Abstract
In rats acute treatment with 5-HT uptake inhibitors antagonize p-chloro-amphetamine (PCA)-induced hypermotility and 5-HT depletion from brain. To compare the acute and chronic effect on neuronal 5-HT uptake these two effects of PCA were studied after 4 weeks feeding with diets containing the three 5-HT uptake inhibitors femoxetine, paroxetine, and chlorimipramine. Prolonged treatment with 5-HT uptake inhibitors reduce blood 5-HT due to blocked 5-HT uptake into platelets. Blood 5-HT and plasma concentrations of the 5-HT uptake inhibitors were determined.
Femoxetine and paroxetine antagonized both effects of PCA and depleted blood 5-HT at plasma concentrations equivalent to those of patients treated with these substances. The results strongly indicate preservation of inhibited 5-HT uptake into neurons and platelets during prolonged treatment of rats with femoxetine and paroxetine.
The plasma concentrations of chlorimipramine at the highest dose were lower than those of chlorimipramine treated patients, but the concentrations of desmethylchlorimipramine (DCIP) were higher. Inhibition of PCA-induced hypermotility and partial blood 5-HT depletion was obtained at these relatively low plasma levels of the substance itself, but the effect of PCA on brain 5-HT was not changed. In rats, it appears difficult under chronic conditions to keep the plasma concentrations of chlorimipramine high enough to inhibit neuronal 5-HT uptake without simultaneous high toxic concentrations of DCIP which is a weak 5-HT uptake inhibitor. The inhibition of PCA-hypermotility by chlorimipramine is probably caused by the dopamine receptor blockade of this substance.
Similar content being viewed by others
References
Bechgaard, E., Lund, J.: Determination of (+)-(3R), (4S)-3-[(4-methoxyphenoxy)methyl]-1-methyl-4-phenylpiperidine hydrochloride (FG 4963) in biological fluids using competition for adsorption to glass. J. Chromatogr. 133, 147–152 (1977)
Buus Lassen, J.: The effect of p-chloroamphetamine on motility in rats after inhibition of monoamine synthesis, storage, uptake and receptor interaction. Psychopharmacologia 34, 243–254 (1974)
Buus Lassen, J.: Potentiation of nialamide-induced hypermobility and depletion of blood 5-HT in mice by the new selective 5-HT inhibitor paroxetine. Abstracts, 11th CINP Congress, Vienna 1978
Buus Lassen, J., Lund, J., Bechgaard, E., Søndergaard, I.: Inhibition of 5-HT uptake into neurons and platelets in mice treated chronically with chlorimipramine and femoxetine. Psychopharmacology 64, 149–153 (1979)
Buus Lassen, J., Petersen, E., Kjellberg, B., Olsson, S. O.: Comparative studies of a new 5-HT-uptake inhibitor and some tricyclic thymoleptics. Eur. J. Pharmacol. 32, 108–115 (1975a)
Buus Lassen, J., Squires, R. F.: Potentiation of nialamide-induced hypermotility in mice by lithium and the 5-HT uptake inhibitors chlorimipramine and FG 4963. Neuropharmacology 15, 665–668 (1976)
Buus Lassen, J., Squires, R. F., Christensen, J. A., Molander, L.: Neurochemical and pharmacological studies on a new 5-HT-uptake inhibitor, FG 4963, with potential antidepressant properties. Psychopharmacologia 42, 21–26 (1975b)
Delini-Stula, A., Vassout, A.: Modulation of dopamine-mediated behavioural responses by antidepressants: Effects of single and repeated treatment. Eur. J. Pharmacol. 58, 443–451 (1979)
