Stimulation Of Sensorimotor Cortex Research Articles

Effect of transcranial direct current stimulation (tDCS) on food craving and eating when using a control method that minimizes guessing of the real vs. control condition.

Validation of transcranial direct current stimulation (tDCS) to treat obesity is hampered by evidence that participants can distinguish real from the traditional-control condition. Correctly guessing the real condition precludes knowing if it is neuromodulation or expectation that suppresses food craving and eating. Therefore, this study tested the putative efficacy of tDCS to the dorsolateral prefrontal cortex (DLPFC) to reduce food craving and eating when an alternative control condition was used that would be difficult to distinguish from the real condition. N = 28 adults with a 26-50 BMI range received a typical 20-min 2mA current session of tDCS targeting the DLPFC as the real condition and a same duration/current tDCS session targeting the sensorimotor cortex (SMC), a region not expected to affect appetite, as the control. Food image craving ratings, in-lab food consumption, and momentary ratings of physical sensations were measured. DLPFC failed to reduce food craving and consumption compared to SMC stimulation. When interviewed, 71% of participants were unable to guess real from control conditions. Those who guessed DLPFC tDCS as real attributed their guess to increased number and frequency of sensations. However, their sensation ratings during tDCS did not differ between conditions. The results question if tDCS suppresses craving and eating at all, or if the DLPFC is the best target to do so. The results also indicate that alternate-site constant stimulation as the control method may strengthen the scientific evaluation of tDCS to treat obesity. Level I, experimental study.

NB‐3 signaling mediates the cross‐talk between post‐traumatic spinal axons and scar‐forming cells

Little is known about the molecules mediating the cross-talk between post-traumatic axons and scar-forming cells after spinal cord injury. We found that a sustained NB-3 induction was simultaneously present in the terminations of post-traumatic corticospinal axons and scar-forming cells at the spinal lesion site, where they were in direct contact when axons tried to penetrate the glial scar. The regrowth of corticospinal axons was enhanced invivo with NB-3 deficiency or interruption of NB-3 trans-homophilic interactions. Biochemical, invitro and invivo evidence demonstrated that NB-3 homophilically interacted in trans to initiate a growth inhibitory signal transduction from scar-forming cells to neurons by modulating mTOR activity via CHL1 and PTPσ. NB-3 deficiency promoted BMS scores, electrophysiological transmission, and synapse reformation between regenerative axons and neurons. Our findings demonstrate that NB-3 trans-homophilic interactions mediate the cross-talk between post-traumatic axons and scar-forming cells and impair the intrinsic growth ability of injured axons.

Different action of a specific NR2B/NMDA antagonist Ro 25-6981 on cortical evoked potentials and epileptic afterdischarges in immature rats.

Ro 25-6981 maleate is a highly selective and activity-dependent antagonist of NMDA ionotropic glutamate receptors containing NR2B subunit (NR2B/NMDARs). The aim of our study was to investigate the influence of Ro 25-6981 administration in developing rats on physiological (single and paired pulse cortical interhemispheric evoked potentials) and epileptic brain activity (cortical afterdischarges (ADs)). Electrophysiological experiments were performed in animals with epidurally implanted electrodes at postnatal days (P) P12, P18, and P25. The drug was injected intraperitoneally at a dose of 1 or 3mg/kg. Control animals were injected with saline (1ml/kg). Single interhemispheric responses were evoked with 0.5-ms biphasic pulses with intensities increasing from 0.4 to 5mA, paired-pulse responses were elicited by twofold threshold intensity. The ADs were elicited by series of 15-s of 1-ms pulses at 8-Hz frequency. Firstly, six stimulations with stable suprathreshold intensity repeated at 30-min intervals were used to determine the time course of Ro 25-6981 effects against ADs in P12 animals. Secondly, similar experiment was performed in all age groups of animals but with 20-min intervals as well as a further experiment using stimulations with stepwise intensities increasing at 10-min intervals from 0.2 to 15 mA. Pretreatment with the 3-mg/kg (but not the lower) dose of Ro 25-9681 decreased significantly the amplitude of single responses evoked with higher stimulation intensities in P12 and P18 animals. Both doses affected responses in P25 animals, only the 1-mg/kg dose was more efficacious than the 3-mg/kg one. Paired pulse responses were not affected by either dose of Ro 25-6981 in any age group. Ro 25-9681 clearly influenced the duration of ADs only in P12 animals. The 1-mg/kg dose did not change the duration of ADs whereas the 3-mg/kg dose suppressed progressive prolongation of ADs with repeated stimulations. This effect was seen even 110-min after the drug injection. The modification of ADs, i.e. stimulations with stepwise increasing intensities (10 min intervals) was used to demonstrate possible dependence on activity. The Ro 25-6981 was administered immediately after the 4-mA stimulation (i.e. when rats experienced six ADs on the average). The 3-mg/kg dose resulted in shorter ADs after high stimulation intensities in P12. There were no significant effects in older animals, only a tendency to ADs shortening was observed in P25 rats. In conclusion, our results indicate that Ro 25-6981 as a selective antagonist of NR2B/NMDARs exhibit age- and activation-dependent anticonvulsant action at early postnatal development. In contrast, the influence of Ro 25-6981 on physiological excitability induced by single pulse stimulation of sensorimotor cortex does not depend on age. This compound may thus represent a useful antiepileptic agent in immature brain since its action against ADs prolongation can be observed even 110 min after the single administration of the drug.

