Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability.

The authors examined set-shifting abilities in rats injected with antagonists of N-methyl-D-aspartate (NMDA) receptors (MK801) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (LY293558) into the medial prefrontal cortex (mPFC). Set-shifting was assessed with a maze-based task requiring a switch between brightness and texture discrimination strategies. Intra-mPFC injection of MK801 prior to training on the 2nd discrimination impaired discrimination strategy acquisition. The MK801-induced deficit was due to increased perseverative responding. AMPA receptor blockade also impaired acquisition of the 2nd discrimination, these impairments were due to more general cognitive deficits. Results suggest that, within the mPFC, both AMPA and NMDA receptors are necessary for set-shifting, and that NNMA receptor hypofunction impairs the capacity to modify existing knowledge or to inhibit responses that are no longer appropriate. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NMDA Antagonist MK-801 Does Not Interfere With the Use of Spatial Representation in a Familiar Environment.

There is disagreement among researchers concerning whether glutamatergic N-methyl-D-aspartate (NMDA) receptors play a role in constructing spatial representations. Therefore, the authors reexamined the effects of the NMDA antagonist on a spatial discrimination task using rats in a water pool. The authors confirmed that MK-801 impaired acquisition of the spatial discrimination task (Experiment 1). When rats were pretrained before drug treatment, MK-801 induced learning deficits in the novel environment but not in the familiar environment (Experiment 2). Moreover, in a familiar environment, MK-801 did not impair spatial learning, even when the task was completely novel for the rats (Experiment 3). These results suggest that NMDA receptors play an important role in the construction of spatial representations but not in the use of them. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Reconstitution of membrane fusion between pancreatic islet secretory granules and plasma membranes: catalysis by a protein constituent recognized by monoclonal antibodies directed against glyceraldehyde-3-phosphate dehydrogenase

This study was conducted to assess the involvement of N-methyl-D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptor systems, located in specific limbic brain regions. in the discriminative stimulus effects of ethanol. Male Long-Evans rats were trained to discriminate between intraperitoneal (i.p.) injections of ethanol (1 g/kg) and saline on a two-lever drug discrimination task. The rats were then implanted with bilateral injector guides aimed at the nucleus accumbens core (AcbC), prelimbic cortex (PrLC), hippocampus area CA1 (CA1), or extended amygdala (i.e., at the border of the central and basolateral nuclei). Infusions of the non-competitive NMDA antagonist MK 801 in the AcbC or CA1 resulted in dose-dependent full substitution for i.p. ethanol. MK 801 infusion in the PrLC or amygdala failed to substitute for ethanol. Injection of the competitive NMDA antagonist CPP in the AcbC also failed to substitute for ethanol. Co-infusion of MK 801 in the hippocampus potentiated the effects of MK 801 in the AcbC, whereas NMDA infusion in the hippocampus attenuated the ability of MK 801 in the AcbC to substitute for ethanol. The direct GABA(A) agonist muscimol resulted in dose-dependent full substitution for i.p. ethanol when it was injected into the AcbC or amygdala, but failed to substitute when administered in the PrLC. Co-infusion of MK 801, but not CPP, potentiated the effects of muscimol in the AcbC. These results demonstrate that ethanol's discriminative stimulus function is mediated centrally by NMDA and GABA(A) receptors located in specific limbic brain regions. The data also suggest that the discriminative stimulus effects of ethanol are mediated by interactions between ionotropic GABA(A) and NMDA receptors in the nucleus accumbens, and by interactions among brain regions.     

NMDA receptor antagonist MK-801 blocks learning of conditioned stimulus-unconditioned stimulus contiguity but not fear of conditioned stimulus in goldfish (Carassius auratus L.).

