dizocilpine-maleate and Tremor

Harmaline is known to produce tremors and retard acquisition of the rabbit's nictitating membrane response. These actions have been demonstrated to depend on the ability of harmaline to activate the inferior olive which gives rise to climbing fibers that project directly onto Purkinje cells in cerebellar cortex. However, the precise receptor systems involved in harmaline's actions remains unknown. This study examined the role of the NMDA receptor in harmaline's actions. Harmaline (10 mg/kg, s.c.) produced intense tremors and impaired the acquisition of conditioned responses. Both of these effects of harmaline were significantly blocked by the prior administration of the noncompetitive NMDA channel blocker, dizocilpine (0.01 mg/kg, s.c. given 20 min prior to the administration of harmaline). This dose od dizocilpine had no effect on acquisition of conditioned responses when given alone. A higher dose of dizocilpine (0.1 mg/kg s.c.) completely blocked the tremorogenic effects of harmaline (10 mg/kg, s.c.). Dizocilpine had no effect on motor behavior when given alone. It was suggested that the blockade of harmaline's actions by dizocilpine may be occurring at NMDA channels within the inferior olive. Regardless of the site of action, these data demonstrate that harmaline's ability to activate the interior olivary nucleus depends on the normal activity of the NMDA receptor.

Topics: Animals; Conditioning, Classical; Dizocilpine Maleate; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Female; Harmaline; Learning Disabilities; Male; Motor Activity; Nictitating Membrane; Olivary Nucleus; Rabbits; Receptors, N-Methyl-D-Aspartate; Tremor

1. The involvement of the N-methyl-D-aspartate (NMDA) receptor macrocomplex in the development of spermine-induced CNS excitation in vivo was investigated. 2. Injection of 100 micrograms of spermine into the left lateral cerebral ventricle of female Laca mice (20-25 g) resulted in the development of two distinct phases of CNS excitatory effects which were quantified by a scoring system. 3. The first phase effects occurred within minutes of injection and generally lasted for about 1 h. Most mice showed scratching of the upper body, frequent face washing and some mice developed clonic convulsions. By about 2 h after injection, the second phase of effects began to develop in the form of body tremor which worsened with time and culminated in fatal tonic convulsions, generally within 8 h of injection. 4. Pretreatment of the mice with dizocilpine (0.3 mg kg-1, i.p.) resulted in antagonism of the first phase of spermine-induced effects, but a higher dose (0.3 mg kg-1, (x2), i.p.) was necessary to inhibit the second phase effects. 5. Whereas the glutamate antagonist, 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic acid (D-CPP) (10, 20 mg kg-1, i.p.), the glycine antagonist 7-chlorokynurenate (10, 30, 50 nmol, i.c.v.), or the polyamine antagonist ifenprodil (30, 60 mg kg-1, i.p.) antagonized the first phase of effects produced by spermine, these agents given as monotherapy, were ineffective against the development of the second phase of effects. 6. Co-administration of ifenprodil with either D-CPP or 7-chlorokynurenate resulted in a dose-dependent antagonism of the development of the second phase of spermine-induced effects. 7. It is concluded that the development of the two temporally distinct phases of spermine-induced effects may be mediated by pharmacologically distinct mechanisms, although the results suggest that the NMDA receptor macrocomplex may be involved in both phases of effects. Furthermore, a moderate dose of D-CPP or 7-chlorokynurenate appears to enhance the inhibitory potential of ifenprodil in vivo.

Topics: Animals; Brain; Cerebral Ventricles; Dizocilpine Maleate; Female; Kynurenic Acid; Mice; Neuroprotective Agents; Piperazines; Piperidines; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate; Seizures; Spermine; Tremor

Administration to mice of harmaline (100 mg/kg SC) resulted in a greater than two-fold increase in cyclic GMP in the cerebellum 15 min later. This response was inhibited by pretreatment 5 min before the harmaline with pentobarbital (ED50 6.5 mg/kg), chlormethiazole (ED50 10.4 mg/kg) and dizocilpine (ED50 0.5 mg/kg). Harmaline-induced tremor was inhibited by pentobarbital (ED50 30 mg/kg) and chlormethiazole (ED50 50 mg/kg) but not dizocilpine. The data demonstrate that the harmaline-induced tremor and cerebellar cyclic GMP rise are probably not associated. They also demonstrate that chlormethiazole is able to inhibit a biochemical response (the increase in cerebellar cyclic GMP) which results from increased glutamate function.