Effect of GABAB Receptor Agonist SKF97541 on Cortical and Hippocampal Epileptic Afterdischarges

Activation of GABA(B) receptors leads to longer inhibitory postsynaptic potentials than activation of GABA(A) receptors. Therefore GABA(B) receptors may be a target for anticonvulsant therapy. The present study examined possible effects of GABA(B) receptor agonist SKF97541 on cortical and hippocampal epileptic afterdischarges (ADs). Epileptic ADs elicited by electrical stimulation of sensorimotor cortex or dorsal hippocampus were studied in adult male Wistar rats. Stimulation series were applied 6 times with 10- or 20-min interval. Either interval was efficient for reliable elicitation of cortical ADs but stimulation at 10-min intervals did not reliably elicit hippocampal ADs, many stimulations were without effect. SKF97541 in dose 1 mg/kg significantly prolonged cortical ADs. Duration of hippocampal ADs was not significantly changed by either dose of SKF97541 in spite of a marked myorelaxant effect of the higher dose. Our present data demonstrated that neither cortical nor hippocampal ADs in adult rats were suppressed by GABA(B) receptor agonist SKF97541. Proconvulsant effect on cortical ADs indicates a different role in these two brain structures. In addition, duration of refractory period for electrically-induced ADs in these two structures in adult rats is different.

Cortical Presynaptic Control of Dorsal Horn C–Afferents in the Rat

Lamina 5 sensorimotor cortex pyramidal neurons project to the spinal cord, participating in the modulation of several modalities of information transmission. A well-studied mechanism by which the corticospinal projection modulates sensory information is primary afferent depolarization, which has been characterized in fast muscular and cutaneous, but not in slow-conducting nociceptive skin afferents. Here we investigated whether the inhibition of nociceptive sensory information, produced by activation of the sensorimotor cortex, involves a direct presynaptic modulation of C primary afferents. In anaesthetized male Wistar rats, we analyzed the effects of sensorimotor cortex activation on post tetanic potentiation (PTP) and the paired pulse ratio (PPR) of dorsal horn field potentials evoked by C–fiber stimulation in the sural (SU) and sciatic (SC) nerves. We also explored the time course of the excitability changes in nociceptive afferents produced by cortical stimulation. We observed that the development of PTP was completely blocked when C-fiber tetanic stimulation was paired with cortex stimulation. In addition, sensorimotor cortex activation by topical administration of bicuculline (BIC) produced a reduction in the amplitude of C–fiber responses, as well as an increase in the PPR. Furthermore, increases in the intraspinal excitability of slow-conducting fiber terminals, produced by sensorimotor cortex stimulation, were indicative of primary afferent depolarization. Topical administration of BIC in the spinal cord blocked the inhibition of C–fiber neuronal responses produced by cortical stimulation. Dorsal horn neurons responding to sensorimotor cortex stimulation also exhibited a peripheral receptive field and responded to stimulation of fast cutaneous myelinated fibers. Our results suggest that corticospinal inhibition of nociceptive responses is due in part to a modulation of the excitability of primary C–fibers by means of GABAergic inhibitory interneurons.