The blockade of learning of Pavlovian fear conditioning by the N-methyl-D-aspartic acid (NMDA)-receptor antagonist MK-801 was examined in 166 goldfish. In previously untrained fish, MK-801 blocked learning of a light-off or a tone conditioned stimulus (CS) paired with an electrical shock unconditioned stimulus (UCS). Pretraining on the light-off CS did not affect the rate of learning of the tone CS but protected the tone learning from disruption by MK-801. Switching from the light-off to the tone CS changed the identity of the CS but not its temporal contiguity with the UCS. Pretraining consisting of pseudoconditioning of the light-off CS did not protect subsequent tone learning from blockade by MK-801. Thus, the NMDA receptor functions are necessary for learning related to the temporal contiguity of the CS and UCS but not to the identity of the CS as a cue to the occurrence of the fearful effects of the UCS. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Competitive and non-competitive NMDA antagonists block the development of antinociceptive tolerance to morphine, but not to selective mu or delta opioid agonists in mice

N-Methyl-D-aspartate (NMDA) receptor antagonists have been shown to block the development of antinociceptive tolerance to morphine. Assessment of the effects of NMDA antagonists on development of antinociceptive tolerance to selective opioid mu (mu) and delta (delta) agonists, however, has not been reported. In these experiments, selective mu and delta receptor agonists, and morphine, were repeatedly administered to mice either supraspinally (i.c.v.) or systemically (s.c.), alone or after pretreatment with systemic NMDA antagonists. Antinociception was evaluated using a warm-water tail-flick test. Repeated i.c.v. injections of mu agonists including morphine, fentanyl, [D-Ala2, NMePhe4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe-D-Pro-NH2 (PL017) or [D-Ala2, Glu4]deltorphin, a delta agonist, or s.c. injections of morphine or fentanyl, produced antinociceptive tolerance as shown by a significant rightward displacement of the agonist dose-response curves compared to controls. Single injections or repeated administration of MK801 (a non-competitive NMDA antagonist) or LY235959 (a competitive NMDA antagonist) at the doses employed in this study did not produce behavioral toxicity, antinociception or alter the acute antinociceptive effects of the tested opioid agonists. Consistent with previous reports, pretreatment with MK801 or LY235959 (30 min prior to agonist administration throughout the tolerance regimen) prevented the development of antinociceptive tolerance to i.c.v. or s.c. morphine. Neither NMDA antagonist, however, affected the development of antinociceptive tolerance to i.c.v. fentanyl, DAMGO, or [D-Ala2, Glu4]deltorphin. Additionally, MK801 pretreatment did not affect the development of antinociceptive tolerance to i.c.v. PL017 or to s.c. fentanyl. Further, MK801 pretreatment also did not affect the development of tolerance to the antinociception resulting from a cold-water swim-stress episode, previously shown to be a delta-opioid mediated effect. These data lead to the suggestion that the mechanisms of tolerance to receptor selective mu and delta opioids may be regulated differently from those associated with morphine. Additionally, these findings emphasize that conclusions reached with studies employing morphine cannot always be extended to 'opiates' in general.     

N-methyl-D-aspartate antagonist D-APV selectively disrupts taste-potentiated odor aversion learning.

Examined in 2 experiments the effects of the competitive N-methyl-{d}-aspartate (NMDA) antagonist {d}-APV ({d}-2-amino-5-phosphonovalerate) on rats' ability to acquire potentiated aversions to the odor element of a taste–odor compound. In Exp 1, pretreatment with {d}-APV (2.5 μg/side icv) caused stereospecific deficits in potentiated odor aversion learning but left simple taste and odor aversion learning intact. In Exp 2, pretreatment with {d}-APV had no effect on rats' acquisition of an illness-based odor discrimination task. These results parallel those previously obtained using a noncompetitive NMDA antagonist (G. S. Robinson et al, 1989) and show that interference with NMDA receptors can selectively impair potentiated odor aversion learning. These results suggest that NMDA receptors play a critical role in some, but not all, forms of learning and memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Systemic morphine-induced Fos protein in the rat striatum and nucleus accumbens is regulated by mu opioid receptors in the substantia nigra and ventral tegmental area

