The Influences of Reserpine and Imipramine on the 5-HT2 Receptor Binding Site and Its Coupled Second Messenger in Rat Cerebral Cortex

10.4077/CJP.2013.BAB126

Ming-Jen Lee；Jiann-Wu Wei

5-HT2 receptor ； antidepressant ； imipramine ； rat cerebral cortex ； reserpine

The Chinese Journal of Physiology

56卷4期（2013 / 08 / 31）

199 - 208

英文

An investigation on the molecular mechanism of depression state, less attention was focused on changes at the intracellular messenger level. In this study the effects of reserpine, a monoamine depletor, and imipramine, an antidepressant, on serotonin-2 (5-HT2) receptor binding and its second messenger system of rat cerebral cortex were studied. The level of inositol 4-monophosphate (IP1) accumulation elicited by 100 μM 5-HT via activation of the 5-HT2 receptor on cerebral cortical slices at twelve hours after a single dose of reserpine (2 mg/kg, i.p.) was significantly higher in treated rats, when compared to that of saline-treated rats ; this significant level lasted for at least four days. The level of IP1 accumulation in rat cerebral cortical slices elicited by 100 μM serotonin was higher in the group pretreated with reserpine (0.25 mg/kg/day) sub-chronically for seven days than the group pretreated with normal saline. In the receptor binding study, the maximum binding (Bmax) of 5-HT2 receptor binding was increased, when compared to the corresponding controls; whereas, the dissociation equilibrium constant (Kd) value of the 5-HT2 receptor was found unchanged in the reserpine treated group. Increases in the sensitivity of phosphoinositol (PI) turnover coupled with the 5-HT2 receptor were also found in the long-term (21 days) low dose (0.1 mg/kg/day) administration of reserpine. However, a long-term administration of imipramine (10 mg/kg/day) reduced the function of the PI turnover coupled with the 5-HT2 receptor. Results obtained from the combined use of reserpine and imipramine demonstrated that this combination was able to antagonize the super-sensitivity of the second messenger responses in 5-HT2 receptor induced by long-term treatment with reserpine. Long term treatment with reserpine but not imipramine also caused an increase in the Bmax of the 5-HT2 receptor. This up-regulation of the 5-HT2 receptor by reserpine could be antagonized by imipramine, if a combined treatment was employed. However, this combination of imipramine with an additional phospholipid liposome did not enhance or decrease the imipramine's effect on the 5-HT2 receptor, or on its coupled second messenger level. In summary, reserpine induced up-regulation of the postsynaptic monoamine receptor and its coupled second messenger responses (such as IP1 formation). Imipramine was capable of antagonizing these same events in a depression animal model with reserpine. This study demonstrated the dynamic changes and adaptability of the receptor system, followed by changes in PI turnover. The results provide an explanation at the molecular level for the bases of depression and the role of antidepressant drugs effects on those pathological linking elements.