Topics: Animals; Cerebellum; Chlormethiazole; Cyclic GMP; Dizocilpine Maleate; Harmaline; Male; Mice; Mice, Inbred Strains; Pentobarbital; Tremor

The ability of [(+-)-5-aminocarbonyl-10,11-dihydro-5H-di-benzo [a,d]cyclohepten-5,10-imine (ADCI) and its structural analogs dizocilipine (MK-801) and carbamazepine to block ethanol withdrawal seizures was tested in mice made physically dependent upon ethanol. Three injections of either ADCI (ranging from 1.0-10.0 mg/kg), dizocilpine (ranging from 0.1-1.0 mg/kg) or carbamazepine (ranging from 17-50 mg/kg) were administered during the first 7 hr of ethanol withdrawal. The severity of ethanol withdrawal seizures was rated during the first 11 hr of withdrawal and again at 24 hr after withdrawal of ethanol. ADCI and dizocilpine suppressed the severity and occurrence of the withdrawal seizures in a dose-dependent fashion, whereas carbamazepine was ineffective in blocking the withdrawal seizures. The relative potencies of dizocilpine, ADCI and carbamazepine in suppressing ethanol withdrawal seizures corresponded with the relative potencies of the compounds in displacing [3H]dizocilpine from mouse cortical membrane preparations. These findings are consistent with the suggestion that blockade of N-methyl-D-aspartate-mediated neurotransmission is an effective treatment for decreasing ethanol withdrawal seizures. ADCI also blocked the occurrence of withdrawal-associated whole body tremors, whereas dizocilpine and carbamazepine were ineffective in blocking the tremors. The doses of ADCI, dizocilpine and carbamazepine that resulted in motor incoordination on an accelerating rotarod task were determined in groups of naive mice. Dizocilpine in doses as low as 0.3 mg/kg produced a decreased ability to remain on the rotarod, whereas ADCI up to 30 mg/kg did not affect rotarod performance.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anticonvulsants; Carbamazepine; Dizocilpine Maleate; Ethanol; Male; Mice; Mice, Inbred C57BL; Motor Activity; N-Methylaspartate; Seizures; Substance Withdrawal Syndrome; Tremor

The in vivo neurophysiological interactions of the non-competitive NMDA receptor antagonist MK801 with the High Pressure Neurological Syndrome have been investigated in the primate Papio anubis. A hyperbaric chamber was used to achieve environmental pressures of 61 ATA (atmospheres absolute) over a period of 5 hr. Eight animals underwent 2 compressions each, one following pretreatment with 0.03 mg/kg (i.v.) MK801, the other a control. Half of the animals received MK801 on their first exposure. Mild signs of the high pressure neurological syndrome, e.g. paw and limb tremor were first observed between 10 and 20 ATA and more severe signs, e.g. whole body tremor, myoclonus and vomiting, appeared after 50 ATA. The onset pressures for the various signs were increased by 10-17 ATA when the animals received MK801 (P = 0.06) and the severity of the signs, over the whole range of pressures at which they appeared, was significantly reduced (P less than 0.001). Additional experiments showed that MK801 afforded considerable protection, at pressures up to 81 ATA, but doses larger than those used for the main experiment produced signs of tranquilisation and sedation. Changes in the EEG were observed in channels associated with the frontal, parietal and occipital regions. Amplitude and frequency spectra were calculated and trends with pressure in the 4 conventional wavebands were analysed. The most striking change was a decrease in amplitude of delta waves (P less than 0.001), which was ameliorated by MK801 (P less than 0.001).

Topics: Animals; Atmospheric Pressure; Dizocilpine Maleate; Electroencephalography; Electromyography; Female; Nervous System Diseases; Papio; Syndrome; Tremor

The high pressure neurological syndrome (HPNS) occurs when man or animals are exposed to hyperbaric pressure. Four non-competitive N-methyl-D-aspartate (NMDA) antagonists - MK-801, phencyclidine (PCP), SKF 10,047 and ketamine were tested in rats for effects on the HPNS. All drugs were injected i.p. prior to compression; ketamine was also infused i.v. Control rats received saline. Rats were exposed individually to increasing helium pressure (PO2 0.5 atmospheres absolute ATA). Three endpoints were used to assess HPNS: onset pressures for tremor, myoclonus and convulsions. Neither MK-801 (0.03 and 0.3 mg/kg) nor SKF 10,047 (50 mg/kg) had any effect on the onset pressures for tremor, myoclonus or convulsions, although the type of seizure was modified from the clonic/tonic seizure seen in controls to purely clonic. PCP (5 mg/kg) had no effect on the endpoints, but pressure enhanced the excitation and stereotypy seen at 1 ATA. Ketamine (100 mg/kg i.p.) did not affect tremor or myoclonus; ketamine infused i.v. at pressure only prevented tremor and myoclonus at 'anaesthetizing' concentrations. Our results show that these non-competitive NMDA antagonists had little effect on HPNS, in contrast to competitive NMDA antagonists, such as AP7, which are highly effective. Possible explanations for this lack of effect include (1) interactions with NMDA receptor channels are pressure dependent; (2) other actions of these antagonists override their effects on the NMDA receptor channel.

Topics: Animals; Binding, Competitive; Dibenzocycloheptenes; Dizocilpine Maleate; Hyperbaric Oxygenation; Ketamine; Male; Myoclonus; Phenazocine; Phencyclidine; Rats; Rats, Inbred Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Seizures; Tremor