Application Of Ketamine Research Articles

The role of the N-methyl- d-aspartate receptor in ketamine-induced apoptosis in rat forebrain culture

Recent data suggest that anesthetic drugs may cause widespread and dose-dependent apoptotic neurodegeneration during development. The window of vulnerability to this neurotoxic effect, particularly with N-methyl- d-aspartate (NMDA) antagonists such as ketamine, is restricted to the period of synaptogenesis. The purposes of this study are to determine whether treatment of forebrain cultures with ketamine results in a dose-related increase in neurotoxicity and whether upregulation of NMDA receptor subunit NR1 promotes ketamine-induced apoptosis. Forebrain cultures were treated for 12 h with 0.1, 1, 10 and 20 μM ketamine or co-incubated with NR1 antisense oligonucleotide (2 μM). After washout of the ketamine, cultures were kept in serum-containing medium (in presence of glutamate) for 24 h. Application of ketamine (10 and 20 μM) resulted in a substantial increase in DNA fragmentation as measured by cell death enzyme-linked immunosorbent assay, increased number of terminal dUTP nick-end labeling positive cells, and a reduction in mitochondrial metabolism of the dye 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. No significant effect was seen in the release of lactate dehydrogenase, indicating that cell death presumably occurred via an apoptotic mechanism. Co-incubation of ketamine with NR1 antisense significantly reduced ketamine-induced apoptosis. Western analysis showed that neurotoxic concentrations of ketamine increased Bax and NR1 protein levels. NR1 antisense prevented this increase caused by ketamine, suggesting that ketamine-induced cell death is associated with a compensatory upregulation of the NMDA receptor. These data suggest that NR1 antisense offers neuroprotection from apoptosis in vitro, and that upregulation of the NR1 following ketamine administration is, at least, partially responsible for the observed apoptosis.

Ketamine-induced changes in rat behaviour: a possible animal model of schizophrenia. Test of predictive validity

Previously, it was shown that subchronic application of the NMDA receptor antagonist ketamine (Ket) induces schizophrenia-related alterations, e.g. decreased non-aggressive behaviour in the social interaction test, which might be a useful animal model in the study of negative symptoms of this disease. In order to further evaluate the predictive validity of this model, the anxioloytic diazepam, the classic neuroleptic haloperidol and the atypical neuroleptics clozapine and risperidone were tested after acute and subchronic treatment. The experiments demonstrated that haloperidol did not normalise the behavioural effects of Ket. After acute administration, diazepam was ineffective in control animals but increased non-aggressive behaviour in Ket-treated animals. Similar effects were found in animals injected with either clozapine or risperidone. Twenty-four hours after discontinuation of subchronic treatment with both substances, there was an increase in the percentage of non-aggressive behaviour in the ketamine group and a decrease in the control animals. This decrease was explained in terms of withdrawal. Different effects in the control groups and the Ket groups were found when the test was performed 1 h after subchronic clozapine or risperidone treatment. The data suggest that atypical antipsychotic drugs (APD) effectively counteract Ket-induced alterations in social behaviour. Regarding false-positive effects by anxiolytic drugs without antipsychotic efficacy, this model may have some predictive validity for identifying anxiolytic effects of novel antipsychotic compounds.

Ketamine blocks non-N-methyl-D-aspartate receptor channels attenuating glutamatergic transmission in the auditory cortex

ObjectiveTo investigate the influence of ketamine on non-N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission in the auditory cortex. Material and MethodsUsing whole-cell patch-clamp techniques on pyramidal neurons, we studied the effects of ketamine on excitatory post-synaptic potentials (EPSPs) evoked by electrical stimulation of internal capsule fibers in slices of gerbil auditory cortex. ResultsAfter blockade of the slow, NMDA receptor-mediated EPSP component with dl-2-amino-5-phosphonovaleric acid, application of ketamine in a concentration-dependent manner led to a reduction in the amplitude of fast, 6-cyano-7-nitroquinoxalinedione (CNQX)-sensitive EPSPs, accompanied by an increased membrane resistance. Blockade of non-NMDA glutamate receptors with CNQX prevented both effects. ConclusionKetamine reduces membrane conductance and glutamatergic excitation, in part by blocking alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor channels that may be constitutively active at a low level in slice preparations of auditory cortex.

Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia

Treatment with the phencyclidine derivative ketamine, a non-competitive N -methyl- d -aspartate receptor antagonist and a well known anesthetic, has recently been introduced to mimic schizophrenia in animals. Using rats repeatedly treated with sub-anesthetic doses we demonstrate in the hippocampal formation the cellular distribution patterns of proteins being relevant to the pathogenesis of schizophrenia. Compared with controls an increase in the density of reduced nicotinamide adenine dinucleotide phosphate diaphorase-, neuronal nitric oxide synthase- and cFOS-positive hippocampal interneurons was found, whereas the density of parvalbumin expressing cells was decreased. Our experiments show that repeated injections of sub-anesthetic doses of ketamine induce significant changes in the nitrergic and GABAergic system which, in part, resemble those described in postmortem brains of human schizophrenics indicating that sub-chronic treatment with sub-anesthetic doses of ketamine might be a useful animal model to study schizophrenia.

Repeated application of ketamine to rats induces changes in the hippocampal expression of parvalbumin, neuronal nitric oxide synthase and cFOS similar to those found in human schizophrenia

Treatment with the phencyclidine derivative ketamine, a non-competitive N-methyl- d-aspartate receptor antagonist and a well known anesthetic, has recently been introduced to mimic schizophrenia in animals. Using rats repeatedly treated with sub-anesthetic doses we demonstrate in the hippocampal formation the cellular distribution patterns of proteins being relevant to the pathogenesis of schizophrenia. Compared with controls an increase in the density of reduced nicotinamide adenine dinucleotide phosphate diaphorase-, neuronal nitric oxide synthase- and cFOS-positive hippocampal interneurons was found, whereas the density of parvalbumin expressing cells was decreased. Our experiments show that repeated injections of sub-anesthetic doses of ketamine induce significant changes in the nitrergic and GABAergic system which, in part, resemble those described in postmortem brains of human schizophrenics indicating that sub-chronic treatment with sub-anesthetic doses of ketamine might be a useful animal model to study schizophrenia.

Intravenous anesthetics differentially modulate ligand-gated ion channels.

Heteromeric neuronal nicotinic acetylcholine receptors (nAChRs) are potently inhibited by volatile anesthetics, but it is not known whether they are affected by intravenous anesthetics. Ketamine potentiates gamma-aminobutyric acid type A (GABAA) receptors at high concentrations, but it is unknown whether there is potentiation at clinically relevant concentrations. Information about the effects of intravenous anesthetics with different behavioral profiles on specific ligand-gated ion channels may lead to hypotheses as to which ion channel effect produces a specific anesthetic behavior. A heteromeric nAChR composed of alpha4 and beta4 subunits was expressed heterologously in Xenopus laevis oocytes. Using the two-electrode voltage clamp technique, peak ACh-gated current was measured before and during application of ketamine, etomidate, or thiopental. The response to GABA of alpha1beta2gamma2s GABAA receptors expressed in human embryonic kidney cells and Xenopus oocytes was compared with and without coapplication of ketamine from 1 microm to 10 mm. Ketamine caused potent, concentration-dependent inhibition of the alpha4beta4 nAChR current with an IC50 of 0.24 microm. The inhibition by ketamine was use-dependent; the antagonist was more effective when the channel had been opened by agonist. Ketamine did not modulate the alpha1beta2gamma2s GABAA receptor response in the clinically relevant concentration range. Thiopental caused 27% inhibition of ACh response at its clinical EC50. Etomidate did not modulate the alpha4beta4 nAChR response in the clinically relevant concentration range, although there was inhibition at very high concentrations. The alpha4beta4 nAChR, which is predominantly found in the central nervous system (CNS), is differentially affected by clinically relevant concentrations of intravenous anesthetics. Ketamine, commonly known to be an inhibitor at the N-methyl-D-aspartate receptor, is also a potent inhibitor at a central nAChR. It has little effect on a common CNS GABAA receptor in a clinically relevant concentration range. Interaction between ketamine and specific subtypes of nAChRs in the CNS may result in anesthetic behaviors such as inattention to surgical stimulus and in analgesia. Thiopental causes minor inhibition at the alpha4beta4 nAChR. Modulation of the alpha4beta4 nAChR by etomidate is unlikely to be important in anesthesia practice based on the insensitivity of this receptor to clinically used concentrations.

