Effects of two benzodiazepines, phenobarbitone, and baclofen on synaptic transmission in the cat cuneate nucleus
- 46 Downloads
The effects of diazepam, flunitrazepam, phenobarbitone and baclofen on excitatory as well as on pre- and postsynaptic inhibitory processes in the cuneate nucleus were studied in decerebrate cats.
Afferent presynaptic inhibition in the cuneate nucleus, evoked by volleys in the median nerve, and assessed by the size of the positive cuneate surface potential (P wave), the dorsal column reflex (DCR), and the increased excitability of primary afferent terminals of the ulnar nerve, was markedly enhanced by diazepam (0.1–3.0 mg/kg i.v.) and flunitrazepam (0.01–0.3 mg/kg i.v.), slightly enhanced by lower doses of phenobarbitone (3–20 mg/kg i.v.), but depressed by baclofen (1–10 mg/kg i.v.). Diazepam, flunitrazepam and phenobarbitone also increased postsynaptic inhibition in the cuneate nucleus which was measured by the decrease after conditioning volleys in the median nerve of the short-latency lemniscal response to cuneate stimulation. The GABA receptor blocking agent, picrotoxin, antagonized the effects of diazepam on pre- and postsynaptic inhibition in a surmountable way. After thiosemicarbazide (TSC), an inhibitor of GABA synthesis, both pre-and postsynaptic inhibition were greatly reduced and the augmenting effect of diazepam on both types of inhibition was nearly abolished. Aminooxyacetic acid (AOAA), an inhibitor of GABA degradation, slightly enhanced pre- and postsynaptic inhibition; the effects of diazepam were unaffected by AOAA. Diazepam, flunitrazepam and phenobarbitone did not alter the resting excitability of primary afferent endings or of cuneo-thalamic relay (CTR) cells in the cuneate nucleus.
After higher doses (30 mg/kg i.v.) of phenobarbitone pre- and postsynaptic inhibition, which were enhanced by 10 mg/kg of this drug, tended to return to pre-drug values or below. Phenobarbitone, in contrast to benzodiazepines, also depressed in a dose-dependent way the N wave, which is an index of the orthodromic excitation of the CTR cells. Baclofen strongly depressed the cuneate N wave, decreased the excitability of CTR cells, reduced pre- and postsynaptic inhibition, but had no effect on the resting excitability of primary afferent endings.
Our findings suggest the following modes of action of the above mentioned drugs: 1. benzodiazepines enhance selectively the GABA-mediated pre- and postsynaptic inhibition in the cuneate nucleus; 2. phenobarbitone slightly enhances pre- and postsynaptic inhibition only in a narrow dose range, and in addition reduces the excitatory processes in the cuneate nucleus; 3. baclofen seems to depress the excitation of cuneate relay cells and interneurones postsynaptically; the depression of relay cells is probably non-specific.
Key wordsBenzodiazepines Phenobarbitone Baclofen GABA Cuneate Nucleus
Unable to display preview. Download preview PDF.
- Andersen, P., Eccles, J. C., Oshima, T., Schmidt, R. F.: Mechanisms of synaptic transmission in the cuneate nucleus. J. Neurophysiol. 27, 1096–1116 (1964)Google Scholar
- Banna, N. R., Jabbur, S. J.: Pharmacological studies on inhibition in the cuneate nucleus of the cat. Int. J. Neuropharmacol. 8, 299–307 (1969)Google Scholar
- Barker, J. L.: CNC depressants: effects on postsynaptic pharmacology. Brain Res. 92, 35–55 (1975)Google Scholar
- Curtis, D. R., Game, C. J. A., Johnston, G. A. R., McCulloch, R. M.: Central effects of β-(p-chlorophenyl)-γ-amino butyric acid. Brain Res. 70, 493–499 (1974)Google Scholar
- Curtis, D. R., Johnston, G. A. R.: Amino acid transmitters in the mammalian central nervous system. Rev. Physiol., Biochem. exp. Pharmacol. 69, 97–188 (1974)Google Scholar
- Davidoff, R. A., Sears, E. S.: The effects of lioresal on synaptic activity in the isolated spinal cord. Neurology (Minneap.) 24, 957–963 (1974)Google Scholar