Anticonvulsant and behavioral effects of GABAB receptor positive modulator CGP7930 in immature rats

Possible anticonvulsant action of GABAB receptor positive allosteric modulator CGP7930 was studied in cortical epileptic afterdischarges (ADs) in rat pups 12, 18, and 25days old. Afterdischarges were induced by six series of stimulation of sensorimotor cortex, and CGP7930 (20 or 40mg/kgi.p.) was administered after the first AD. In addition, the effects of CGP7930 on sensorimotor performance and behavior in open field and elevated plus maze were assessed.CGP7930 decreased duration of ADs in 12-day-old but not in older rats. Motor phenomena (movements accompanying stimulation and clonic seizures) were not changed. CGP7930 only moderately affected sensorimotor performance, altered slightly spontaneous behavior in the open field, and did not influence behavior in the elevated plus maze in terms of an adaptive form of learning or anxiety-like behavior. Marked anticonvulsant action with subtle deficits in sensorimotor performance in 12-day-old rats suggests a possible use of CGP7930 as an age-specific anticonvulsant.

Chronological Changes in Astrocytes Induced by Chronic Electrical Sensorimotor Cortex Stimulation in Rats

Motor cortex stimulation (MCS) is a treatment option for various disorders such as medically refractory pain, poststroke hemiplegia, and movement disorders. However, the exact mechanisms underlying its effects remain unknown. In this study, the effects of long-term chronic MCS were investigated by observing changes in astrocytes. A quadripolar stimulation electrode was implanted on the dura over the sensorimotor cortex of adult rats, and the cortex was continuously stimulated for 3 hours, 1 week, 4 weeks, and 8 weeks. Immunohistochemical staining of microglia (ionized calcium-binding adaptor molecule 1 [Iba1] staining) and astrocytes (glial fibrillary acidic protein [GFAP] staining), and neuronal degeneration histochemistry (Fluoro-Jade B staining) were carried out to investigate the morphological changes following long-term chronic MCS. Iba1 staining and Fluoro-Jade B staining showed no evidence of Iba1-positive microglial changes or neurodegeneration. Following continuous MCS, GFAP-positive astrocytes were enlarged and their number increased in the cortex and the thalamus of the stimulated hemisphere. These findings indicate that chronic electrical stimulation can continuously activate astrocytes and result in morphological and quantitative changes. These changes may be involved in the mechanisms underlying the neuroplasticity effect induced by MCS.

Cortical stimulation and tooth pulp evoked potentials in rats: a model of direct anti-nociception.

While the effect of cortex stimulation on pain control is widely accepted, its physiological basis remains poorly understood. We chose an animal model of pain to study the influence of sensorimotor cortex stimulation on tooth pulp stimulation evoked potentials (TPEPs). Fifteen awake rats implanted with tooth pulp, cerebral cortex, and digastric muscle electrodes were divided into three groups, receiving 60 Hz, 40 Hz and no cortical stimulation, respectively. TPEPs were recorded before, one, three and five hours after continuous stimulation. We observed an inverse relationship between TPEP amplitude and latency with increasing tooth pulp stimulation. The amplitudes of the early components of TPEPs increased and their latency decreased with increasing tooth pulp stimulation intensity. Cortical stimulation decreased the amplitude of TPEPs; however, neither the latencies of TPEPs nor the jaw-opening reflex were changed after cortical stimulation. The decrease in amplitude of TPEPs after cortical stimulation may reflect its anti-nociceptive effect.

Controversial action of positive modulator of subtype 7 of metabotropic glutamate receptors AMN082 on cortical epileptic afterdischarges in immature rats

Some age-dependent epilepsies of infancy and childhood cannot be sufficiently treated with contemporaneous antiepileptics, therefore search for new mechanisms and new drugs active in pediatric patients is necessary. Possible anticonvulsant action of AMN082 (N,N′-dibenzhydryl-ethane-1,2-diamine dihydrochloride), a positive allosteric modulator of metabotropic glutamate receptor subtype 7, was examined in a model of epileptic afterdischarges elicited in three age groups of immature rats (12, 18 and 25 days old) by electrical stimulation of sensorimotor cortex. AMN082 did not exhibit an anticonvulsant action against spike-and-wave type of afterdischarges generated in the thalamocortical system; on the contrary, moderate proconvulsant action was found in 12- and 18-day-old rats (more marked prolongation of afterdischarges with repeated stimulations). On the other hand, AMN082 significantly shortened the second type of afterdischarges reflecting spread of epileptic activity into limbic system frequently recorded in 25-day-old rats. These contradictory results mean that AMN082 will not be a broad-spectrum anticonvulsant but it might be useful as a seizure-specific antiepileptic drug.