To characterize how systemic morphine induces Fos protein in dorsomedial striatum and nucleus accumbens (NAc), we examined the role of receptors in striatum, substantia nigra (SN), and ventral tegmental area (VTA). Morphine injected into medial SN or into VTA of awake rats induced Fos in neurons in ipsilateral dorsomedial striatum and NAc. Morphine injected into lateral SN induced Fos in dorsolateral striatum and globus pallidus. The morphine infusions produced contralateral turning that was most prominent after lateral SN injections. Intranigral injections of [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO), a mu opioid receptor agonist, and of bicuculline, a GABAA receptor antagonist, induced Fos in ipsilateral striatum. Fos induction in dorsomedial striatum produced by systemic administration of morphine was blocked by (1) SN and VTA injections of the mu1 opioid antagonist naloxonazine and (2) striatal injections of either MK 801, an NMDA glutamate receptor antagonist, or SCH 23390, a D1 dopamine receptor antagonist. Fos induction in dorsomedial striatum and NAc after systemic administration of morphine seems to be mediated by dopamine neurons in medial SN and VTA that project to medial striatum and NAc, respectively. Systemic morphine is proposed to act on mu opioid receptors located on GABAergic interneurons in medial SN and VTA. Inhibition of these GABA interneurons disinhibits medial SN and VTA dopamine neurons, producing dopamine release in medial striatum and NAc. This activates D1 dopamine receptors and coupled with the coactivation of NMDA receptors possibly from cortical glutamate input induces Fos in striatal and NAc neurons. The modulation of target gene expression by Fos could influence addictive behavioral responses to opiates.     

NMDA receptor involvement in spatial delayed alternation in developing rats.

Two experiments examined the effect of the noncompetitive NMDA receptor antagonist, dizocilpine maleate (MK-801), on spatial working memory during development. Rats were trained on spatial delayed alternation (SDA) in a T-maze after ip administration of 0.06 mg/kg MK-801, 0.1 mg/kg MK-801, or saline on postnatal days (P) P23 and P33 (Experiment 1), or following bilateral intrahippocampal administration of 2.5 or 5.0 υg per side MK-801 or saline on P26 (Experiment 2). In Experiment 1, MK-801 dose-dependently impaired SDA learning at both ages. Because the same doses of systemic MK-801 have no effect on T-maze position discrimination learning, impairment of SDA by MK-801 likely reflects disruption of spatial working memory. Both doses of MK-801 abolished acquisition of SDA performance in Experiment 2. Disruption of hippocampal plasticity may account for the effects produced by systemic MK-801 administration. These results confirm and extend earlier lesion studies by implicating plasticity of hippocampal neurons in the ontogeny of spatial delayed alternation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Plasmodium falciparum: influence of malarial and host erythrocyte skeletal protein interactions on phosphorylation in infected erythrocytes

Striatopallidal output neurons, which coexpress D2-dopamine receptors and NMDA receptors, are logically a potential site of interaction between corticostriatal glutamatergic input and dopaminergic systems. Recent hypotheses about the etiology of schizophrenia have implicated both excitatory amino acid and dopamine systems. The present study was designed to examine, in vivo, the interaction between D2-dopamine receptors and NMDA receptors in the regulation of the expression of the early immediate genes (IEGs), zif 268 and jun B, in striatopallidal neurons. We tested whether coadministration of NMDA antagonists interacted with the actions of the D2 agonist, quinpirole, on IEG expression following dopamine depletion with reserpine. When rats were pretreated with the non-competitive NMDA receptor antagonists, MK 801 (1 mg/kg) or PCP (20 mg/kg), together with quinpirole, the quinpirole reversal of reserpine induction of zif 268 mRNA was potentiated in all regions examined. MK 801 alone had no significant effect on reserpine induction of zif 268 mRNA. Pretreatment with the competitive NMDA receptor antagonist, CPP (5 mg/kg), did not significantly alter the dose response of zif 268 mRNA expression to quinpirole in any region. There was no significant effect of MK 801 on jun B mRNA expression, either on the response to quinpirole or when administered alone with reserpine. Our findings provide evidence of an interaction between the NMDA receptor channel system and the D2-dopamine system on a molecular level in striatopallidal neurons carrying output from the basal ganglia.     

Phencyclidine injections into the dorsal hippocampus disrupt long- but not short-term memory within a spatial learning task

Since the hippocampus is likely to be a major site of phencyclidine (PCP) action, the effects of various doses of PCP (1.8, 18 or 36 nM) as well as 3.6 nM MK-801 or saline injected directly into the dentate gyrus of the hippocampus was tested for acquisition of a spatial navigation task (dry land version of a water maze) using a paradigm that assesses short term memory based on learning within a day and long term memory based on learning between days. Results indicated that relative to saline or 1.8 nM PCP injected rats, rats with 18 or 36 nM PCP or 3.6 nM MK-801 injections were impaired in acquisition of the task as measured by increased distances traveled to find the food location between days but not within days. In additional experiments 36 nM PCP or 3.6 nM MK-801 did not produce any deficits in the acquisition of an object discrimination task. It is suggested that PCP through its blocking action of the NMDA receptor in the dentate gyrus or CA1 region of the dorsal hippocampus mediates the consolidation of new spatial location information.     

