Abstract
Although antidepressant drugs have been successfully used in the treatment of depression for more than two decades, the mechanism(s) by which these drugs produce their therapeutic effect is not understood. Tricyclic antidepressants have been shown to inhibit the neuronal uptake of norepinephrine (noradrenaline; NA) and serotonin, (5-hydroxytryptamine; 5-HT) (Glowinski and Axelrod, 1964) and their therapeutic effect has been related to this activity (Schildkraut, 1965). However, the effect of these drugs on the uptake of biogenic amines occurs immediately and does not correlate with the time course of the therapeutic response that usually sets in after only 1–3 wk of treatment. Moreover, there are other antidepressants, such as iprindole and mianserin, that do not block 5-HT and/or NA reuptake, but have been shown to lessen the symptoms of depression. Other drugs, such as cocaine, block the uptake of biogenic amines, but are not clinically effective antidepressants (Post et al., 1974). Some tricyclic antidepressants have also been shown to interact with the in vitro binding of specific radioactive ligands to several classes of neurotransmitter receptors in brain membrane preparations: (α-and γ-adrenergic (U’Prichard et al., 1978), serotonergic (Peroutka and Snyder, 1980), H1-histaminergic (Tran et al., 1981), and muscarinic cholinergic (Snyder and Yamamura, 1977) receptors.
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References
Ahtee L., Briley M., Raisman R., Lebrec D., and Langer S. Z. (1981) Reduced uptake of serotonm but unchanged 3H-Imipramine binding in the platelets from cirrhotic patients. Life Sci 29, 2323–2329.
Anderson G. M., Minderaa R. B., van Bentheem P-P.G., Volkmar F. R, and Cohen D J. (1984) Platelet imipramine binding in autistic subjects. Psychiatry Res. 11, 133–141
Angel I., Goldman M. E., and Paul S. M. (1984) Inhibition of synaptosomal (3H)-serotonin uptake and (3H)-imipramine binding by an Endogenous substance(s) isolated from rat and human blood 14th CINP Congress (Abstracts), June 19-23, 1984, Florence, Italy, p. 283
Arora R. C, Tong C., Jackman H. L, Stoff D., and Meltzer H. Y (1983) Serotonm uptake and imipramine binding in blood platelets and brain of Fawn-hooded and Sprague-Dawley rats Life Sci 33, 437–442.
Asarch K. B., Shih J. C., and Kulcsar A. (1980) Decreased 3H-imipramine binding in depressed males and females. Commun. Psychopharmacol. 4, 425–432.
Banerjee S. P., Kung L. S., Riggi S. J., and Chanda S. K (1977) Development Of β-adrenergic receptor subsensitivity by antidepressants Nature (Lond.) 268, 455–456
Barbaccia M L, Brunello N, Chuang D M, and Costa E. (1983a) On the mode of action of imipramme relationship between serotonergic axon terminal function and down-regulation of β-adrenergic receptors Neuropharmacol. 22, 373–383
Barbaccia M. L., Gandolfi O, Chuang D M., and Costa E. (1983b) Modulation of neuronal serotonin uptake by a putative endogenous ligand of imipramine recognition sites Proc Nutl. Acad Sci USA 80, 5134–5138.
Baron M., Barkai A., Gruen R, Kowalik S., and Quitkin F (1983) 3H-Imipramine platelet binding sites in unipolar depression Biol Psychait 18, 1403–1409.
Berrettiniw H, Nurnberger Jr. J. I, Post R M, and Gershon E S (1982) Platelet 3H-imipramme binding in euthymic bipolar patients. Psychiatry Res. 7, 215–219.
Biegon A. And Samuel D. (1979) Binding of a labeled antidepressant to rat bram tissue. Biochem. Pharmacol 28, 3361–3366.
Biegon A. And Rainbow T C. (1982) Quantitative autoradiography of (3H)-desipramine binding sites in rat brain. Eur J Pharmacol 82, 245–246
Bowling A C. And Delorenzo R. J. (1982) Micromolar affinity benzodiazepine Receptors. Identification and characterization in central nervous system. Science 216, 1247–1250.
Briley M. And Langer S. Z. (1981) Sodium dependency of (3H)-imipramine binding in rat cerebral cortex. Eur J Pharmacol. 72, 377–380
Briley S., Raisman R, and Langer S Z. (1979) Human platelets possess a high-affinity binding site for (3H)-imipramine. Eur J Pharmacol. 58. 347–348
Briley M S, Langer S Z, Raisman R., Sechter D., and Zarifian E. (1980) Tritiated imipramme binding sites are decreased in platelets of untreated Depressed patients. Science 209, 303–305
Briley M. S., Ralsman R., Arbilla S., Casadamont M, and Langer S. S. (1982) Concomitant decrease in (3H)-imipramme binding in cat brain and platelets after chronic treatment with imipramine Eur J. Pharmacol. 81, 309–314.
