Abstract
The effects of imipramine, desipramine, promazine and monodesmethyl promazine on the EEG of the isolated perfused rat brain were studied. The brain preparation was perfused for 30 min with simulated blood, containing of the drugs in a concentration of 10−5 M. Control experiments were performed without a drug added to the simplified blood. The EEG was recorded at various times on a magnetic tape and was evaluated visually and quantitatively (amplitude and interval histography). The EEG effects of imipramine and promazine as well as the effects of these drugs with their monodesmethyl metabolites were compared. The drugs produced clear EEG changes compared with the control EEG. An increase of the amplitude and a slowing of the frequency were found for all drugs. Only the changes produced by desipramine were not statistically significant. Furthermore, imipramine and promazine provoked grouped spikes, whereas monodesmethyl promazine caused grouped sharp waves; such characteristic patterns could not be observed after desipramine. The pronounced similarity of the EEG effects produced by imipramine and promazine as well as the clear difference between the imipramine and desipramine effects were pointed out as the most striking results. It was suggested that imipramine becomes a typical antidepressant in the whole organism after demethylation.
Similar content being viewed by others
References
Ahthee, L., Paasonen, M. K.: Potentiation of 5-hydroxytryptamine release from platelets by desmethylation of chlorpromazine and related agents. Acta pharmac. tox. 26, 213–221 (1968)
Andjus, R., Suhara, K., Sloviter, H. A.: An isolated, perfused rat brain preparation, its spontaneous and stimulated activity. J. appl. Physiol. 22, 1033–1039 (1967)
Bente, D., Hippius, H., Pöldinger, W., Stach, K.: Chemische Konstitution und klinische Wirkung von antidepressiven Pharmaka. Arzneimittel-Forsch. 14, 487–490 (1964)
Bickel, M. H.: Untersuchungen zur Biochemie und Pharmakologie der Thymoleptika. Fortschr. Arzneimittelforsch. 11, 121–225 (1968)
Bickel, M. H., Fluckiger, M., Baggiolini, M.: Vergleichende Demethylierung von tricyclischen Psychopharmaka durch Rattenleber-Mikrosomen. Naunyn-Schmiedebergs Arch. Pharmak. exp. Path. 256, 360–366 (1967)
Bickel, M. H., Sulser, F., Brodie, B. B.: Conversion of tranquilizers to antidepressants by removal of one N-methyl group. Life Sci. 4, 247–253 (1963)
Cazzullo, C. L., de Martis, D., Terranova, R.: The effects of iminobenzyl-chloride imipramine (tofranil) and allied compounds in mental patients. Its mode of action in the central nervous system. In: Depression. Davis, H. E. B., ed., pp. 288–305. Cambridge: University Press 1964.
Fink, M.: Quantitative electroencephalography and human psychopharmacology. I. Frequency spectra and drug action. Med. exp. (Basel) 5, 364–369 (1961)
Fink, M.: Electroencephalography in human psychopharmacology. Electroenceph. clin. Neurophysiol. Suppl. 23, 68 (1964)
Fleck, W., Krieglstein, J., Urban, W.: Zwei Apparaturen zur Perfusion des isolierten Rattenhirns. Arzneimittel-Forsch. 22, 1225–1230 (1972)
Forrest, I. S., Green, D. E., Udale, B. P.: In vivo metabolism of chlorpromazine. Proc. W. Pharmacol. Soc. 7, 35–38 (1964)
Glasser, H., Krieglstein, J.: Die Eiwei\bindung einiger Psychopharmaka mit tricyclischem Ringsystem in AbhÄngigkeit von ihrer chemischen Konstitution. Naunyn-Schmiedebergs Arch. Pharmak. 265, 321–334 (1970)
Grüner, J., Krieglstein, J., Rieger, H.: Comparison of the effects of chloral hydrate and trichloroethanol on the EEG of the isolated perfused rat brain. Naunyn-Schmiedeberg's Arch. Pharmacol. 277, 333–348 (1973)
Hackenberg, H., Krieglstein, J.: Comparative study on the inhibition of Na+, K+-activated ATPase activity by chlorpromazine, promazine, imipramine, and their monodesmethyl metabolites. Naunyn-Schmiedeberg's Arch. Pharmacol. 274, 63–73 (1972)
Hammer, W., Martens, S., Sjöqvist, F.: A comparative study of the metabolism of desmethylimipramine, nortriptyline, and oxyphenylbutazone in man. Clin. Pharmacol. Ther. 10, 45–49 (1969)
Itil, T. M.: Elektronezephalographische Befunde zur Klassifikation neuro- und thymoleptischer Medikamente. Med. exp. (Basel) 5, 347–363 (1961)
