Abstract
Rats were treated with lithium administered either via the food or by intraperitoneal injection. Lithium administration via the food results in a rather stable serum lithium concentration, whereas lithium injection results in a varying serum lithium concentration whereby a sharp increase shortly after the injection is followed by an exponential decline until the next injection (Plenge et al. 1981) After 5 months of lithium treatment the 5HT transport protein, theβ-adrenergic receptor and several other brain proteins were determined. The 5HT transport protein, labelled with [3H]paroxetine, was found to be decreased in the lithium-injected rats (Bmax=347 fmol/mg protein) but was unchanged in the lithium-fed rats (Bmax=389 fmol/mg protein), as compared with control rats (Bmax=396 fmol/mg protein), and therefore probably is a specific effect only seen with varying lithium concentration. In contrast, the neuronal membrane marker protein D3 was decreased in the lithium-fed rats (88% of the control value), and showed a trend towards decrease in the lithium-injected rats. The decrease in D3 in the lithium-fed rats may indicate some neuronal damage due to the continous presence of lithium. This damage may be more pronounced than in rats, where periods of low lithium concentration enable repair to take place. Theβ-adrenergic receptor and the neural cell adhesion molecule NCAM were unaffected by the different lithium treatment regimens. Lithium has been reported to inhibit the 5HT1B receptor (the serotonin autoreceptor). We postulate that the two effects, i.e. overall lithium-induced inhibition of the 5HT autoreceptor and the down-regulation of the 5HT transport protein in rats with changing lithium concentration shown in the present study, may combine to augment the 5HT concentration in the synaptic cleft; increased 5HT in the cleft possibly being relevant in prophylactic lithium treatment of manic depressive disorders.
Similar content being viewed by others
Abbreviations
- 5HT:
-
serotonin
- IP:
-
intraperitoneally
- NCAM:
-
neural cell adhesion molecule
- [3H]DHAP:
-
[3H]dihydroalprenolol
References
Amdisen A (1978) Clinical and serum-level monitoring in lithium therapy and lithium intoxication. J Anal Toxicol 2:193–202
Edelman GM (1988) Morphoregulatory molecules. Biochemistry 27:3533–3543
Friedman E, Wang HY (1988) Effect of chronic lithium treatment on 5-hydroxytryptamine autoreceptors and release of3H-5-hydroxytryptamine from rat brain cortical hippocampal, and hypothalamic slices. J Neurochem 50:195–201
Hetmar O, Nielsen M (1988) Chronic treatment with lithium chloride: reduced number of GABA receptors in frontal cortex of rat brain. Pharmacol Toxicol 62:107–109
Hide I, Yamawaki S (1989) Inactivation of presynaptic 5HT autoreceptors by lithium in rat hippocampus. Neurosci Lett 107:323–326
Hotta I, Yamawaki S (1986) Lithium decreases 5HT1 receptors but increases 5HT sensitive, adenylate cyclase activity in rat hippocampus. Biol Psychiatry 21:1382–1390
Hotta I, Yamawaki S (1988) Possible involvement of presynaptic 5-HT autoreceptors in effect of lithium on 5-HT release in hippocampus of rat. Neuropharmacology 27:987–992
Jensen HV, Olafsson K, Bille A, Andersen J, Mellerup ET, Plenge P (1990) Lithium every second day. A new treatment regimen? Lithium 1:55–58
Jørgensen OS (1981) Neuronal membrane D2 protein during rat brain ontogeny. J Neurochem 37:939–946
Jørgensen OS (1983) D2-protein and D3-protein as markers for synaptic turnover and concentration. J Neural Transm Suppl 18:245–255
Jørgensen OJ, Delouvée A, Thiery JP, Edelman GM (1980) The nervous system specific protein D2 is involved in adhesion among neurits from cultured rat ganglia. FEBS Lett 111:39–42
Jørgensen OS, Mogensen J, Divac I (1987) The NCAM D2 protein, as marker for synaptic remodelling in the red nucleus. Brain Res 405:39–45
Jørgensen OS, Brooksbank BWL, Balazs R (1990) Neuronal plasticity and astrocytic reaction in down syndrom and alzheimer disease. J Neurol Sci 98:63–79
Lazarus, JH (1986) Endocrine and metabolic effects of lithium. Plenum Publishing Corporation, New York