Brunello N., Chuang D. M., and Costa E. (1982a) Different synaptic location of mianserm and imipramine binding sites. Science 215, 1112–1115.
Brunello N., Chuang D. M., and Costa E. (1982b) Specific binding of (3HH)-mianserin and (3H)-imipramine to structures of rat hippocampus. Eur. J. Pharmacol. 78, 383–384
Cash R., Raisman R., Ploska A., and Agid Y. (1984) 3H-Imipramine binding in brain of Parkinsonian patients. 24th CINP Congress, June 19-23, 1984, Florence, Italy, p. 17
Clements-Jewery S. (1978) The development of cortical β-adrenoceptor subsensitivity in the rat by chronic treatment with trazodone, doxepin, And mianserin. Neuropharmacology 17, 779–781.
Dumbrille-Ross A. And Tang S W. (1981) Absence of high-affinity (3H)-imipramine binding in platelets and cerebral cortex of Fawn-hooded rats. Eur. J. Pharmacol. 72, 137–138.
Dumbrille-Ross A., Tang S. W, and Coscina D. W. (1981) Differential binding of 3H-imipramine and 3H-mianserin in rat cerebral cortex. Life Sci, 29, 2049–2058.
Friedi W., Propping P, and Week B. (1983) 3H-Imipramine binding in Platelets: influence of varying proportions of intact platelets in membrane Preparations on binding. Psychopharmacol 80, 96–99
Glowinski J. And Axelrod J (1964) Inhibition of uptake of tritiated noradrenaline In the intact rat brain by imipramine and structurally related compounds Nature (Lond.) 204, 1318–1319.
Gross G., Gothert M., Ender H. P., and Schumann H-J (1981) 3H-Imipramine binding sites in the rat brain. Selective localization on serotonergic neurons. Naunyn-Schmiedeberg’s Arch. Pharmacol 317, 310–314.
Hall H. And Ogren S-O. (1981) Effects of antidepressant drugs on different Receptors in the brain. Eur. J. Pharmacol 70, 393–407.
Horn A S (1976) The interaction of tricyclic antidepressants with the biogenic amine uptake systems in the central nervous system Postgrad. Med J 52, (Suppl) 25–30.
Hrdina P. D. (1981) Pharmacological characterization of (3H)-desipramine binding in rat. Cerebral cortex. Prog. Neuro-Psychopharmacol. 5, 553–557.
Hrdina P. D. And Dubas T. C. (1981) Brain distribution and kinetics of desipramine in the rat Can. J. Physiol. Pharmacol 59, 163–167.
Hrdina P. D., Elson-Hartman K., Roberts D C. S., and Pappas B. A. (1981) High-affinity (3H)-desipramine binding in rat cerebral cortex decreases after selective lesion of noradrenergic neurons with 6-hydroxydopamine. Eur. J. Pharmacol. 73, 375–376.
Hrdina P. D. (1982) Tricyclic Antidepressants: Differences in High-Affinity Binding of (3H)-Desipramine and (3H)-Imipramine in the Brain, in New Vistas in Depression (Langer S Z., Takahashi R., and Briley M., eds.) Pp. 125–132, Pergamon, London.
Hrdina P. D., Pappas B. A., Bialik R.J., and Ryan C. L. (1982) Regulation of (3H)-imipramine binding sites in rat brain regions: effect of neonatal 5,7-dihydroxytryptamine treatment. Eur. J. Pharmacol. 82, 343–344.
Hrdina P. D. (1983) Antidepressant binding. Implications for the mode of action of antidepressants and the biology of depression. Progr Neuropsychopharmacol Biol. Psychiat. 7, 457–462.
Hrdina P. D. (1984a) 3H-Imipramine binding sites in brain down-regulated by chronic nortriptyline and haloperidol but not mlanserin treatment. Psychiatry Res. 11, 271–278.
Hrdina P. D. (1984b) Differentiation of two components of specific (3H)-imipramine binding in rat brain. Eur. J. Pharmacol. 102, 481–488.
Hrdina P. D., Lapierre Y D., Horn E., et al (1985a) Platelet 3H-imipramine binding A possible predictor of response to antidepressant Treatment. Prog. Neuropsycho-pharmacol. Biol. Psychiat. 9, in press
Hrdina P. D., Pappas B. A., Roberts D. C. S., Bialik R. J, and Ryan C. L (1985b) Relationship between levels and uptake of serotonin and high affinity [3H]imipramine recognition sites in the rat brain. Can. J Physiol. Pharmacol. 63, 1239–1244.
