Actions of steroids and bemegride on the GABAA receptor of mouse spinal neurones in culture.
The effects of a synthetic and an endogenous steroid were studied on the GABAA receptors of isolated mouse spinal neurones, maintained in culture. Low doses of alphaxalone reversibly increased GABA-evoked whole-cell currents. Alphaxalone at higher doses (10-50 microM), when pressure ejected onto spinal neurones, also directly evoked a membrane chloride current. Such currents were reversibly suppressed by bicuculline (a GABAA antagonist) and enhanced by phenobarbitone. 5 beta-Pregnan-3 alpha-ol-20-one, a progesterone metabolite, dose-dependently potentiated the amplitude of GABA-evoked whole-cell currents. The mechanism of potentiation was examined at the single-channel level using outside-out patches from spinal neurones. The main action of the steroid on the GABAA receptor appears to be similar to that found for barbiturates, in that they prolonged GABA-activated bursts of channel openings. Bemegride had an antagonistic action on the GABAA receptor, suppressing both GABA- and pentobarbitone-evoked whole-cell currents to similar extents. (+info)
Carisoprodol tolerance and precipitated withdrawal.
An analysis of the drugs acting on cerebral energy metabolism.
The behaviour of (a) the redox potential of the lactate/pyruvate system and the changes of the redox potential of the lactate/pyruvate system across the brain; (b) the energy charge potential of the adenylate pool, was studied in the brain of curarized beagle dogs. The influence of certain drugs (amobarbital, nicergoline, theophylline, papaverine, bamethan, dipyridamole, bemegride) on these parameters was evaluated under control conditions, during hypoxemia and during post-hypoxiemic recovery. On the whole, the action on energetic metabolism appears to be unrelated to the action believed to be exerted by drugs on cerebral vessels. (+info)
Effects of drugs acting alone and in combination on the motor activity of intact mice.
1. When administered to intact white mice, the central depressants-diphenhydramine, promethazine, chlorpromazine, gammahydroxybutyrate, gammabutyrolactone, hyoscine, and pethidine-produced sedation in small doses, but excitement and convulsions in higher doses. When given to mice pretreated with subanaesthetic doses of phenobarbitone these drugs abolished the righting reflex both in convulsant doses (hyoscine excepted) and in non-convulsant doses. These effects are similar to the effects previously observed with local anaesthetics.2. Meprobamate, diazepam and chlorpromazine produced a loss of righting reflex both when given alone and following phenobarbitone. When given alone in higher doses, chlorpromazine induced convulsions.3. The central stimulants bemegride and picrotoxin antagonized the loss of righting reflex produced by phenobarbitone, but nikethamide, caffeine and strychnine did not alter the depressant effects of phenobarbitone.4. On the basis of these and previous studies with intact white mice a tentative classification of drugs having generalized depressant and stimulant effects on the central nervous system was proposed and discussed. (+info)
Effects of general stimulant drugs on the electrical responses of isolated slabs of cat's cerebral cortex.
1. In the neuronally isolated cortex of the cat, local application of bemegride, picrotoxin, nikethamide, caffeine and strychnine facilitated the surface positive response of the isolated cortex and lowered the stimulus threshold for this response. Excepting nikethamide, they all produced convulsive discharge in the isolated cortex unrelated to the applied stimulus.2. Local application of glutamate to the cortex produced spreading depression, which was sometimes preceded by spontaneous positive bursting.3. In contrast to the "general depressants" which produce a relatively consistent pattern of effects on the electrical responses of isolated cortex, the "general stimulants", although they all have excitatory effects on isolated cortex, each produced a greatly different type of electrical response in the isolated cortex, suggesting that several different mechanisms of action are responsible for their effects. (+info)
Physiological and drug-induced changes in the glycogen content of mouse brain.