Histological Findings After Long-Term Infusion of Intrathecal Ketamine for Chronic Pain: A Case Report

Ketamine, a selective, noncompetitive N-methyl- d-aspartate (NMDA)-receptor antagonist, is able to alter pain perception at the spinal level. Little clinical data exist on the intrathecal and epidural use of ketamine in chronic pain. Histopathologic findings after intrathecal injection of ketamine with and without preservatives are rarely reported. This outcome was evaluated in a 72-year-old woman with abdominal pain due to cancer who was treated with the intrathecal application of bupivacaine, clonidine, and morphine. We reached satisfactory pain relief with the addition of ketamine to the mixture for 7 days. On postmortem, focal lymphocytic vasculitis close to the catheter injection site was found. This finding has not been described previously after long-term application of ketamine intrathecally. The intrathecal infusion of ketamine with preservative, or the mixture of ketamine, clonidine, morphine, and bupivacaine resulted in isolated lymphocytic vasculitis of the spinal cord and leptomeninges without any clinical signs of neurological deficit.

Transdermal Application of Ketamine: A Pilot Study

Transdermal Application of Ketamine: A Pilot Study

Involvement of NMDA receptors in the control of respiratory rhythm generated by medullo-spinal preparations of early postnatal rats

Effects of a non-competetive blocker of glutamate NMDA receptors, ketamine, on respiratory activity recorded from the phrenic nerve were studied in experiments on superfusedin situ semi-isolated medullo-spinal preparations (SIMSP) of 3− to 4-day-old rats. The experiments were carried out under conditions where the ventrolateral medullary region (VLM) was left intact, or its rostral portion (projectionally corresponding to the chemosensitiveM zone) was separated by transection. Three-min-long application of 1.0 μM ketamine evoked a slight increase in the duration of inspiratory discharges (ID) and a statistically significant increase in their frequency. After the rostral VLM had been separated, similar ketamine application resulted in significant increases in the duration, amplitude, and integral intensity of ID and some drop in their frequency. An increase to 10 μM ketamine concentration in the superfusing solution determined a significant rise of the ID duration, which indicates the possibility of inhibition of the mechanisms switching inspiration to expiration. Concurrently, the ID frequency significantly dropped, while their amplitude and integral intensity increased. After separation of the rostral VLM, the latter ketamine concentration ceased to increase the ID duration, and their frequency and amplitude significantly dropped. Application of ketamine in the concentration of 100 μM resulted in rather profound decreases of all measured ID parameters, and separation of the rostral VLM exerted no influence on the direction of the above modifications. Thus, we obtained evidence of the involvement of NMDA receptors of the VLM in the control of temporal and frequency-amplitude parameters of respiratory activity of early postnatal rats. Possible localization of NMDA receptors and mechanisms of their involvement in inspiration-expiration switching and tonic inhibitory control of respiratory rhythms are discussed.

S-(+)-ketamine. Circulatory interactions during total intravenous anesthesia and analgesia-sedation

General cardiovascular properties of ketamine: "In vitro", ketamine has moderate negative inotropic effects. "In vivo", a significant central sympathomimetic action with consecutive hemodynamic effects is dominant. The sympathomimetic potency of ketamine is one of the most significant pharmacological features of the substance with direct clinical implications. Monoanaesthesia with S-(+)-ketamine: After application of racemic ketamine or S(+)-ketamine as well, identic and significant increases in plasma catecholamines, arterial pressure and heart rate are observed. This outstanding sympathomimetic action is beneficial in induction of patients with shock or asthmatic state. TIVA and analgosedation with S-(+)-ketamine and midazolam: The sympathomimetic effect of S(+)-ketamine, and racemic ketamine as well, is mitigated by midazolam. Nevertheless, significant increases in heart rate and arteriel pressure might be observed. Clinical use of the combination is common in short procedures like reposition maneuvers. Of greater importance is the use for analgosedation in patients with cardiovascular instability, particularly in patients with exogenous catecholamine demand. TIVA and analgosedation with S-(+)-ketamine and propofol: When S(+)-ketamine is combined with propofol, the sympatholytic effects of propofol are counteracted by S(+)-ketamine, and stable hemodynamic conditions are presented. This combination seems useful for TIVA in patients with hypotonic dysregulation or endocrine deficits like hypothyreosis and adrenal insufficiency. Furthermore, analgosedation with S(+)-ketamine and propofol is advantageous, when rapid recovery is necessary and negative circulatory effects should be avoided. Sympathoadrenergic and hemodynamic effects of S(+)-ketamine and racemic ketamine are generally identical. The distinctest action is observed, when S(+)-ketamine is used as a monoanaesthetic. In combination with midazolam, a significant reduction is achieved. In combination with propofol, the sympatholytic effects of this hypnotic agent are compensated by S(+)-ketamine. With respect to sympathoadrenergic and hemodynamic reactions, the clinical position of S(+)-ketamine is unchanged. Nevertheless, a significant clinical progress can be expected due to improved recovery and reduced substance load, when racemic ketamine is replaced by S(+)-ketamine.