Molecular characterization of N-methyl-D-aspartate receptors expressed in mammalian cells yields evidence for the coexistence of three subunit types within a discrete receptor molecule

The N-methyl-D-aspartate R1 (NMDA R1), NMDA R2A, and NMDA R2C subunits were expressed transiently in double or triple combinations in human embryonic kidney (HEK) 293 cells. The biochemical and pharmacological properties of the cloned receptors were compared with those of adult mouse forebrain and cerebellum. Under conditions established for maximal expression, cotransfection of the NMDA R1 and R2C subunits yielded a protein detected immunologically with a molecular size of 780,000-850,000 daltons. No cell death was observed in the transfected cells, and the KD for [3H]MK801 binding to the NMDA R1/R2C receptor was 346 +/- 158 nM. This was in contrast to a value of KD = 22 +/- 9 nM found for native cerebellar receptors. Co-transfection with NMDA R1/R2A/R2C subunits with a DNA ratio, 1:3:3, resulted in the expression of a protein with a size similar to the NMDA R1/R2C combination, but the affinity of [3H]MK801 was now 22 +/- 5 nM, and the percentage cell death post-transfection was 89 +/- 17%. Immunoprecipitation assays of detergent-solubilized transfected cells with NMDA R1 subunit-specific antibodies co-precipitated the NMDA R2A and NMDA R2C subunits in 1/2A and 1/2C transfections, respectively. Similarly, immunoprecipitations with either NMDA R1 or NMDA R2C subunit-specific antibodies co-precipitated the NMDA R2A subunit in the R1/2A/2C triple transfections. These results show that the three NMDA receptor subunit types can co-assemble following their co-expression in mammalian cells with a pharmacological profile that is similar to that found for adult cerebellar NMDA receptors.     

Effects of MK801 on Fos expression in the rat brainstem after unilateral labyrinthectomy

Unilateral labyrinthectomy (UL) causes ocular and postural asymmetries, which disappear over time in the processes of equilibrium recovery known as vestibular compensation. It has been reported that N-methyl-D-aspartate (NMDA) receptors are involved in vestibular compensation. In the present study, in order to elucidate the NMDA receptor-mediated neural circuit responsible for the development of vestibular compensation, we used Fos expression as a marker of neural activation and examined the effects of MK801, a specific antagonist of NMDA receptors, on UL-induced Fos expression in the rat brainstem. After UL, Fos-like immunoreactive (-LIR) neurons were observed in the ipsilateral medial vestibular nucleus (ipsi-MVe), the contralateral prepositus hypoglossal nucleus (contra-PrH) and the contralateral inferior olive beta subnucleus (contra-IOb). Fos-LIR neurons gradually disappeared in the processes of vestibular compensation. It is suggested that the activation of the ipsi-MVe, the contra-PrH and the contra-IOb neurons after UL are the initial event of vestibular compensation. Intraperitoneal injection of MK801 in the processes of vestibular compensation caused reappearance of UL-induced behavioral deficits. During the decompensation induced by MK801, Fos-LIR neurons appeared in the contra-MVe, the ipsi-PrH and the bilateral-IOB. It is suggested that the contra-MVe, the ipsi-PrH and the bilateral-IOb neurons are inhibited by glutamatergic synapses driving inhibitory neurons via NMDA receptors in the processes of vestibular compensation and that disinhibition of these nuclei induced by MK801 causes decompensation. However, MK801 caused neither Fos expression nor behavioral decompensation after vestibular compensation is accomplished. All these findings that the NMDA receptor-mediated inhibitory modulation in the central vestibular system plays an important role for the initial processes of the development of vestibular compensation.     

NMDA receptor antagonism impairs reversal learning in developing rats.