Kamal L. A., Raisman R., Meyer P., and Langer S. Z. (1984) Reduced v max of 3H-serotonin uptake but unchanged 3H-imipramine binding in the platelets of untreated hypertensive subjects. Life Sci 34, 2083–2088.
Kinnier W. J., Chuang D.-M., Gwynn G., and Costa E. (1980) Down-regulation of dihydroalprenolol and impramine binding sites in brain of rats repeatedly treated with imipramine. Eur. J. Pharmacol 67, 289–291.
Kinnier W. J., Chuang D.-M, Gwynn G., and Costa E. (1981) Characteristics And regulation of high-affinity (3H)-imipramine binding to rat hippocampal membranes. Neuropharmacol 20, 411–419.
Koe B. K. (1975) Effects of Antidepressant Drugs on Brain Catecholamines And Serotonin, in Antidepressants (Fielding S and La1 H., eds) pp. 143–180, Futura Publishing, Mount Kisco, NY
Laduron P. M. (1984) Criteria for receptor sites in binding studies. Biochem. Pharmacol 33, 833–839.
Laduron P. M., Robbyns M., and Schotte A. (1982) (3H)-Desipramine and (3H)-imipramine binding are not associated with noradrenaline and serotonin uptake in the brain. Eur. J Pharmacol 78, 491–493.
Langer S. Z. (1980) Presynaptic regulation of the release of catecholamines. Pharmacol Rev. 32, 337–362
Langer S. Z and Raisman R. (1983) Binding of (3H)-imipramine and (3H)-desipramme as brochemical tools for studies in depression. Neuropharmacol 22, 407–413.
Langer S. Z., Moret C., Raisman R., Dubocovich M. L, and Briley M. (1980a) High-affinity (3H)-imipramine binding in rat hypothalamus: Association with uptake of serotonin but not of norepinephrine. Science 210, 1133–1135.
Langer S. Z., Raisman R., and Briley M. S. (1980b) Stereoselective inhibition Of 3H-imipramine binding by antidepressant drugs and their derivatives. Eur. J. Pharmacol. 64, 89–90.
Langer S. Z., Briley M. S., Raisman R., Henry J.-F., and Morselli P. L. (1980c) Specific 3H-imipramine binding in human platelets. Influence of age and sex. Naunyn-Schmiedeberg’s Arch. Pharmacol. 313, 189–194.
Langer S. Z., Javoy-Agid F., Raisman R., Briley M., and Agid Y. (1981a) Distribution of specific high-affinity binding sites for (3H)-imipramie in human brain. J. Neurochem. 37, 267–271.
Langer S. Z., Raisman R., and Briley M. (1981b) High-affinity (3H)-DMI binding is associated with neuronal noradrenaline uptake in the periphery and the central nervous system. Eur. J. Pharmacol. 72, 423–424.
Lee C.-M. And Snyder S. H. (1981) Norepephrme neuronal uptake binding Sites in rat brain membranes labeled with (3H)-desipramine. Proc. Natl. Acad. Sci USA 78, 5250–5254.
Lee C. M., Javitch J. A., and Snyder S. H. (1982) Characterization of (3H)-desipramine binding associated with neuronal norepinephrine uptake sites in rat brain membrenes. J. Neurosci. 2, 1515–1525.
Lee C. M., Javitch J. A., and Snyder S. H. (1983) Recognition sites for norepinephrine uptake: regulation by neurotransmitter. Science 220, 626–629.
Lewis D. A. And McChesney C. (1985) Tritiated imipramine binding distinguishes among subtypes of depression. arch. Gen. Psychiat. 42, 485–488.
Lowry D. H., Rosebrough N. J., Farr A. L., and Randall R. J. (1951) Protein measurement with the Folin phenol reagent. J. Biol. Chem. 192, 265–275.
Mellerup E. T., Plenge P., and Rosenberg R. (1982) 3H-Imipramine binding Sites in platelets from psychiatric patients. Psychiatry Res. 7, 221–227.
Meltzer H. Y., Arora R. C., Robertson A., and Lowy M. (1984) Platelet 3H-imipramine binding and platelet 5-HT uptake in affective disorders And schizophrenia. Clin. Neuropharmacol. 7(suppl. 1) S169.
Mocchetti I., Brunello N., and Racagni G. (1982) Ontogenic study of (3H)-imipramine binding sites and serotonin uptake system: indication Of possible interdependence. Eur. J. Pharmacol. 83, 151–152.
