurons in the ventrolateral SCN that are activated at a median latency of 10 ms after stimulation of the contralateral optic nerve. These neurons apparently receive direct excitatory input from RHT synapses. Other SCN neurons are activated at longer latencies, possibly through input from interneurons. The population field potentials evoked in the SCN by optic nerve volleys consist of a calcium-insensitive transient generated by optic tract axons in the chiasm, followed by calcium-sensitive waves generated by postsynaptic activity. The postsynaptic waves have the form of a field EPSP, negative in the dorsolateral SCN and positive in the ventrolateral SCN, upon which is superimposed a population spike of opposite polarity. The population spike occurs at the same latency as the monosynaptic single unit responses, which were all found near or ventral to the point of reversal of field potential. These findings suggest that neurons in the ventrolateral SCN are excited by synapses on dorsally extended dendrites. The conduction velocity of the RHT in the optic nerve was found to be 0.59 +/- 0.03 mm/ms, while that of the optic tract volley was 2.4 +/- 0.75 mm/ms. The low conduction velocity of the RHT indicates that, within the optic nerve, these axons are thin and/or unmyelinated in the optic nerve.     

N-methyl-D-aspartate, quisqualate and kainate receptors are all involved in transmission of photic stimulation in the suprachiasmatic nucleus in rats.

In order to clarify the neuronal transmission mechanism of photic stimulation in the suprachiasmatic nucleus (SCN), the effects of agonists and antagonists for excitatory amino acid receptors on N-acetyltransferase (NAT) activity in the pineal gland were observed following the microinjection of drugs into both sides of the nuclei. N-Methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, and kainate (which are selective agonists for three different subtypes, i.e. NMDA, quisqualate and kainate receptors, respectively) significantly decreased NAT activity similarly to the suppressive effect of light. Moreover, compared with a control group, all the groups pretreated with a selective competitive antagonist for NMDA receptor (D-2-amino-5-phosphonovalerate or 3-((+-)-2-carboxypiperazine-4-yl)-propyl-1-phosphonate), or a selective non-competitive antagonist for non-NMDA receptors (Joro spider toxin-3 or 1-naphthylacetyl spermine) partially blocked the suppressive effect of photic stimulation on NAT activity. These results suggest that NMDA, quisqualate and kainate receptors are all involved in mediating photic stimulation in the SCN.     

Muscarinic agonist carbachol depresses excitatory synaptic transmission in the rat basolateral amygdala in vitro

Intracellular recordings in slice preparations of the basolateral amygdala were used to test which excitatory amino acid receptors mediate the excitatory postsynaptic potentials due to stimulation of the external capsule. These recordings were also used to examine the action of muscarinic agonists on the evoked excitatory potentials. Intracellular recordings from amygdaloid pyramidal neurons revealed that carbachol (2-20 microM) suppressed, in a dose-dependent manner, excitatory postsynaptic responses evoked by stimulation of the external capsule (EC). This effect was blocked by atropine. The estimated effective concentration to produce half-maximal response (EC(50)) was 6.2 microM. Synaptic suppression was observed with no changes in the input resistance of the recorded cells, suggesting a presynaptic mechanism. In addition, the results obtained using the paired-pulse protocol provided additional support for a presynaptic action of carbachol. To identify which subtype of cholinergic receptors were involved in the suppression of the EPSP, four partially selective muscarinic receptor antagonists were used at different concentrations: pirenzepine, a compound with a similar high affinity for muscarinic M1 and M4 receptors; gallamine, a noncompetitive antagonist for M2; methoctramine, an antagonist for M2 and M4; and 4-diphenylacetoxy-N-methylpiperidine, a compound with similar high affinity for muscarinic receptors M1 and M3. None of them independently antagonized the suppressive effect of carbachol on the evoked EPSP completely, suggesting that more than one muscarinic receptor subtype is involved in the effect. These experiments provide evidence that in the amygdala muscarinic agonists block the excitatory synaptic response, mediated by glutamic acid, by acting on several types of presynaptic receptors.     

Pharmacological characterization of calcium currents and synaptic transmission between thalamic neurons in vitro.