Four experiments examined the effect of dizocilpine maleate (MK-801), a noncompetitive N-methyl-Daspartate (NMDA) receptor antagonist, on reversal learning during development. On postnatal days (PND) 21, 26, or 30, rats were trained on spatial discrimination and reversal in a T-maze. When MK-801 was administered (intraperitoneally) before both acquisition and reversal, 0.18 mg/kg generally impaired performance, whereas doses of 0.06 mg/kg and 0.10 mg/kg, but not 0.03 mg/kg, selectively impaired reversal learning (Experiments 1 and 3). The selective effect on reversal was not a result of sensitization to the second dose of MK-801 (Experiment 2) and was observed when the drug was administered only during reversal in an experiment addressing state-dependent learning (Experiment 4). Spatial reversal learning is more sensitive to NMDA-receptor antagonism than is acquisition. No age differences in sensitivity to MK-801 were found between PND 21 and 30. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Age- and dose-dependent facilitation of associative eyeblink conditioning by {d}-cycloserine in rabbits.

Normal aging selectively impairs some forms of learning. For example, aging rabbits require more than twice as many trials to acquire 500-ms trace eyeblink conditioning than do young rabbits. N-methyl-{d}-aspartate (NMDA) receptor antagonists also impair trace conditioning. The effects of daily {d}-cycloserine (DCS; a partial agonist of the NMDA receptor-glycine site) treatment were tested on trace conditioning of young or aging rabbits using a conservative quantitative approach. DCS dose dependently improved acquisition, maximally reducing trials to criterion by ≈50%. Dose-response curves were right-shifted by aging (twice the dose was required to achieve the same enhancement compared with controls). DCS did not affect nonassociative performance but sharpened the conditioned stimulus tone intensity discrimination. DCS thus can functionally modulate NMDA receptors in normal aging, enhance associative learning at all ages, and reduce or reverse age-dependent learning deficits. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The contribution of the rat prelimbic-infralimbic areas to different forms of task switching.

The experiments examined the effects of prelimbic-infralimbic inactivation in rats on the acquisition and reversal learning of different discrimination tasks: 2- or 4-choice odor discrimination in Experiments 1 and 2, the shift from 2-choice odor discrimination to 2-choice place discrimination in Experiment 3, and the shift from 2-choice place to 2-choice odor discrimination in Experiment 4. Infusions of 2% bupivacaine did not impair performance in the odor discrimination tests. Prelimbic-infralimbic inactivation did not impair acquisition but did impair the shift from an odor to a place discrimination and vice versa. Analysis of the errors revealed that the deficit was due to perseveration of the previously learned strategy. The selective deficits observed in the odor-place tests suggest that the prelimbic-infralimbic areas enable behavioral flexibility when conditions demand inhibiting the use of one type of attribute information and learning a new type of attribute information. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Comparison of the amnestic effects on NMDA receptor antagonist MK-801 and nitric oxide synthase inhibitors: L-NAME and L-NOARG in goldfish.

Investigations indicate that the induction of long-term potentiation (LTP) may be mediated by postsynaptic N-methyl-D-aspartate (NMDA) receptors and that the maintenance of LTP may be initiated by nitric oxide (NO), a retrograde messenger carrying signals backward from the postsynaptic to the presynaptic neuron. The present study compared amnestic effects of dizocilpine maleate (MK-801), an NMDA receptor antagonist, and nitro-L-arginine-methyl-ester (L-NAME) and N-nitro-L-arginine (L-NOARG), nitric oxide (NO) inhibitors, in goldfish, using active-avoidance conditioning as the learning paradigm. The results showed that MK-801 and NO inhibitors produced anterograde amnesia at doses that did not impair performance processes necessary for learning to occur. Furthermore, MK-801 did not produce retrograde amnesia, whereas L-NAME did, suggesting that MK-801 impaired learning whereas NO inhibitors impaired memory consolidation and possibly also learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

NMDA receptor antagonists impair memory for nonspatial, socially transmitted food preference.

Rats avoid unfamiliar foods and learn to prefer those that they smell on the breath of conspecifics. Hippocampal lesions produce rapid forgetting of this socially acquired memory. The authors report that NMDA receptor antagonists impair this memory. Rats given CPP were trained in the social transmission of food preference task. Normal rats showed robust memory 72 hr later. CPP-injected rats performed normally 24 hr, but randomly 72 hr, after training. Spatial context was irrelevant: Rats trained and tested in different rooms performed the same as rats trained and tested in 1 room. MK801 and intrahippocampal injections of APV produced amnestic effects similar to CPP. Thus, NMDA receptor activation is crucial for the persistence of socially acquired, hippocampus-dependent, nonspatial memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The contribution of NMDA receptors in the dorsolateral striatum to egocentric response learning.