The action of 5Hz repetitive transcranial magnetic stimulation of sensorimotor cortex on cutaneous sensation and corticospinal function in human chronic spinal cord injury

The action of 5Hz repetitive transcranial magnetic stimulation of sensorimotor cortex on cutaneous sensation and corticospinal function in human chronic spinal cord injury

C-Fos Expression After Chronic Electrical Stimulation of Sensorimotor Cortex in Rats

Objectives. Motor cortex stimulation has been used as a treatment for intractable pain. However, the mechanisms underlying its effects remain unclear. In this study, neuroplasticity induced by chronic sensorimotor cortex stimulation was investigated experimentally on the basis of c-Fos expression. Materials and Methods. The experimental animals employed were adult male Wistar rats. A quadripolar stimulation electrode was positioned over the sensorimotor cortex. We examined the neural activation in response to chronic stimulation using c-Fos immunopositivity. Results. The results are as follows: 1) c-Fos was significantly expressed immediately after the stimulation compared with that in the control; 2) c-Fos expression became extensive over the various regions with an increase in stimulation duration; and 3) after twomonths of stimulation, c-Fos was expressed not only on the stimulation side, but also within the contralateral cerebral hemisphere. Conclusions. Changes in c-Fos expression induced by long-term stimulation indicate the existence of a time-dependent neural plasticity.

Changes of cortical epileptic afterdischarges after status epilepticus in immature rats

Status epilepticus (SE) in developing rats leads to neuronal degeneration in many brain structures including neocortex but the functional consequences of cortical damage were studied only exceptionally. Lithium-pilocarpine SE was elicited in 12- (P12) and 25-day-old (P25) rats, convulsions were interrupted after 2h by paraldehyde. Cortical electrodes were implanted 3, 6, 9, 13 and/or 26 days after SE. Low-frequency stimulation of sensorimotor cortex was repeated with at least 10-min intervals with a stepwise increasing intensity (0.2-14 mA). Thresholds for movements elicited by stimulation, spike-and-wave afterdischarges (ADs), clonic seizures, mixed ADs (transition into a limbic type of ADs) and recurrent ADs as well as duration of ADs were evaluated. The first three phenomena were not influenced by SE with the exception of lower thresholds for movements during stimulation. Transition into limbic seizures and recurrent seizures were delayed in both age groups and threshold intensities for limbic ADs were at some intervals higher in SE than in control animals. Duration of ADs was changed only at short intervals after SE; it was shortened at 3 and 6 days in P25 and 3 days in P12 rats, respectively. P12 group then exhibited a transient increase in duration of ADs 6 days after SE. Our results did not prove a higher cortical excitability after SE in either age group. On the contrary, there were some signs of a decreased excitability.

Contradictory effects of GABA-B receptor agonists on cortical epileptic afterdischarges in immature rats

Classical GABA-B receptor agonist baclofen exhibits anticonvulsant as well as proconvulsant effects and these effects change during postnatal development. Epileptic afterdischarges (ADs) elicited by stimulation of sensorimotor cortex were used to analyze if it is a specific feature of baclofen or if another agonist SKF97541 possesses the same properties. To study developmental point of view 12-, 18- and 25-day-old rats were used. Both agonists exhibited anticonvulsant (decreased intensity of motor phenomena) and proconvulsant (decreased threshold intensities necessary for transition of epileptic activity into limbic structures; prolongation of ADs) action and these actions changed with age. SKF97541 is much more potent than baclofen. In addition to similarities marked differences between the two drugs were found. SKF97541 was able to increase threshold intensities of stimulation current necessary for elicitation of movements directly bound to stimulation, spike-and-wave type of ADs and accompanying clonic seizures in 12- and 18-day-old rats, baclofen was without effect. Suppression of intensity of both motor phenomena (movements and clonic seizures) was marked with SKF97541 in 12- and 18-day-old rats; this effect was only marginal in baclofen-treated animals. We can speculate that different subsets of GABA-B receptors are influenced by the two agonists but further studies are necessary.