Maggi A, Enna SJ (1980) Regional alterations in rat brain neurotransmitter systems following chronic lithium treatment. J Neurochem 34:888–892
Mellerup ET, Lauritsen BJ, Dam H, Rafaelsen OJ (1976) Lithium effects on diurnal rhythm of calcium, magnesium, and phosphate metabolism in manic-melancholic disorder. Acta Psychiatr Scand 53:360–370
Meltzer HY, Lowy MT (1987) The serotonin hypothesis of depression. In: Meltzer HY (ed) Psychopharmacology: The third generation of progress. Raven Press, New York, pp 513–533
Mizuta T, Segawa T (1988) Chronic effects of imipramine and lithium on postsynaptic 5-HT1A and 5-HT1B sites and on presynaptic 5-HT3 sites in rat brain. Jpn J Pharmacol 47:107–113
Mørk A (1990) Actions of lithium on second messenger activity in the brain. The adenylate cyclase and phosphoinositide systems. Lithium 1:131–147
Odagaki Y, Koyama T, Matsubara S, Matsubara R, Yamashita I (1990) Effects of chronic lithium treatment on serotonin binding sites in rat brain. Jpn J Pharmacol 24:271–277
Peterson GL (1977) A simplification of the protein assay method of Lowry et al. which is more generally applicable. Anal Biochem 83:346–356
Plenge P (1978) Lithium effects on rat brain glucose metabolism in long-term lithium-treated rats studied in vivo. Psychopharmacology 58:317–322
Plenge P (1982) Lithium effects on rat brain glucose metabolism in vivo. Effects after administration of lithium by various routes. Psychopharmacology 77:348–355
Plenge P, Rafaelsen OJ (1982) Lithium effects on calcium, magnesium and phosphate in man: effects on balance, bone mineral content, faecal and urinary excretion. Acta Psychiatr Scand 66:361–373
Plenge P, Mellerup ET, Nørgaard T (1981) Functional and structural rat kidney changes caused by peroral or parenteral lithium treatment. Acta Psychiatr Scand 63:303–313
Plenge P, Mellerup ET, Bolwig TG, Brun C, Hetmar O, Ladefoged J, Larsen S, Rafaelsen OJ (1982) Lithium treatment: does the kidney prefer one daily dose instead of two? Acta Psychiatr Scand 66:121–128
Plenge P, Mellerup ET, Jensen HV, Olafsson K, Bille A, Andersen J (1990) Dosage schedules in the treatment of mood disorders with lithium. Clin Neuropharmacol 13 [suppl 2]:289–290
Reilly MA, Wajda IJ, Banay-Schwartz M, Lajtha A (1983) Influence of chronic lithium administration on binding to benzodiazepine and histamine H1-receptors in rat brain. J Recept Res 3:703–710
Rosenblatt JE, Pert CB, Tallman JF (1979) The effect of imipramine and lithium on alpha and beta receptor binding in rat brain. Brain Res 160:186–191
Rosenblatt JE, Pert A, Layton B, Bunney WE (1980) Chronic lithium reduces3H-spiroperidol binding in rat striatum. Eur J Pharmacol 67:321–322
Schou M, Amdisen A, Thomsen K, Vestergaard P, Hetmar O, Mellerup ET, Plenge P, Rafaelsen OJ (1982) Lithium treatment regimen and renal water handling: the significance of dosage pattern and tablet type examined through comparison of results from two clinics with different treatment regimens. Psychopharmacology 77:387–390
Stengård-Pedersen K, Schou M (1982) In vitro and in vivo inhibition by lithium of enkephalin binding to opiate receptors in rat brain. Neuropharmacology 21:817–823
Treiser S, Kellar KJ (1979) Lithium effects on adrenergic receptor supersensitivity in rat brain. Eur J Pharmacol 58:85–86
Treiser S, Cascio CS, O'Donohue TL, Thoa NB, Jacobowitz DM, Kellar KJ (1981) Lithium increases serotonin release and decreases serotonin receptors in the hippocampus. Science 213:1529–1531
Vendsborg P (1979) Lithium treatment and glucose tolerance in manic-melancholic patients. Acta Psychiatr Scand 59:306–316
Wang HY, Friedman E (1988) Chronic lithium: desensitization of autoreceptors mediating serotonin release. Psychopharmacology 94:312–314
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Plenge, P., Mellerup, E.T. & Jørgensen, O.S. Lithium treatment regimens induce different changes in [3H]paroxetine binding protein and other rat brain proteins. Psychopharmacology 106, 131–135 (1992). https://doi.org/10.1007/BF02253600
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02253600