We recorded from pairs of cultured, synaptically connected thalamic neurons. Evoked excitatory postsynaptic currents (EPSCs) reversed at +17 mV and were blocked reversibly by 1 mM kynurenic acid, a glutamate receptor antagonist. NMDA and non-NMDA receptors mediated excitatory post-synaptic responses, as shown by selective block of EPSC components with 50 microM (+/-)-2-amino-5-phosphonopentanoic acid and 10 microM 6,7-dinitroquinoxaline-2,3-dione, respectively. Inhibitory postsynaptic responses were evoked less frequently and were blocked by the GABAA receptor antagonist (-)-bicuculline methochloride. The pharmacological profiles of whole-cell calcium currents and evoked EPSCs were compared. With 50 microM cadmium chloride (Cd), whole-cell low voltage-activated (LVA) calcium currents were reduced in amplitude and high voltage-activated (HVA) calcium currents and excitatory synaptic transmission were completely blocked. This suggests that the residual calcium influx through LVA channels into the presynaptic terminal does not suffice to trigger transmitter release. A saturating concentration of omega-conotoxin GVIA (omega-CgTx) (2.5 microM) blocked one-third of whole-cell HVA calcium currents and evoked EPSCs. The dihydropyridine nifedipine (50 microM) reversibly reduced whole-cell HVA calcium currents in a voltage-dependent manner but not excitatory synaptic transmission. Cd and omega-CgTx did not alter amplitude distributions of miniature EPSCs, demonstrating that the inhibition of synaptic transmission was due to block of presynaptic calcium channels. We conclude that excitatory glutamatergic transmission in thalamic neurons in vitro was mediated mainly by HVA calcium currents, which were insensitive to omega-CgTx and nifedipine.     

Involvement of AMPA Receptors in Trigeminal Post-synaptic Potentials Recorded in Rat Abducens Motoneurons In Vivo

The pharmacology of trigeminal excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of the vibrissal pad was investigated in vivo in rat abducens motoneurons using intracellular recordings combined with microionophoretic applications of excitatory amino acid agonists [α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), NMDA, kainate] and a selective non-NMDA receptor antagonist (GYKI-52466). Intravenous applications of GYKI-52466 were also performed during synaptic and amino acid excitations. GYKI-52466, applied intravenously or microionophoretically, reversibly antagonized AMPA-induced depolarizations and trigeminal EPSPs in rat abducens motoneurons without affecting NMDA and kainate responses. The inhibition of AMPA-induced depolarizations was similar following i.v. and ionophoretic applications of GYKI-52466. Intravenous applications of GYKI-52466 (0.3–4 mg/kg) reversibly and dose-dependently reduced trigeminal EPSPs, which could be totally suppressed at the highest doses of GYKI-52466 (2–4 mg/kg). The antagonist effect, which developed very quickly, could last several minutes and recovered gradually. The effect of GYKI-52466 on the EPSPs and AMPA responses were compared in the same motoneurons. The partial inhibition of trigeminal EPSPs during microionophoretic applications of GYKI-52466 was probably due to the distribution of the synapses in the dendritic arborization of abducens motoneurons. Our results show that AMPA receptors are involved in the generation of trigeminal EPSPs in rat abducens motoneurons in vivo.     

Serotonin Differentially Modulates Responses Mediated by Specific Excitatory Amino Acid Receptors in the Rat Locus Coeruleus

Microiontophoretic application of selective agonists for the three major excitatory amino acid receptors, N -methyl- d -aspartate (NMDA), quisqualate and kainate, increased the discharge rate of noradrenergic locus coeruleus (LC) neurons in vivo. NMDA activation was selectively attenuated by iontophoretic application of 2-amino-5-phosphonopentanoate (AP5), an antagonist at NMDA receptors, whereas kainate- and quisqualate-evoked responses were attenuated by both NMDA and non-NMDA antagonists iontophoresis. NMDA- and quisqualate-evoked responses were significantly decreased by co-iontophoresis of serotonin (5-HT). When the NMDA receptor-mediated component of the response to kainate was blocked with AP5 iontophoresis, 5-HT increased the response of LC neurons to kainate. These results revealed that 5-HT differentially modulates the responsiveness of LC neurons to excitatory amino acids, depending on the receptor subtypes responsible for the neuronal activation.     