Comparison of Cortical Epileptic Afterdischarges in Immature Genetic Absence Epilepsy WAG/Rij Rats with Those in Two Other Strains (ACI and Wistar)

The aim of this study was to examine the development of cortical epileptic afterdischarges (ADs) in genetic absence epilepsy WAG/Rij rats, and to compare them with two strains with minimal incidence of spike-and-wave (SW) episodes (ACI and Wistar). Epileptic ADs were elicited by stimulation of sensorimotor cortex in 12-, 18-, and 25-day-old rats of the three strains. The threshold current intensities were established for movements accompanying stimulation, for ADs of the SW type and accompanying clonic seizures and for transition into limbic type of ADs (characterized by behavioral automatisms). Individual groups were formed by 7-12 rats. There were no differences among the three strains in the thresholds for elicitation of stimulation-bound movements. In contrast, WAG/Rij and ACI rats exhibited easier elicitation of SW ADs than Wistar rats at the age of 18 and 25 days. There was no difference among the three strains in transition into the limbic type of ADs in 18- and 25-day-old rats. Lower thresholds for SW ADs in 18- and 25-day-old WAG/Rij and ACI rats in comparison with Wistar rats are in agreement with our data from adult animals as well as with development of pharmacologically induced models of absence seizures. The failure to find a specific difference between WAG/Rij rats and the other two strains might indicate a difference in generation of SW episodes and SW cortical AD.

Reduction of seizure thresholds following electrical stimulation of sensorimotor cortex is dependent on stimulation intensity and is not related to synaptic potentiation

Epilepsy is characterized as a chronic brain state with a very low seizure threshold, and the occurrence of repeated seizure activity. Currently, there is no animal model of induced epilepsy that allows for the exploration of the brain mechanisms underlying a low seizure threshold without the elicitation of seizures. In this study, we employed repeated application of different intensities of electrical stimulation in an attempt to reduce afterdischarge (seizure) thresholds without eliciting seizures. We utilized an in vivo model of neocortical activation via stimulation of the corpus callosum of the adult rat. The intensities were chosen to be subthreshold (20, 30, 40, 50 μA), near threshold (150 μA), and suprathreshold (250, 500 μA) relative to the mean initial afterdischarge threshold (ADT). We also examined changes in the evoked field responses of the transcallosal pathway to the sensorimotor cortex as a measure of synaptic efficacy. Our results indicated that stimulation at 50 μA was effective at reducing the ADT, while minimizing the number of seizures elicited. Stimulation at 150 μA resulted in the concomitant reduction of ADT and repeated seizures typical of most electrical kindling studies. Finally, the 500 μA group showed repeated seizures, but no reduction of afterdischarge threshold. These stimulation intensities (50 μA, 150 μA, 500 μA and 0 μA-control) can be used to independently determine the brain mechanisms responsible for 1) the acquisition of a low afterdischarge threshold independent of the reorganizing effect of repeated seizures, and 2) the elicitation of repeated seizures independent of stimulation induced reduction of afterdischarge threshold.

Spinal and Supraspinal Effects of Long-Term Stimulation of Sensorimotor Cortex in Rats

Sensorimotor cortex (SMC) modifies spinal cord reflex function throughout life and is essential for operant conditioning of the H-reflex. To further explore this long-term SMC influence over spinal cord function and its possible clinical uses, we assessed the effect of long-term SMC stimulation on the soleus H-reflex. In freely moving rats, the soleus H-reflex was measured 24 h/day for 12 wk. The soleus background EMG and M response associated with H-reflex elicitation were kept stable throughout. SMC stimulation was delivered in a 20-day-on/20-day-off/20-day-on protocol in which a train of biphasic 1-ms pulses at 25 Hz for 1 s was delivered every 10 s for the on-days. The SMC stimulus was automatically adjusted to maintain a constant descending volley. H-reflex size gradually increased during the 20 on-days, stayed high during the 20 off-days, and rose further during the next 20 on-days. In addition, the SMC stimulus needed to maintain a stable descending volley rose steadily over days. It fell during the 20 off-days and rose again when stimulation resumed. These results suggest that SMC stimulation, like H-reflex operant conditioning, induces activity-dependent plasticity in both the brain and the spinal cord and that the plasticity responsible for the H-reflex increase persists longer after the end of SMC stimulation than that underlying the change in the SMC response to stimulation.