Della Corte, L., broadhurst, A. D., Sgaragli, G. P., Filippini, S., Heeley, A. F., James, H. D., Faravelli, C., Pazzagli, A.: Clinical response and tricyclic plasma levels during treatment with clomipramine. Br. J. Psychiatry 134, 390–400 (1979)
Eggum, B. O., Møllegaard Hansen, K. E.: Nord. Veterinærmed. 19, 592–597 (1976) (Norwegian)
Fuller, R. W., Perry, K. W., Molloy, B. B.: Effect of 3-(p-trifluoromethylphenoxy)-n-methyl-3-phenylpropylamine on the depletion of brain serotonin by 4-chloroamphetamine. J. Pharmacol. Exp. Ther. 193, 796–803 (1975)
Heltberg, J., Larsen, J. K., Kirk, L., Bjørum, N.: Nord. Psykiatr. Tidsskr. 29, 485–486 (1975) (Norwegian)
Hyttel, J.: Effect of a specific 5-HT uptake inhibitor, citalopram (lu 10-171), on 3H-5-HT uptake in rat brain synaptosomes in vitro. Psychopharmacology 60, 13–18 (1978)
Jones, R. B., Luscombe, D. K.: Plasma levels of chlomipramine and its N-desmethylmetabolite following oral administration of clomipramine in man. Br J. Pharmacol. 57, 430 (1976)
Jonsson, J., Lewander, T.: A method for the simultaneous determination of 5-hydroxy-3-indole-acetic acid (5-HIAA) and 5-hydroxy-tryptamine (5-HT) in brain tissue and cerebrospinal fluid. Acta Physiol. Scand. 78, 43–51 (1970)
Keller, H. H., Burkard, W. P., Da Prade, M.: Dopamine receptor blockade in rat brain after acute and subchronic treatment with tricyclic antidepressant. Abstracts, Intern. Symposium, Long-term effects of neuroleptics, Monte-Carlo, March 19–22 (1979)
Nagy, A.: Blood and brain concentrations of imipramine, clomipramine and their monomethylated metabolites after oral and intramuscular administration in rats. J. Pharm. Pharmacol. 29, 104–107 (1977)
Nagy, A., Johansson, R.: The demethylation of imipramine and clomipramine as apparent from their plasma kinetics. Psychopharmacology 54, 125–131 (1977)
Nagy, A., Treiber, L.: Quantitative determination of imipramine and desipramine in human blood plasma by direct densitometry of thin-layer chromatograms. J. Pharm. Pharmacol. 25, 599–603 (1973)
Petersen, E. N., Bechgaard, E., Sortwell, R. J., Wetterberg, L.: Potent depletion of 5-HT from monkey whole blood by a new 5-HT uptake inhibitor, paroxetine (FG 7051). Eur. J. Pharmacol. 52, 115–119 (1978)
Ross, S. B., Jansa, S., Wetterberg, L., Fyrö, B., Hellner, B.: Decreased blood level of 5-hydroxytryptamine by inhibitors of the membranal 5-hydroxytryptamine uptake. Life Sci 19, 205–210 (1976)
Squires, R.: Antagonism of p-chloroamphetamine (PCA) induced depletion of 5-HT from rat brain by some thymoleptics and other psychotropic drugs. Acta Pharmacol. Toxicol. [Suppl.] (Kbh.) 31, 35 (1972)
Squires, R. F.: Evidence that 5-methoxy-N,N-dimethyl tryptamine is a specific substrate for MAO-A in the rat: implications for the indoleamine dependent behavioural syndrome. J. Neurochem. 24, 47–50 (1975)
Sugrue, M. F., Goodlet, I., Mireyless, S. E.: On the selective inhibition of serotonin uptake in vivo by ORG 6582. Eur. J. Pharmacol 40, 121–130 (1976)
Svensson, T. H., Thieme, G.: An investigation of a new instrument to measure motor activity of small animals. Psychopharmacologia 14, 157–163 (1969)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Lassen, J.B., Lund, J. & Søndergaard, I. Central and peripheral 5-HT uptake in rats treated chronically with femoxetine, paroxetine, and chlorimipramine. Psychopharmacology 68, 229–233 (1980). https://doi.org/10.1007/BF00428108
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00428108