1. The effect of the method of killing on the concentration of glycogen in mouse brain was determined. The cerebral glycogen content of mice killed by immersion in liquid nitrogen did not differe significantly from that of animals decapitated and the heads immediately frozen. A delay before freezing led to the rapid loss of brain glycogen, with a 17% fall at 10 s and an 82% loss after 5 min.2. Hyperglycaemia, induced by the administration of D-glucose, resulted in an 8.3% loss of brain glycogen after 120 min. Insulin hypoglycaemia produced a 10.7% fall in glycogen at 60 min followed by an 11.2% increase at 120 min.3. Exposure to either high (32 degrees C) or low (10 degrees C) ambient temperatures caused a depletion of brain glycogen.4. A circadian rhythm of brain glycogen concentration was found, with a nadir which was coincident with the peak of locomotor activity and body temperature.5. Drugs from several pharmacological classes were studied for their in vivo effect on the concentration of glycogen in mouse brain.6. Brain glycogen was increased by all the depressant drugs tested, and by some drugs which had little effect on behaviour (diphenhydramine, phenytoin and propranolol), or which caused excitation (caffeine and nialamide).7. Glycogen was depleted only by amphetamine-like compounds or by bemegride-induced convulsions.8. The results are discussed with particular reference to the possible relation between catecholamines and glycogen metabolism in the brain. (+info)
Postsynaptic effects of some central stimulants at the neuromuscular junction.
1 Miniature endplate currents (m.e.p.cs) were recorded with extracellular electrodes from sartorius muscles of toads. 2 Central excitant analogues of amylobarbitone (3M2B) and halothane (DBE) decreased the amplitude and time constant of decay of m.e.p.cs and hence reduced the amplitude of miniature endplate potentials. The decay remained exponential with single time constant. 3 A central excitant analogue of ether (indoklon) reduced the amplitude of m.e.p.cs and made their decay biphasic. The decay could be fitted by the sum of two exponentials. 4 Bemegride, a central excitant, prolonged m.e.p.cs. Their decay remained exponential with single time constant. The effect was not due to inhibition of acetylcholinesterase. 5 All of the drugs tested, including amylobarbitone, reduced the temperature-sensitivity of the decay of m.e.p.cs. 6 The biphasic decay of m.e.p.cs caused by indoklon could not be explained simply by supposing that the drug blocked open endplate channels unless it was assumed that the normal rate of channel closing also increased and became much less temperature-sensitive than normal. (+info)
Studies on the muscle relaxation effects of ethyl loflazepate (CM6912) and evaluation as an anti-anxiety drug.
A new anti-anxiety drug, CM6912 (ethyl loflazepate, ethyl 7-chloro-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepine-3- carboxylate), was investigated for its effects on the alpha- and gamma-motor systems and on the cooperative muscular motions and for its interactions with other CNS drugs. The results obtained are as follows: Muscular discharges (EMG) induced by decerebrate rigidity were unaffected by 10 mg/kg (p.o.) of CM6912, but the amplitudes of the EMG were reduced by 50% for 3 hr by 30 mg/kg of CM6912 at 30 min after administration. Diazepam (10 mg/kg) also decreased the amplitudes of the EMG even at 5 min after administration, indicating that diazepam had a stronger than CM6912. Both monosynaptic spinal reflex (MSR) and polysynaptic spinal reflex (PSR) were unaffected by CM6912 (100 mg/kg). Dorsal root reflex potential was slightly enhanced by CM6912 (100 mg/kg), but not at a dose of 30 mg/kg. Diazepam (10 mg/kg) did not decrease MSR, but slightly reduced PSR. Dorsal root reflex potential was almost doubled by diazepam. The frequency of spontaneous discharges of Gla spindle afferent fiber of the extensor muscle of the hindlimb of anesthetized cats was unchanged by 10 mg/kg CM6912, but was suppressed by diazepam at the same dose while at a dose of 30 mg/kg, it was reduced mildly by CM6912, and markedly by diazepam. ED50 values for the antagonistic action on bemegride-induced convulsions were 0.30 mg/kg for CM6912 and 0.49 mg/kg for diazepam at 1 hr after administration, and they were 0.30 mg/kg and 0.67 mg/kg for CM6912 and diazepam, respectively, at 4 hr. The potentiating action of CM6912 on chlorprothixene-induced anesthesia was far weaker than that of diazepam. The suppressive potency of CM6912 on the adaptability to the rotarod was about half that of diazepam, and the muscle relaxant action of CM6912, examined by the inclined board test and the hanging test, was found to be similar to that of diazepam. These results suggest that CM6912 is less potent than diazepam in reducing muscular tone and in inducing sleep, while it has a stronger and longer-lasting anti-anxietic activity than diazepam. (+info)