Summary
Desipramine (DMI), like many antidepressant drugs, inhibits the production of paradoxical sleep (PS). In the present experiment, we have investigated the relationships between brain level of DMI and PS inhibition. Groups of rats had their sleep monitored after 1, 2 or 4 mg/kg of DMI. In other animals, the brain concentration of DMI was assayed at various times after the same treatments. The results indicate that a critical threshold concentration of 300 ng/g DMI in the brain is necessary for Complete PS inhibition. This stage reappears only when the DMI level falls below this value, and its production resumes at a normal rate, provided the DMI level reached initially was not largely in excess of the threshold concentration.
The results are discussed with regard to the present knowledge of specific binding of tricyclics in brain and their“ex vivo” action on norepinephrine uptake resulting in enhancement of collateral inhibition of noradrenergic cells.
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References
Baumann, P., Koeb, L., Tinguely, D., Rivier, L.: A method for the analysis of free, total plasma and saliva amitriptyline and nortriptyline by dialysis and GC/MS. Europ. J. Mass Spectrometry2, 19–26 (1982).
Bickel, M. H., Weder, H. J.: The total fate of a drug: kinetics of distribution, excretion, and formation of 14 metabolites in rats treated with imipramine. Arch. int. Pharmacodyn.173, 433–463 (1968).
Biegon, A., Samuel, D.: Thein vivo distribution of an antidepressant drug (DMI) in male and female rats. Psychopharmacology65, 259–263 (1979 a).
Biegon, A., Samuel, D.: Binding of a labeled antidepressant to rat brain tissue. Biochem. Pharmac.28, 3361–3366 (1979 b).
Brezinova, V., Adam, K., Chapman, K., Oswald, I., Thomson, J.: Viloxazine, sleep, and subjective feelings. Psychopharmacology55, 121–128 (1977).
Briley, M. S., Fillion, G., Beaudoin, D., Fillion, M.-P., Langer, S. Z.:3H-imipramine binding in neuronal and glial fractions of horse striatum. Eur. J. Pharmacol.64, 191–194 (1980).
Dunleavy, D. L. F., Brezinova, V., Oswald, I., MacLean, A. W., Tinker, M.: Changes during weeks in effects of tricyclic drugs on the human sleeping brain. Br. J. Psychiat.120, 663–672 (1972).
Gaillard, J.-M.: Temporal organization of human sleep: general trends of sleep stages and their ultradian cyclic components. Encéphale5, 71–93 (1979).
Gaillard, J.-M., Kafi, S. Justafré J.-C.: On the role of brainα 1-adrenergic systems in the production of paradoxical sleep. Encéphale8, 413–434 (1982).
Glowinski, J., Axelrod, J.: Inhibition of uptake of tritiated noradrenaline in the intact rat brain by imipramine and structurally related compounds. Nature, Lond.204, 1318–1319 (1964).
Hartmann, E., Cravens, J.: The effects of long-term administration of psychotropic drugs on human sleep. III. The effects of amitriptyline. Psychopharmacologia33, 185–202 (1973).
Hill, S. Y., Reyes, R. B., Kupfer, D. J.: Imipramine and REM sleep: cholinergic mediation in animals. Psychopharmacology69, 5–9 (1980).
Hrdina, P. D., Dubas, T. C.: Brain distribution and kinetics of desipramine in the rat. Can. J. Physiol. Pharmacol.59, 163–167 (1981).
Jori, A., Bernardi, D., Muscettola, G., Garattini, S.: Brain levels of imipramine and desipramine after combined treatment with these drugs in rats. Eur. J. Pharmacol.15, 85–90 (1971).
Justafré, J.-C., Gaillard, J.-M.: Diminution du sommeil paradoxal chez le rat sous antidépresseur tricyclique: rôle de l'inhibition collatérale. Rev. E.E.G. Neurophysiol.11, 228–235 (1981).
King, C. D.: The pharmacology of rapid eye movements sleep. Adv. Pharmacol. Chemother.9, 1–91 (1971).
Maître, L., Moser, P., Baumann, P. A., Waldmeier, P. C.: Amine uptake inhibitors criteria of selectivity. In: Biogenic amines and affective disorders (Svenson, T. H., Carlsson, A., eds.) (Proceedings of a symposium held in London January 18–21, 1979), pp. 97–110. (Acta Psychiat. Scand., Suppl. 280.) Copenhagen: Munksgaard. 1980.
Nagy, A.: Blood and brain concentrations of imipramine, clomipramine and their monomethylated metabolites after oral and intramuscular administration in rats. J. Pharm. Pharmac.29, 104–107 (1977).
Passouant, P., Cadilhac, J., Ribstein, M.: La privation de sommeil avec mouvements oculaires par les antidépresseurs. Rev. neurol.127, 173–192 (1972).
Raisman, R., Briley, M. S., Langer, S. Z.: Specific tricyclic antidepressant binding sites in rat brain. Nature281, 148–150 (1979).
Raisman, R., Briley, M. S., Langer, S. Z.: Specific tricyclic antidepressant binding sites in rat brain characterized by high-affinity3H-imipramine binding. Eur. J. Pharmacol.61, 373–380 (1980).
Schlicht, H.-J., Gelbke, H.-P.: Gas Chromatographic determination of dibenzepine and its basic metabolites in biological material. J. Chromatogr.166, 599–603 (1978).
Toyoda, J.: The effects of chlorpromazine and imipramine on the human nocturnal sleep electroencephalogram. Folia Psychiat. Neurol. Jap.18, 198–221 (1964).
Van Wijk, M., Korf, J.: A quantitative study in the rat on the relationship between imipramine levels in brain and serum. Psychopharmacology76, 48–51 (1982).
Weiner, D., Garteiz, D., Cawein, M., Dusebout, T., Wright, G., Okerholm, R.: Pharmacokinetic linearity of desipramine hydrochloride. J. Pharmac. Sci.70, 1079–1080 (1981).
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Baumann, P., Gaillard, J.M., Perey, M. et al. Relationships between brain concentrations of desipramine and paradoxical sleep inhibition in the rat. J. Neural Transmission 56, 105–116 (1983). https://doi.org/10.1007/BF01243270
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DOI: https://doi.org/10.1007/BF01243270