1. Wang, H.L.,Wei, J.W.(2012).Effects of 2-azafluorenones on phosphatidylinositol specific phospholipase C activation in C6 glioma cells.Chin. J. Physiol.,55,101-107.
   連結：
2. Banerjee, S.P.,Kung, L.S.(1977).Development of ß-adrenergic receptor subsenitivity by antidepressants.Nature,268,455-456.
3. Baraban, J.M.,Worley, P.F.,Snyder, S.H.(1989).Second messenger systems and psychoactive drug action: focus on the phosphoinositide system and lithium.Am. J. Psychiatry,146,1251-1260.
4. Barkai, I.A.,Dunner, D.L.,Gross, H.A.,Mayo, P.,Fieve, R.R.(1978).Reduced myo-inositol levels in cerebrospinal fluid from patients with affective disorder.Biol. Psychiatry,13,65-72.
5. Berridge, M.J.,Downes, C.P.,Hanley, M.R.(1982).Lithium amplifies agonist-dependent phosphatidylinositol response in brain and salivary gland.Biochem. J.,206,587-595.
6. Brodie, B.B.,Olin, J.S.,Kuntzman, R.G.,Shore, P.A.(1957).Possible interrelationship between release of brain norepinephrine and serotonin by reserpine.Science,125,1293-1294.
7. Brown, E.,Kendall, D.A.,Nahorski, S.R.(1984).Inositol phospholipid hydrolysis in rat cerebral cortical slices. I. Receptor characterization.J. Neurochem.,42,1379-1387.
8. Drago, F.,Continella, G.,Mason, G.A.,Hemandez, D.E.,Scapagnini, U.(1985).Phospholipid liposomes potentiate the inhibitory effect of antidepressant drugs on immobility of rats in a despair test (constrained swim).Eur. J. Pharmacol.,115,179-184.
9. Eison, A.S.,Eison, M.S.,Torrente, J.R.,Wright, R.N.,Yocca, F.D.(1990).Nefazodone: preclinical pharmacology of a new antidepressant.Psychopharmacolog. Bull.,26,311-315.
10. Feighner, J.P.(1983).The new generation of antidepressants.J. Clin. Psychiatr.,44,49-55.
11. Fuxe, K.,Ogren, S.O.,Agnati, L.F.,Andersson, K.,Eneroth, P.(1982).Effect of subchronic antidepressant drug treatment on central serotonergic mechanism in the male rat.Adv. Biochem. Phsychopharmacol.,31,91-107.
12. Gray, J.A.,Roth, B.L.(2011).Paradoxical trafficking and regulation of 5-HT (2A) receptors by agonist and antagonists.Brain Res. Bull.,56,441-451.
13. Heiligenstein, J.H.,Tollefson, G.D.,Faries, D.E.(1993).A doubleblind trial of fluoxetine, 20 mg, and placebo in outpatient with DSM-II-R major depepreaaion and melancholia.Int. Clin. Psychopharmacol.,8,247-251.
14. Kendall, D.A.,Nahorski, S.R.(1985).5-Hydroxytryptamine-stimulated inositol phospholipid hydrolysis in rat cerebral cortex slices: pharmacological characterization and effects of antidepressants.J. Pharmacol. Exp. Ther.,233,473-479.
15. Klerman, G.L.,Cole, J.O.(1965).Clinical pharmacology of imipramine and related antidepressant compounds.Pharmacol. Rev.,17,101-141.
16. Lehmann, H.E.,Cahn, C.H.,De Verteuil, R.L.(1958).The treatment of depressive conditions with imipramine (G 22355).Can. Psychiatr. Assoc. J.,3,155-164.
17. Levine, J.,Rapaport, A.,Lev, L.,Bersusaky, Y.,Kodman, O.,Belmaker, R.H.,Shapiro, J.,Agam, G.(1993).Inositol treatment raises CSF inositol levels.Brain Res.,627,168-170.
18. Levine, J.K.,Barak, Y.,Gonzalves, M.,Szor, H.,Elizur, A.,Kofman, O.,Belmaker, R.H.(1995).Double-blind, controlled trail of inositol treatment of depression.Am. J. Psychiatry,152,793-794.
19. Leysen, J.E.,Niemegeer, C.J.E.,Van Neuten, J.M.,Laduron, P.M.(1982).[3H] ketanserin (R41468), a selective [3H]ligand for serotonin 2 receptor binding sites.Mol. Pharmacol.,21,301-314.
20. Lopez-Munoz, F.,Alamo, C.(2009).Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today.Curren. Pharmaceut. Design,15,1563-1586.
21. Montgomery, S.A.(1989).The efficacy of fluoxetine as an antidepressant in the short and long term.Int. Clin. Psychopharmacol.,4(Suppl 1),113-119.
22. Payvandi, N.,Elliott, J.M.,Heal, D.J.(1991).Phosphatidylinositol potentiates the effect of amitriptyline on ß1-adrenoceptor number and on noradrenaline-stimulated adenylate cyclase activity in rat frontal cortex.Brit. J. Pharmacol.,102,275P.
23. Siever, L.J.,Davis, F.L.(1985).Overview: toward dysregulation hypothesis of depression.Am. J. Psychiatry,142,1017-1031.
24. Slater, I.H.,Rathbun, R.C.,Kattau, R.(1979).Role of 5-hydroxytryptaminergic and adrenergic mechanism in antagonism of reserpine-induced hypothermia in mice.J. Pharm. Phamacol.,31,108-110.
25. Sulser, F.(1983).Mode of action of antidepressant drugs.J. Clin. Psychiat.,44,14-20.
26. Tondo, L.,Jamison, K.,Baldessarini, R.J.(1997).Antisuicide effects of lithium.Ann. N.Y. Acad. Sci.,836,339-351.
27. Tseng, C.L.,Wei, J.W.(2012).Investigation on signal transduction pathways after H1 receptor activated by histamine in C6 glioma cells: Involvement of phosphatidylinositol and arachidonic acid metabolisms.J. Chin. Med. Assoc.,75,143-150.
28. Twarog, B.M.(1988).Serotonin: History of a discovery.Com. Biochem. Physiol.,91C,21-24.
29. Wei, J.W.,Lee, M.J.,Yeh, S.R.(1991).Biochemical events coupled to the activation of serotonin receptors in brain regions of the rat.Chinese J. Physiol.,34,387-398.
30. Yildiz, A.(2002).Phosphoinositide metabolism, lithium and manic depressive illness.Spectroscopy,16,307-316.