Postictal behavior after two types of cortical epileptic afterdischarges in rats

Objective The aim of this study was to determine if behavioral patterns during the postictal state depend on the type of seizure. Methods Rhythmic electrical stimulation of sensorimotor cortex can elicit two types of epileptic afterdischarges (ADs) in adult rats: the spike-and-wave type accompanied by clonic convulsions, and a transition to a nonconvulsive type characterized by behavioral automatisms (mixed type). Rats in which stimulation did not induce ADs constituted the control group. The behavior of the animals was recorded for 20 minutes after the end of ADs or stimulation. Results Stimulation elicited only shortlasting minimal changes in control rats. Spike-and-wave ADs led to alternation of normal and unsteady walking, a decrease in normal sitting and lying (rigid lying appeared instead), and wet dog shakes (WDS). Mixed-type ADs abolished normal walking and sitting and induced unsteady walking, rigid lying, and a substantial number of WDS. Conclusions Abnormal phenomena induced by the two types of ADs differ mostly quantitatively, but also qualitatively.

Opposite effects of a GABA B antagonist in two models of epileptic seizures in developing rats

The action of a GABA B antagonist CGP 35348 and a GABA B agonist baclofen was studied in two models of epileptic seizures characterized by EEG spike-and-wave rhythm in freely moving immature rats. Rhythmic metrazol activity (RMA, model of human absences) was induced by low systemic dose of pentylenetetrazol (PTZ) in 18- and 25-day-old rats, epileptic after discharges (ADs, model of human myoclonic seizures) were elicited by electrical stimulation of sensorimotor cortex in rat pups 12, 18, and 25 days old. CGP 35348 (50, 100 and 200 mg/kg i.p.) suppressed RMA in both age groups in a dose-dependent manner. Simultaneously it increased the incidence of clonic seizures, potentiating thus an effect of PTZ. Baclofen (1, 3 and 6 mg/kg i.p.) augmented markedly RMA in 25-day-old rats. On the contrary, baclofen suppressed RMA in a part of 18-day-old animals. Incidence of seizures was not changed by baclofen in either age group. As ADs are concerned CGP 35348 (100 and 200 mg/kg i.p.) exhibited a proconvulsant action, baclofen (3, 6 or 12 mg/kg i.p.) was anticonvulsant, but again an irregularity of action was found in 18-day-old rats. The role of GABA B-mediated inhibition in epileptogenesis depends on the type of seizures and also on the stage of maturation.

Biphasic effect of chronic postnatal caffeine treatment on cortical epileptic afterdischarges during ontogeny in rats

EEG and motor phenomena elicited by stimulation of sensorimotor cortex were used to study the effects of chronic postnatal administration of caffeine (10 and 20 mg/kg, s.c. from P7 to P11) in rats. Rhythmic electrical stimulation was applied to 12-, 18-, 25- and 67-day-old rats with implanted electrodes. Animals with the higher dose of caffeine exhibited increased thresholds for elicitation of stimulation-bound movements, spike-and-wave afterdischarges (ADs) and clonic seizures accompanying these ADs at the age of 12 days and decreased duration of spike-and-wave ADs at postnatal days (P) 18 and 25. In contrast, chronic administration of the lower dose of caffeine resulted in a proconvulsant effect expressed as a significant prolongation of spike-and-wave ADs in P12, P18 and P25 groups as well as of the second “limbic” type of ADs (significant only in P12 and P25). The biphasic action of chronic postnatal caffeine treatment was transient and was no longer present in 67-day-old rats. Our results demonstrate that early postnatal caffeine exposure results in either pro- or anticonvulsant effect during brain maturation in relation to the dose used. Caffeine is a mixed adenosine receptor antagonist, therefore its effects could be due to a different action on adenosine receptor subtypes; an additional mechanism of action cannot be excluded.

Cortical epileptic afterdischarges in immature rats are differently influenced by NMDA receptor antagonists

Epileptic afterdischarges elicited by stimulation of sensorimotor cortex were chosen to test anticonvulsant effects of NMDA receptor antagonists in developing rats (12, 18 and 25 days old) with implanted electrodes. Afterdischarges were elicited four times with 10-min intervals in the experiments with dizocilpine and 20 min with the other two drugs. Dizocilpine (0.5 or 1 mg/kg), CGP 40116 (0.1, 0.5 or 1 mg/kg) or 2-amino-7-phosphonoheptanoic acid (AP7, 30 or 60 mg/kg) was injected intraperitoneally between the first and second stimulation. Intensity of movements accompanying stimulation was diminished regularly only by CGP 40116. Duration of afterdischarges was reduced and intensity of clonic seizures was decreased by CGP 40116 in all age groups; dizocilpine exhibited similar action in 25- and 18-day-old rats, AP7 only in 25-day-old animals. Anticonvulsant action of the three NMDA antagonists exhibited different developmental profiles in our model; this difference might be due to developmental changes of NMDA receptors.