Hypoxia-induced dysfunction in developing rat neocortex.

Neocortical slices from young [postnatal day (P) 5-8], juvenile (P14-18), and adult (>P28) rats were exposed to long periods of hypoxia. Field potential (FP) responses to orthodromic synaptic stimulation, the extracellular DC potential, and the extracellular Ca2+ concentration ([Ca2+]o] were measured simultaneously in layers II/III of primary somatosensory cortex. Hypoxia caused a 42 and 55% decrease in the FP response in juvenile and adult cortex, respectively. FP responses recorded in slices from young animals were significantly more resistant to oxygen deprivation as compared with the juvenile (P < 0.01) and adult age group (P < 0.001) and declined by only 3% in amplitude. In adult cortex, hypoxia elicited, after 7 +/- 4.5 min (mean +/- SD), a sudden anoxic depolarization (AD) with an amplitude of 14 +/- 6 mV and a duration of 0.89 +/- 0.28 min at half-maximal amplitude. Although the AD onset latency was significantly longer in P5-8 (12.5 +/- 4.9 min, P < 0.001) and P14-18 (8.7 +/- 3.2 min, P < 0.002) cortex, the amplitude and duration of the AD was larger in young (45.7 +/- 7.6 mV, 2.19 +/- 0.71 min, both P < 0.001) and juvenile animals (29.9 +/- 9.1 mV, P < 0.001, 0.96 +/- 0.26 min, P > 0.05) when compared with the adults. The hypoxia-induced [Ca2+]o decrease was significantly (P < 0.002) larger in young cortex (1,115 +/- 50 microM) as compared with the adult (926 +/- 107 microM). Prolongation of hypoxia after AD onset for >5 min elicited in young and juvenile cortex a long-lasting AD with an amplitude of 40.5 mV associated with a decrease in [Ca2+]o by >1 mM. On reoxygenation, only slices from these age groups showed spontaneous repetitive spreading depression in 3 out of 26 cases. In adults, the same protocol caused a significantly (P < 0.05) smaller and shorter AD and never a spreading depression. However, recovery in synaptic transmission after this long-term hypoxia was better in young and juvenile cortex, indicating a prolonged or even irreversible deficiency in synaptic function in mature animals. Application of ketamine caused a 49% reduction in the initial amplitude of the AD in juvenile cortex but did not significantly affect the AD in slices from adult animals. These data indicate that the young and juvenile cortex tolerates much longer periods of oxygen deprivation as compared with the adult, but that a sufficiently long hypoxia causes severe pathophysiological activity in the immature cortex. This enhanced sensitivity of the immature cortex is at least partially mediated by activation of N-methyl-D-aspartate receptors.

Blockade of myocardial ATP-sensitive potassium channels by ketamine.

The adenosine triphosphate (ATP)-sensitive potassium (KATP) channel underlies the increase in potassium permeability during hypoxia and ischemia. The increased outward potassium current during ischemia may be an endogenous cardioprotective mechanism. This study was designed to determine the effects of ketamine on KATP channel in rat hearts. Inside-out and cell-attached configurations of patch-clamp techniques and 3 M potassium chloride-filled conventional microelectrodes were used to investigate the effect of ketamine on KATP channel currents in single rat ventricular myocytes and on the action potential duration of rat papillary muscles, respectively. Ketamine inhibited KATP channel activity in rat ventricular myocytes in a concentration-dependent manner. In the inside-out patches, the concentration of ketamine for half-maximal inhibition and the Hill coefficient were 62.9 microM and 0.54, respectively. In a concentration-dependent manner, ketamine inhibited pinacidil- and 2,4-dinitrophenol-activated KATP channels in cell-attached patches. The application of ketamine to the intracellular side of membrane patches did not affect the conduction of single-channel currents of KATP channels. Ketamine increased the action potential duration, which was then shortened by pinacidil in a concentration-dependent manner. Ketamine inhibited KATP channel activity in a concentration-dependent manner. These results suggest that ketamine may attenuate the cardioprotective effects of the KATP channel during ischemia and reperfusion in the rat myocardium.