Effects of nitric oxide synthase inhibitors onN-methyl-d-aspartate-induced phase delay of circadian rhythm of neuronal activity in the rat suprachiasmatic nucleus in vitro

Excitatory amino acid (EAA) receptors such asN-methyl-d-aspartate (NMDA) and non-NMDA receptors have been suggested to play an important role in the regulation of photic information from the retina to the suprachiasmatic nucleus (SCN). Therefore, we investigated the role of glutamate as a retinohypothalamic transmitter by analyzing the phase-resetting effects of NMDA and a non-NMDA agonist, (R, S)-α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), on the circadian rhythm of SCN firing activity. Nitric oxide (NO) production is believed to be an essential intermediate in NMDA-induced cGMP production in the CNS. Thus, we examined the effects of blockers of NO production on NMDA- or AMPA-induced phase delay of SCN activity rhythm.N-nitro-l-arginine methylester (l-NAME) blocked NMDA- but not AMPA-induced phase shift, indicating the involvement of NO synthesis in NMDA-induced phase changes.l-arginine but notd-arginine caused a phase delay, andl-NAME blockedl-arginine-induced phase delay. In addition, cotreatment with NMDA andl-arginine did not have an additive effect. These results suggest that NO production itself is involved in the phase change of SCN neuron activity, and NMDA-induced phase changes are also mediated via activation of NO synthesis in this nucleus.     

Effects of a spider toxin (JSTX) on hippocampal CA1 neurons in vitro

The effect of a toxin (JSTX) obtained from Nephila clavata (Joro spider) on the CA1 pyramidal neurons of the hippocampus was studied using slice preparations. JSTX blocked the excitatory postsynaptic potentials (EPSPs) in the pyramidal neuron evoked by Schaffer collateral stimulation but was without effect on the antidromic action potentials or on the resting conductance. Depolarization induced by ionophoretic application of glutamate was readily suppressed by JSTX but aspartate-induced depolarization was much less sensitive to the toxin. Among preferential agonists activating 3 receptor subtypes for excitatory amino acids, quisqualate responses were most effectively suppressed by JSTX. Kainate responses were similarly suppressed but in some cells higher concentration of the toxin was needed to block the responses. N-methyl-D-aspartate (NMDA) responses were the least sensitive to JSTX but they were suppressed by +/- 2-amino-5-phosphonovaleric acid (APV). Long term potentiation (LTP) once it had taken place was not completely inhibited by APV. In the presence of JSTX, however, LTP was blocked and tetanic stimuli produced only a short-lived potentiation. In Mg2+ free solution, an orthodromic stimulation evoked repetitive spike responses which were superimposed on the depolarization following the initial spike. APV suppressed the depolarization and associated spikes leaving an orthodromic response which was sensitive to JSTX. The results suggest that JSTX blocks EPSPs in CA1 pyramidal neurons which are mediated by non-NMDA type receptors.     

Effect of glutamate receptor antagonists on excitatory postsynaptic potentials in striatum

Glutamate, as the main transmitter of corticostriatal pathway, has a crucial role in the regulation of the activity of striatal cells as well as in pathogenesis of some diseases characterized by striatal malfunction caused by overexcitation of neurons. In the present study, the role of ionotropic excitatory amino acid receptors was investigated in the striatal synaptic transmission. Using conventional intracellular electrophysiological methods in brain slices, we have investigated the effects of the N-methyl-D-aspartate (NMDA) antagonist (±) 2-amino-5-phosphono-valerate (APV) and the α-amino-3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA) antagonist (±) 1-(4-aminophenyl)-3-methyl-carbamoyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 53655) on the excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of corpus callosum. The AMPA antagonist significantly decreased electrically evoked responses and a weak inhibition was also observed after APV application. The results were compared to similar data obtained in a cortical slice study.     

Pharmacological characterization of excitatory synaptic potentials in rat basolateral amygdaloid neurons.

The pharmacological properties of synaptic responses in rat basolateral amygdaloid (BLA) neurons were studied using intracellular recording techniques. Three distinct types of synaptic potential were evoked by stimulation of the adjacent ventral endopyriform nucleus: 1) a fast excitatory postsynaptic potential (f-EPSP); 2) a late EPSP (1-EPSP) following the f-EPSP; and 3) a multiphasic hyperpolarization following the initial depolarizing potential. Superfusion of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), a selective non-N-methyl-D-aspartate (non-NMDA) receptor antagonist, blocked the f-EPSP in a concentration-dependent manner. The ED50 for this effect was around 4 microM. In the presence of CNQX, however, a small depolarizing potential remained. This residual depolarizing component was markedly enhanced on removing Mg++ from the perfusing medium and could subsequently be abolished by DL-2-amino-5-phosphonovaleate (DL-APV, 50 microM) indicating its mediation via NMDA receptor-coupled ionophore. The l-EPSP was reversibly blocked by DL-APV. These results suggest that the pyriform cortex-amygdala pathway is mediated through excitatory amino acids acting on non-NMDA as well as NMDA receptors located on the BLA neurons.     