Itil, T. M.: Quantitative pharmacoelectroencephalography: a new approach to the discovery of a new psychotropic drug. CINP meeting in Copenhagen, August 12 (1972)
Itil, T. M., Saletu, B.: Neurophysiologische Untersuchungsmethoden in der Psychopharmakologie. Nervenarzt 44, 65–74 (1973)
JÄhnchen, E., Krieglstein, J.: Die Aufnahme von Promazin, Chlorpromazin und deren Desmethylmetaboliten in das isoliert perfundierte Rattenhirn. Naunyn-Sehmiedebergs Arch. Pharmak. 268, 300–309 (1971)
Krieglstein, G., Krieglstein, J., Stock, R.: Suitability of the isolated perfused rat brain for studying effects on cerebral metabolism. Naunyn-Schmiedeberg's Arch. Pharmacol. 275, 124–134 (1972a)
Krieglstein, G., Krieglstein, J., Urban, W.: Long survival time of an isolated perfused rat brain. J. Neurochem. 19, 885–886 (1972b)
Krieglstein, J., Meiler, W., Staab, J.: Hydrophobic and ionic interactions of phenothiazine derivatives with bovine serum albumin. Biochem. Pharmacol. 21, 985–997 (1972c)
Krieglstein, J., Stock, R.: Comparative study of the effects of chloral hydrate and trichloroethanol on cerebral metabolism. Naunyn-Schmiedeberg's Arch. Pharmacol. 277, 323–332 (1973)
Krieglstein, J., Stock, R.: The isolated perfused rat brain as a model for studying drugs acting on the CNS. Psychopharmacologia (Berl.) 35, 169–177 (1974).
Krieglstein, J., Stock, R., Rieger, H.: Influence of therapeutic and toxic doses of neuroleptics and antidepressants on energy metabolism of the isolated perfused rat brain. Naunyn-Schmiedeberg's Arch. Pharmacol. 279, 243–254 (1973)
Lyberi, G., Last, S.: The use of chlorpromazine as an activating agent. Electroenceph. clin. Neurophysiol. 8, 711–712 (1956)
Maxwell, R. A., Keenan, P. D., Chaplin, E., Roth, B., Eckhardt, S. B.: Molecular features affecting the potency of tricyclic antidepressants and structurally related compounds as inhibitors of the uptake of tritiated norepinephrine of rabbit aortic strips. J. Pharmacol. exp. Ther. 166, 320–329 (1969)
Plas, R., Naquet, R.: Contribution á l'étude neurophysiologique de l'imipramine. C. R. Soc. Biol. (Paris) 155, 840–843 (1961)
Rieger, H., Krieglstein, J.: Effects of psycho-active tricyclic drugs on the EEG of the isolated perfused rat brain. Electroenceph. clin. Neurophysiol. 34, 730 (1973)
Roubicek, J., Matejcek, M., Montague, S.: EEG changes after psychoactive drugs (spectral analytic study). Electroenceph. clin. Neurophysiol. 34, 719 (1973)
Sachs, L.: Statistische Auswertungsmethoden, 2. Aufl. Berlin: Springer 1969
Saltzberg, B., Burch, N. R.: A new approach to signal analysis in electroencephalography. IRE Trans. med. Electron. 8, 24–30 (1957)
Saunders, M. G.: Amplitude probability density studies on alpha and alpha-like patterns. Electroenceph. clin. Neurophysiol. 15, 761–767 (1963)
Schneider, J., Thomalske, G., Perrin, J., Siffermann, A.: Die Modifikation des EEG unter der Behandlung mit Psychopharmaka. Nervenarzt 34, 521–530 (1963)
Stach, K., Pöldinger, W.: Strukturelle Betrachtungen der Psychopharmaka: Versuch einer Korrelation von chemischer Konstitution und klinischer Wirkung. Fortschr. Arzneimittelforsch. 9, 130–190 (1966)
Steiner, W. G., Himwich, H. E.: Effects of antidepressant drugs on limbic structures of rabbits. J. nerv. ment. Dis. 137, 277–284 (1963)
Stewart, L. F.: Chlorpromazine: use to activate EEG seizure patterns. Electroenceph. clin. Neurophysiol. 9, 427–440 (1957)
Wennberg, A., Zetterberg, L. H.: Application of a computer-based model for EEG analysis. Electroenceph. clin. Neurophysiol. 31, 457–468 (1971)
Author information
Authors and Affiliations
Additional information
This work was supported by a grant from Deutsche Forschungsgemeinschaft. We thank Miss. H. Quallich for epert technical assistance.
Rights and permissions
About this article
Cite this article
Rieger, H., Krieglstein, J. Quantitative analysis of the EEG effects produced by imipramine, desipramine, promazine, and monodesmethyl promazine in the isolated perfused rat brain. Psychopharmacologia 39, 163–179 (1974). https://doi.org/10.1007/BF00440846
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00440846