Neuroprotection by ketamine at the cellular level

A key question in cellular neuroprotection is how pharmacologic agents may protect neurons when applied after injury in clinically relevant concentrations. Of special importance is the N-methyl-D-aspartate (NMDA) antagonist ketamine, which offers the potential for regulation of intracellular calcium levels and pathophysiological NO induction by blocking excessive NMDA-receptor stimulation. This may reduce progressive neuronal degeneration and cell death. Initial evidence for ketamine's neuroprotective effects came from cell culture studies demonstrating increased neuronal and astroglial viability, preserved cellular morphology, and reduced cell swelling subsequent to anoxia-hypoxia or glutamate injury and ketamine application. Moreover, ketamine was found to protect cellular energy status after ischaemic insults and maintained ATP production, glucose metabolism, and mitochondrial transmembrane potentials. Subsequent studies have revealed ketamine's regulating effects on intracellular ion homeostasis, thus stabilising neuronal electrophysiological functions. In addition, ketamine was reported to maintain a glutamate-associated induction of intrinsic-neuronal protective nerve growth factors, and recent evidence suggests that S(+)-ketamine has a greater neuroprotective potential than ketamine racemate. S(+)-ketamine demonstrated a unique neuroregenerative potential that was associated with greater re-outgrowth of axonal neurites after mechanical injury and increased expression of growth-associated proteins after glutamate damage. S(+)-ketamine has a two- to four-fold higher affinity for the phencyclidine receptor of the NMDA receptor complex than ketamine racemate, and it is conceivable that the induction of a differentiated pattern of genes induces cellular growth activities via ketamine-mediated NMDA-receptor activation or blockade. However, further investigations elucidating ketamine's effects in animals and humans have to be performed before final decisions regarding a potential application of ketamine as a neuroprotective agent in the clinical setting can be made.

Ketamine antagonizes hypoxia-induced dopamine release in rat striatum

The purpose of this study is to investigate the hypothesis that ketamine, a non-competitive antagonist of the N-methyl- d-aspartate (NMDA) receptor, attenuates hypoxia-induced striatal dopamine release in vivo. High-speed chronoamperometric recording techniques, using Nafion-coated carbon fiber electrodes, were used to evaluate extracellullar dopamine (DA) concentration in the striatum. KCl and DA were locally applied directly to the striatum of urethane-anesthetized Sprague-Dawley rats, in order to measure release and clearance, respectively, of DA. These anesthetized animals were paralyzed with d-tubocurarine and connected to a respirator to allow controlled inspired air and the rate of the respirator. Our data indicate that lowering the respiratory rate from 90 to 20 times/min for 5 min, in room air, caused a decrease in blood O 2 while increasing the CO 2 concentration. These changes in blood gas concentration were reversible and reproducible. We also found that lowering the respiratory rates potentiated K +-induced DA release but not DA clearance in the striatum. In an attempt to induce hypercapnia, the room air was replaced with high CO 2-containing air (15% CO 2 + 20% O 2 + 65% N 2), and this change resulted in increased blood CO 2 levels without lowering O 2 concentration. The hypercapnia did not alter K +-induced DA release in the striatum. Next, we attempted to simulate anoxic hypoxia in the absence of hypercapnia. Respiration with pure N 2 for 30 s resulted in lowering blood O 2 without increasing CO 2 levels. Both basal and K +-evoked DA releases were increased during N 2-induced anoxic hypoxia. These data suggested that transient hypoxia facilitates DA release in the striatum. It has been suggested that NMDA is involved in many hypoxia-mediated responses. We also found that systemic application of ketamine, which itself did not affect blood O 2 or CO 2 levels, antagonized hypoxia-induced electrochemical responses. These data suggest that the increase in DA release in vivo during short-term hypoxia may probably be mediated through NMDA receptors.