Mogilnicka E., Arbilla S., Depoortere H., and Langer S. Z. (1980) Rapid eye movement sleep deprivation decreases the density of 3H-dihydroalprenolol and 3H-imipramine binding sites in the rat cerebral Cortex. Eur. J. Pharmacol. 65, 289–292.
Palkovits M., Raisman R., Briley M., and Langer S. Z. (1981) Regional distribution of (3H)-imipramine in rat brain. Brain Res. 210, 493–498.
Paul S. M., Rehavi M., Skolnick P., and Goodwin F. K. (1980) Demonstration Of specific high-affinity binding sites for (3H)-imlpramine in human platelets. Life Sci. 26, 953–959.
Paul S. M., Rehavi M., Skolnick P., Ballenger J., and Goodwin F. K. (1981) Depressed patients have decreased binding of tritiated imipramine to platelet serotonin “transporter”. Arch. Gen. Psychiat. 38, 1315–1317.
Peroutka S. J. And Snyder S. H. (1980) Long-term antidepressant treatment Decreases spuopendol-labeled serotonin receptor binding. Science 210, 88–90.
Perry E. K., Marshall E F., Blessed G., Tomlinson B. E., and Perry R. H. (1983) Decreased imipramine binding in the brains of patients with depressive illness. Brit J. Psychrat. 142, 188–192.
Plenge P. And Mellerup E. T. (1982) 3H-Imipramme high-affinity binding sites in rat brain. Effects of imipramine and lithium Psychopharmacol. 77, 94–97.
Post R. M., Kotin J, and Goodwin F. K. (1974) The effect of cocaine on depressed patients. Am J. Psychiat. 131, 511–517
Raisman R., Briley M., and Langer S. Z (1979a) High-affinity 3H-imipramine binding in rat cerebral cortex. Eur. J. Pharmacol 54, 307–308.
Raisman R., Briley M., and Langer S. Z. (1979b) Specific tricyclic antidepressant Binding sites in rat brain. Nature (Lond.) 281, 148–150.
Raisman R., Briley M. S., and Langer S. Z (1980) Specrfic tricyclic antidepressant Binding sites in rat brain characterized by high-affinity 3H-imipramine binding. Eur. J Pharmacol. 61, 373–380
Raisman R., Sechter D., Briley M S., Zarifian E., and Langer S Z. (1981) High-affinity 3H-imipramme binding in platelets from untreated and treated depressed patients compared to healthy volunteers. Psychopharmacol 75, 368–371
Raisman R., Sette M., Pimoule C., Briley M., and Langer S. Z. (1982) High-affinity (3H)-desipramme binding in the peripheral and central nervous system a specific site associated with the neuronal uptake of noradrenaline. Eur. J. Pharmacol 78, 345–351
Rehavi M., Paul S. M., Skolnick P., and Goodwin F. K. (1980) Demonstration of specific high-affinity binding sites for (3H)-imipramine in human brain. Life Sci. 26, 2273–2279.
Rehavi M., Skolnick P., Hulihan B, and Paul S. M (1981) “High affinity” binding of (3H)-desipramine to rat cerebral cortex: relationship to tricyclic antidepresssant-induced inhibition of norepinephrine uptake. Eur. J. Pharmacol. 70, 597–599
Rehavi M., Skolnick P., Brownstein M. J., and Paul S. M. (1982) Highaffinity Binding of (3H)-desrpramine to rat brain a presynaptic marker For noradrenergic uptake sites. J Neurochem. 38, 889–895.
Rehavi M., Skolnick P., and Paul S M. (1983) Subcellular distribution of High-affinity (3H)-imipramine binding and (3H)-serotonin uptake in rat brain Eur. J Pharmacol 87, 335–339
Rehavi M., Ventura I., and Sarne Y (1984) Endogenous regulator of imipramine recognition site. 14th CINP Congress (Abstracts) June 19-23, 1984, Florence, Italy, p. 282
Reith M. E. A., Sershen H, Allen D., and Lajtha A (1983) High-and low-affinity binding of (3H)-imipramine in mouse cerebral cortex J Neurochem. 40, 389–395
Rosenthal E. H. (1967) A graphic method for the determination and presentation of binding parameters in a complex system. Anal. Biochem 20, 525–532.