- Eccles, J. C., Schmidt, R. F., Willis, W. D.: Pharmacological studies on presynaptic inhibition. J. Physiol. (Lond.) 168, 500–530 (1963)Google Scholar
- Fehr, H. U., Bein, H. J.: Sites of action of a new muscle relaxant (baclofen, Lioresal®, Ciba 34647-Ba). J. int. med. Res. 2, 36–47 (1974)Google Scholar
- Galindo, A., Krnjević, K., Schwartz, S.: Patterns of firing in cuneate neurones and some effects of flaxedil. Exp. Brain Res. 5, 87–101 (1968)Google Scholar
- Haefely, W., Kulcsár, A., Möhler, H., Pieri, L., Polc, P., Schaffner, R.: Possible involvement of GABA in the central actions of benzodiazepines. Advanc. Biochem. Psychopharmacol. 10, 131–152 (1975)Google Scholar
- Keller, H. H., Schaffner, R., Haefely, W.: Interaction of benzodiazepines with neuroleptics at central dopamine neurons. Naunyn-Schmiedeberg's Arch. Pharmacol 294, 1–7 (1976)Google Scholar
- Kelly, J. S., Renaud, L. P.: On the pharmacology of ascending, descending and recurrent postsynaptic inhibition of the cuneothalamic relay cells in the cat. Brit. J. Pharmacol. 48, 396–408 (1973)Google Scholar
- Levy, R. A.: GABA: a direct depolarizing action at the mammalian primary afferent terminal. Brain Res 76, 155–160 (1974)Google Scholar
- Nicoll, R. A.: Pentobarbital: action on frog motoneurones. Brain Res. 96, 119–123 (1975)Google Scholar
- Nicoll, R. A., Eccles, J. C., Oshima, T., Rubia, F.: Prolongation of hippocampal inhibitory potentials by barbiturates. Nature (Lond.) 258, 625–627 (1975)Google Scholar
- Nistri, A.: Further investigations into the effects of baclofen (Lioresal) on the isolated spinal cord. Experientia (Basel) 31, 1066–1068 (1975)Google Scholar
- Norton, A. C.: The dorsal column system of the spinal cord. Los Angeles: Brain Information Service/Brain Research Institute, University of California, 1973Google Scholar
- Pierau, F. K., Zimmermann, P.: Action of a GABA-derivative on postsynaptic potentials and membrane properties of cat's spinal motoneurones. Brain Res 54, 376–380 (1973)Google Scholar
- Polc, P., Haefely, W.: The effect of diazepam on inhibition in the cuneate nucleus of decerebrate cats. Experientia (Basel) 31, 731 (1975)Google Scholar
- Polc, P., Möhler, H., Haefely, W.: The effect of diazepam on spinal cord activities: possible sites and mechanisms of action. Naunyn-Schmiedeberg's Arch. Pharmacol. 284, 319–337 (1974)Google Scholar
- Ransom, B. R., Barker, J. L.: Pentobarbital modulates transmitter effects on mouse spinal neurones grown in tissue culture. Nature (Lond.) 254, 703–705 (1975)Google Scholar
- Saito, K., Konishi, S., Otsuka, M.: Antagonism between Lioresal and substance P in rat spinal cord. Brain Res. 97, 177–180 (1975)Google Scholar
- Schaffner, R., Haefely, W.: The effects of diazepam and bicuculline on the strio-nigral evoked potential. Experientia (Basel) 31, 732 (1975)Google Scholar
- Schlosser, W.: Action of diazepam on the spinal cord. Arch. int. Pharmacodyn. 194, 93–102 (1971)Google Scholar
- Schmidt, R. F., Vogel, E., Zimmermann, M.: Die Wirkung von Diazepam auf die präsynaptische Hemmung und andere Rückenmarksreflexe. Naunyn-Schmiedeberg's Arch. Pharmak. exp. Path. 258, 69–82 (1967)Google Scholar
- Thomson, T. D., Turkanis, S. A.: Barbiturate-induced transmitter release at a frog neuromuscular junction. Brit. J. Pharmacol. 48, 48–58 (1973)Google Scholar
- Walberg, F.: Axoaxonic contacts in the cuneate nucleus, probable basis for presynaptic depolarization. Exp. Neurol. 13, 218–231 (1965)Google Scholar
- Wall, P. D.: Excitability changes in afferent fibre terminations and their relation to slow potentials. J. Physiol. (Lond.) 142, 1–21 (1958)Google Scholar
- Zakusov, V. V., Ostrovskaya, R. V., Markovitch, V. V., Molodavkin, G. M., Bulayev, V. M.: Electrophysiological evidence for an inhibitory action of diazepam upon cat brain cortex. Arch. int. Pharmacodyn. 214, 188–205 (1975)Google Scholar