Glutamate Receptors on type I Vestibular Hair Cells of Guinea-pig

Afferent nerve calyces which surround type I vestibular hair cells (VHCI) have recently been shown to contain synaptic-like vesicles and to be immunoreactive to glutamate antibodies. In order to understand the physiological significance of these observations, the presence of glutamate receptors on type I vestibular sensory cells has been investigated. The effect of excitatory amino acids applied by iontophoresis was examined by spectrofluorimetry using fura-2 sensitive dye. Glutamate application caused a rapid and transient increase in intracellular calcium concentration ([Ca²⁺]ⁱ), in a dose-dependent manner. The ionotropic glutamate receptors agonists N -methyl- d -aspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and quisqualic acid (QA) induced an increase of [Ca²⁺]_i. The NMDA receptor antagonist 2-amino-5-phosphonovaleric acid and the AMPA receptor antagonist 6,7-dinitro-quinoxaline-2,3-dione partially blocked the glutamate response, by 39 ± 10 and 53 ± 11% respectively. Metabotropic receptors were also revealed by the specific agonist trans -1-amino-cyclopentyl-1,3-dicarboxylate. The presence of different glutamate receptors on the VHCI membrane suggests two kinds of feedback, (i) At the base of the sensory cell, autoreceptors may locally control the synaptic transmission, (ii) At the apex, postsynaptic receptors may modulate sensory transduction from glutamate release at the upper part of the afferent nerve calyx. These feedbacks suggest presynaptic modulation of the vestibular hair cell response which could affect its sensitivity.     

Glutamate neurotoxicity in the developing rat cochlea is antagonized by kynurenic acid and MK-801

Glutamate (Glu) is neurotoxic in the neonatal rat cochlea, producing hearing impairment which is largely due to the death of spiral ganglion cells, whereas the receptor hair cells are spared. Dendritic processes of the spiral ganglion are postsynaptic to the primary afferent synapse of the auditory system. The experiments reported here were designed to test whether this apparent excitotoxicity can be blocked by Glu antagonist. The broad-spectrum antagonist kynurenic acid (KYNA) was coadministered with Glu initially to determine whether the high-frequency hearing deficit caused by Glu may be mediated by excitatory amino acid receptors. Subsequently, the (NMDA)-specific receptor blocker MK-801 was used to test whether NMDA receptors may be involved in the effect. Both antagonists partially blocked the high-frequency hearing impairment caused by Glu. The blocker-alone control groups exhibited mid-frequency effects of unknown origin. The significant antagonism of Glu-induced impairment is consistent with the hypothesis that Glu or a similar excitatory amino acid is an important afferent transmitter in the cochlea.     

AMPA/kainate receptor antagonist DNQX blocks the acute increase of Per2 mRNA levels in most but not all areas of the SCN

The daily light:dark cycle synchronizes the circadian timing system by resetting the phase of the circadian pacemaker on a daily basis. Light acutely increases mRNA levels of the clock genes Per1 and Per2 in the suprachiasmatic nucleus (SCN), the site of the primary circadian pacemaker in mammals. Light is conveyed to the SCN through the retinohypothalamic tract (RHT), an efferent projection from retinal ganglion cells that releases the excitatory amino acid (EAA) neurotransmitter glutamate in the SCN. EAA receptor activation in the SCN is critical for the ability of light to phase-shift the circadian pacemaker. In a previous study, we demonstrated that EAA receptor activation is necessary and sufficient for light to acutely increase Per1 mRNA levels in the SCN. In the current study, we determined whether EAA receptor activation in the SCN is necessary for the ability of light to increase Per2 mRNA levels in the SCN in Syrian hamsters. The NMDA receptor antagonist AP5 and the AMPA/kainate receptor antagonist DNQX inhibited the ability of light and NMDA to acutely increase Per2 mRNA levels in the SCN. In hamsters injected with DNQX, Per1 and Per2 mRNA levels remained slightly elevated in the ventrolateral SCN, suggesting that AMPA/kainate receptor activation in this region is not critical for the effects of light on the circadian pacemaker.