The present study examined the effects of the N-methyl-D-aspartate (NMDA) competitive antagonist, 2-amino-5-phosphonopentanoic acid (AP-5), injected into the dorsolateral striatum on the acquisition and reversal learning of a response discrimination. Male Long-Evans rats were tested across 2 consecutive days in a modified cross-maze. An infusion of either saline or AP-5 (5 or 25 nM) occurred 5 min prior to testing. In acquisition rats learned to turn left or right. In reversal learning rats learned to turn in the opposite direction. An AP-5 infusion at 25 nmol, but not 5 nmol, impaired response acquisition. Neither AP-5 dose impaired response reversal learning. The results suggest that NMDA receptors in the dorsolateral striatum are critical for the initial learning of an egocentric response discrimination. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pre- and posttraining infusion of N-methyl-D-aspartate receptor antagonists into the amygdala impair memory in an inhibitory avoidance task

Involvement of amygdaloid N-methyl-D-aspartate (NMDA) receptors in memory processes was investigated. Rats with cannulas implanted in the basolateral amygdala were trained on a 1 trial step-through inhibitory avoidance task and tested for 24-hr retention. Pretraining infusion of 2-amino-5-phosphonovaleric acid (APV) into the amygdala, but not striatum or hippocampus, produced a dose-dependent retention deficit, which was attenuated by immediate posttraining intra-amygdala infusion of NMDA. Posttraining APV infusion also caused a dose- and time-dependent retention deficit. Pretest APV infusion had no effect on performance in the retention test. Further, pre- or posttraining infusion of 5.0 micrograms APV failed to affect acquisition and retention in the Morris water maze task. These findings suggest that amygdala NMDA receptors are normally activated by aversive training and play a critical role in memory formation for affective experience.     

Differential regulation by MK801 of immediate-early genes, brain-derived neurotrophic factor and trk receptor mRNA induced by a kindling after-discharge

Transient changes in immediate-early genes and neurotrophin expression produced by kindling stimulation may mediate secondary downstream events involved in kindling development. Recent experiments have demonstrated conclusively that both kindling progression and mossy fibre sprouting are significantly impaired by administration of the N-methyl-D-aspartate (NMDA) receptor antagonist MK801. To further examine the link between kindling, changes in gene expression and the NMDA receptor, we examined the effects of MK801 on neuronal induction of immediate-early genes, brain-derived neurotrophic factor (BDNF) and trk receptor mRNA expression produced by a single electrically induced hippocampal after-discharge in rats. The after-discharge produced a rapid (after 1 h) increase in Fos, Jun-B, c-Jun, Krox-24 mRNA and protein and Krox-20 protein in dentate granule neurons and a delayed, selective expression of Fos, Jun-D and Krox-24 in hilar interneurons. MK801 pretreatment produced a very strong inhibition of Fos, Jun-D and Krox-20 increases in dentate neurons but had a much smaller effect on Jun-B and c-Jun expression. MK801 did not inhibit Krox-24 expression in granule neurons or the delayed expression of Fos, Jun-D and Krox-24 in hilar interneurons. BDNF protein and trk B and trk C mRNA expression were also strongly induced in dentate granule cells 4 h following an after-discharge. MK801 abolished the increase in BDNF protein and trk B, but not trk C mRNA in granule cells at 4 h. These results demonstrate that MK801 differentially regulates the AD-increased expression of a group of genes previously identified as being likely candidates for an involvement in kindling. Because MK801 significantly retards the development of kindling and mossy fibre sprouting, it can be argued that those genes whose induction is not significantly attenuated by MK801 are unlikely to play an important role in the MK801-sensitive component of kindling and the changes in neural connectivity (mossy fibre sprouting) associated with kindling. Conversely, the role in kindling of those genes whose expression was significantly attenuated by MK801 (Fos, Jun-D, Krox-20, trkB and BDNF) requires further examination.