dizocilpine-maleate and caramiphen

Male Sprague-Dawley rats were trained to discriminate dextromethorphan (DM, 30 mg/kg, ip) from saline using a standard two-lever, fixed ratio 10, food reinforcement procedure. The DM-saline discrimination was acquired, and a range of doses of DM produced a dose-related generalization to the DM-lever choice. Stimulus generalization tests were conducted with dextrorphan, an active metabolite of DM, and with drugs selected from different pharmacological families. Dextrorphan induced a full generalization to DM, but only at a dose higher than the DM training dose. Morphine, a mu opiate receptors agonist, and U 50488, a kappa opiate receptors agonist, failed to substitute for DM. Cyclazocine, a benzomorphan derivative, with high affinity for sigma receptors, was able to produce a complete generalization to DM, without a change in the number of rats responding. Dizocilpine (MK 801), a phencyclidine-like drug, produced a complete generalization, but only at a dose that markedly reduced the number of rats responding. Carbetapentane and caramiphen, antitussive drugs with high affinity for the 'specific DM receptors', failed to substitute for DM. These results show that the discriminative stimulus of DM, did not result primarily from its metabolism to dextrorphan; and the discriminative stimulus properties of DM appear to more closely resemble those of cyclazocine than those of the other drugs tested. This suggests a role of sigma receptors in the mediation of the DM stimulus. These experimental data are discussed with reference to the cyclazocine-like subjective effects produced in man by large doses of DM.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Antitussive Agents; Cyclazocine; Cyclopentanes; Dextromethorphan; Dextrorphan; Discrimination Learning; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Morphine; Neuroprotective Agents; Pyrrolidines; Rats; Rats, Sprague-Dawley; Receptors, Opioid, kappa; Receptors, sigma

Organophosphate poisoning is associated with adverse effects on the central nervous system such as seizure/convulsive activity and long term changes in neuronal networks. This study reports on investigations designed to assess the consequences of soman exposure on excitatory amino acids receptors in the rat brain. In addition, the protective effects of caramiphen which acts at these receptors, and scopolamine, which does not, was determined on soman-induced alteration in rat brain functions. Administration of soman (1xLD50) to pyridostigmine pretreated rats produced seizure activity (measured by EEG monitoring) in all animals tested. Estimation of [3H]MK-801 binding to brain membranes from intoxicated rats revealed a marked decrease in Bmax value 24 but not 2 hrs following soman administration. The specific nature of these effects of soman was demonstrated by the findings that [3H]flunitrazepam binding to central benzodiazepine receptors remained unchanged in soman-poisoned rat brain membranes. Both scopolamine and caramiphen, when used prophylactically prevented the lethal effect of soman and completely blocked the development of electrographic seizure activity (EGSA). In contrast, only caramiphen abolished soman-induced modifications in NMDA/ion channel characteristics. Caramiphen displaced [3H]MK-801 bound to the NMDA/ion channel complex, possibly by interacting with the Zn2+ site whereas scopolamine did not. Moreover, caramiphen, but not scopolamine, partially protected mice from NMDA-induced lethality. Thus, it is suggested that an important component of the protective efficacy of caramiphen against organophosphate poisoning might be attributed to its ability to modulate NMDA receptors in addition to its anticholinergic properties.

Topics: Animals; Brain; Cholinesterase Inhibitors; Cyclopentanes; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Electroencephalography; Excitatory Amino Acid Antagonists; Flunitrazepam; In Vitro Techniques; Male; Mice; Mice, Inbred ICR; Parasympatholytics; Protein Binding; Pyridostigmine Bromide; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Scopolamine; Seizures; Soman; Time Factors

The effects of the non-opioid oral antitussives dextromethorphan (DM) and caramiphen (CP) were tested against the behavioural and EEG effects elicited by the N-methyl-D-aspartate (NMDA) antagonists dizocilpine (MK 801) and phencyclidine (PCP) in rats and mice. PCP (1.25-10 mg/kg i.p.) induced a dose-dependent increase/decrease of the locomotor/exploratory activity of mice. DM (25-50 mg/kg i.p.) and MK 801 (0.125-0.250 mg/kg i.p.) induced an increase of the locomotor/exploratory activity of mice, while CP (25-50 mg/kg i.p.) did not produce such an effect. CP (12.5 mg/kg i.p.) and DM (12.5 mg/kg i.p.) significantly potentiated the effects of PCP (1.25 mg/kg i.p.) and MK 801 (0.062 mg/kg i.p.) in the open field test in mice. In rats, PCP (1.25-10 mg/kg i.p.) induced three dose-dependent EEG stages: 1) increase of the cortical desynchronization periods; 2) increase of the amplitude of cortical background activity; 3) appearance of cortical slow wave-spike complexes. Even though DM (up to 100 mg/kg i.p.) only induced PCP-like EEG stage 1 by itself, and CP (up to 50 mg/kg i.p.) did not affect basal cortical EEG activity, these drugs, at the doses of 30-50 mg/kg i.p., potentiated all the EEG effects induced by PCP. These data support the view of an interaction between non-opioid antitussives and non-competitive NMDA antagonists.

Topics: Animals; Antitussive Agents; Behavior, Animal; Cyclopentanes; Dextromethorphan; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Synergism; Electroencephalography; Ion Channels; Male; Mice; Phencyclidine; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate

1. The effects of the non-opioid antitussives caramiphen and carbetapentane and of the anticonvulsants 5,5-diphenylhydantoin and MK 801 were tested towards hypoxia-induced electrical changes in rat hippocampal slices. 2. The incidence of appearance of hypoxia-induced epileptiform bursting was significantly decreased (P < 0.05) by carbetapentane (50-100 microM), caramiphen (50-100 microM), 5,5-diphenylhydantoin (25-50 microM), and the glutamate antagonist dizocilpine (MK 801, 25-50 microM). 3. The incidence of reappearance of the CA1 population spike after hypoxia was significantly increased (P < 0.05) by carbentapentane (50-100 microM), caramiphen (50-100 microM), 5,5-diphenylhydantoin (25-50 microM), and MK 801 (25-50 microM). 4. The results suggest a useful role for non-opioid antitussives and some anticonvulsants in the treatment of hypoxia-induced functional disturbances.

Topics: Animals; Anticonvulsants; Antitussive Agents; Cyclopentanes; Dizocilpine Maleate; Electrophysiology; Epilepsy; Hippocampus; Hypoxia, Brain; In Vitro Techniques; Male; Membrane Potentials; Phenytoin; Rats; Rats, Wistar