GYKI 52466 antagonizes glutamate responses but not NMDA and kainate responses in rat abducens motoneurones

A new non-N- methyl- d-aspartate (non-NMDA) glutamate receptor antagonist, GYKI 52466, was tested on l-glutamate (Glu)-, kainate (KAI)- and NMDA-induced responses in vivo, using both extracellular recording of antidromic field potentials and intracellular recording from rat abducens motoneurones. Intravenous (5–10 mg/kg) or iontophoretic applications of GYKI 52466 blocked the Glu-induced depression of antidromic field potentials only. Furthermore, intravenous application of ketamine blocked the NMDA-induced depression only. Iontophoretic application of GYKI 52466 reduced the Glu-induced neuronal depolarization but not those induced by NMDA and KAI. Our results show a selective blockade of Glu responses by GYKI 52466, probably by acting at the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subtype in rat abducens motoneurones.

Effects of MK-801, ketamine and alaptide on quinolinate models in the maturing hippocampus

The ability of the N-methyl- d-aspartate receptor antagonists, MK-801, ketamine and alaptide [a newly synthesized cyclo(1-amino-1-cyclopentane-carbonyl- l-alanyl) with protective properties in models of hypoxia], to prevent neuronal degeneration caused by intracerebroventricular application of quinolinic acid was investigated. Neurodegenerative effects of quinolinate in the hippocampal formation were found to increase with the degree of maturity of glutamatergic target structures. A protective potency of the N-methyl- d-aspartate receptor antagonists was observed at all developmental stages studied (12- and 30-day-old and adult rats). MK-801 showed the highest efficacy, alaptide the lowest. These findings suggest a parallelism in maturity of glutamatergic transmission processes as one prerequisite of quinolinate vulnerability and postnatal increases of target fields of the protectives. Application of MK-801 or ketamine after quinolinate injection intensified their protective effects when compared to simultaneous or preadministration. This observation is interpreted as indicating that quinolinate is a prompter of a delayed neurodegenerative process rather than acting immediately as a toxicant.

A novel bivalent opioid tetrapeptide : Effect of administration route in comparison with morphine

Biphalin is an opioid peptide analogue that currently is under clinical development as a new type of site-directed analgesic. In rats, the intrathecal (i.t.) analgesic potency of biphalin is 1000-fold greater than morphine. Such a high activity may reflect this compound’s activation of three types of opioid receptors (μ, δ and κ). NMDA receptors also play an important role in nociceptive processing. Therefore, we investigated in rats whether an NMDA antagonist may influence biphalin-induced antinociception. In the present study, ketamine was chosen because of the widespread safe use of this drug in clinical practice. I.t. application of ketamine alone had relatively little analgesic effect and its excitatory effects limited possible doses of the drug. Co-administration of ketamine with biphalin or morphine produced markedly greater antinociception than biphalin or morphine alone in acute, thermal tail flick testing. These results suggest that NMDA antagonists may be useful potentiators of biphalin analgesia. Thus, to obtain the same spinal antinociceptive effect, lower doses of biphalin or morphine are required when ketamine is co-administered.

Ketamine selectively suppresses synchronized afterdischarges in immature hippocampus

The role of excitatory amino acid neurotransmission in epileptogenesis was investigated in the developing hippocampus. Bath application of ketamine blocked penicillin-induced, synchronized afterdischarges in immature rat CA 3 hippocampal neurons. Ketamine also decreased the duration of the preceding intracellularly recorded depolarization shift but had no measurable effect on the resting membrane potential or input impedance of pyramidal cells. Concentrations of ketamine that blocked afterdischarge generation dramatically depressed intracellular depolarizations produced by iontophoretic application of N-methyl- d-aspartate (NMDA) but not quisqualate. The effects of the NMDA antagonist 2-amino-7-phosphonoheptanoic acid on epileptiform discharges were identical to those of ketamine. These results suggest that an endogenous excitatory amino acid acting on an NMDA receptor plays a key role in the pronounced capacity of immature hippocampus for seizures.

Tremor in the monkey with a cerebellar lesion

Signs of cerebellar disorder, especially tremor, were observed in monkeys after partial cerebellectomy, and the cerebellar lesion was histologically examined after autopsy. The tremor during motion and/or posture appeared in the monkeys whose lateral and interpositus cerebellar nuclei were concomitantly damaged to a fair extent. Lesion of only the lateral nucleus barely resulted in tremor. Systemic application of ketamine, megimide, or harmaline increased muscular tonus in normal monkeys, and induced spontaneous tremor in monkeys with concomitant lesions of the lateral and interpositus cerebellar nuclei. We suggest that tremor is elicitable in the cerebellectomized monkey during muscular contraction due to voluntary movements as well as during the muscular hypertonus produced by the drugs.