Ross S. B. (1976) Long-term effects of n-2-chloroethyl-n-ethyl-2-bromobenzylamme hydrochloride on noradrenergic neurons in the rat brain and heart Brit. J. Pharmacol. 58, 521–527
Ross S. B. And Renyi A (1975) Tricyclic antidepressant agents, I. Comarison Of the inhibition of the uptake of 3H-noradrenaline and 14C-5-hydroxytryptamine in slices and crude synaptosome preparation Of the midbrain-hypothalamus region of the rat brain. Acta Pharmacol. Toxicol 36, 382–394
Sachs C and Jonsson G (1975) 5,7-Dihydroxytryptamine induced changes in the postnatal development of central 5-hydroxytryptamine neurons Med Blol. 53, 156-164
Schildkraut J J (1965) The catecholamme hypothesis of affective disorders A review of the supporting evidence Am J Psychiat 122, 509–522.
Sette M., Raisman R., Briley M., and Langer S Z (1981) Localization of tricyclic antidepressant binding sites on serotonin nerve terminals J Neurochem. 37, 40–42.
Sette M., Briley M S, and Langer S. Z. (1983a) Complex inhibition of (3H)-imipramine binding by serotonin and nontricyclic serotonin uptake blockers. J. Neurochem. 40, 622–628
Sette M, Ruberg M., Raisman R., Scatton B., Zivkovic B., Agid Y., and Langer S. Z. (1983b) (3H)-Imipramine binding in subcellular fractions of the rat cerebral cortex after chemical lesion of serotonergic neurons. Eur. J Pharmacol 95, 41–51
Smith C B., Garcia-Sevilla J A., and Hollingsworth P J (1981) (α2-Adreno-receptors in rat brain are decreased after long-term tricyclic antidepressant treatment. Brain Res 210, 413–418
Snyder S H and Yamamura H. I (1977) Antidepressants and the muscarinic acetylcholme receptors Arch Gen Psychiat. 34, 236–239
Stanley M., Virgilio J., and Gershon S. (1982) Tritiated imipramine binding Sites are decreased in the frontal cortex of suicides Science 216, 1337–1339.
Suranyi-Cadotte B. E., Wood P. L., Nair N. P. V., and Schwartz G. (1982) Normalization of platelet 3H-imipramine binding in depressed patients during remission. Eur. J Pharmacol 85, 357–358
Suranyi-Cadotte B. E, Wood P. L., Schwartz G., and Narr N. P. V. (1983) Altered platelet (3H)-imipramine binding in schizo-affective and depressive Disorders Biol Psychiatry 18, 923–927
Tran V T., Lebovitz R., Toll L., and Snyder S. H. (1981) (3H)-Doxepin interactions with histamine H1-receptors and other sites in guinea pig and rat brain homogenates. Eur. J Pharmacol 70, 501–509
Tuomisto J and Tukrainen E (1976) Decreased uptake of 5-hydroxy-tryptamine in blood platelets from depressed patients Nature (Lond.) 262, 596–598
U’Prichard D. C., Greenberg D. A., Sheehan P. R, and Snyder S H. (1978) Tricyclic antidepressants therapeutic properties and affinity for α-noradrenergic receptor binding sites in the brain Science 199, 197–199
Vetulani J., Stawarz R. J., Dingell J. V., and Sulser F. (1976) A possible common mechanism of action of antidepressant treatments-reduction in the sensitivity of noradrenergic cyclic AMP generating system in the rat limbic forebrain Naunyn-Schmiedeberg’s Arch Pharmacol 293, 109–114.
Whitaker P. M., Warsh J J., Stancer H. C., Persad E, and Vint C K. (1984) Seasonal vanation in platelet 3H-imrpramine binding comparable Values in control and depressed populatrons. Psychiatry Res. 11, 127–131
Wong D. T., Bymaster F P., Horng J. S, and Molloy B. B. (1975) A new selective inhibitor for uptake of serotonin into synaptosomes of rat brain 3-(p-trifluoromethylphenoxy)-n-methyl-3-phenylpropylamine. J Pharmacol Exp. Therap 193, 804–811
Wood P. L., Suranyi-Cadotte B. E., Nair N P. V., Lafaille F., and Schwartz G. (1983) Lack of association between (3H)-imipramine binding sites and uptake of serotonin in control, depressed, and schizophrenic patients Neuropharmacol 22, 1211–1214
Zsilla G, Barbaccia M. L., Gandolfi O., Knoll J, and Costa E (1983) (-)-Deprenyl a selective MAO “B” inhibitor increases (3H)-imipramine Binding and decreases β-adrenergic receptor function Eur. J Pharmacol 89, 111–117
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Hrdina, P.D. (1986). Binding Sites for Antidepressants. In: Boulton, A.A., Baker, G.B., Hrdina, P.D. (eds) Receptor Binding. Neuromethods, vol 4. Humana Press. https://doi.org/10.1385/0-89603-078-4:455
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