Involvement of 5-HT₂ Receptor in Imipramine-Induced Hyperglycemia in Mice

Abstract

Effects of imipramine on plasma glucose levels were investigated in mice. Imipramine i. p. induced dose-dependent hyperglycemia, which was enhanced by pretreatment with 5-HT_1/2/5/7 receptor antagonist methysergide and 5-HT_2A/2B/2C receptor antagonist LY 53 857. 5-HT_2C/2B receptor antagonist SB 206 553 also augmented imipramine-induced hyperglycemia although 5-HT_1A and 5-HT_1B receptor antagonist (-)-propranolol,5-HT_2A receptor antagonist ketanserin and 5-HT_3/4 receptor antagonist tropisetron each had no effect. Imipramine i. p.-induced hyperglycemia was antagonized by the 5-HT_2C/2B receptor agonist 1-(3-chlorophenyl)piperazine (mCPP), while the 5-HT_2B receptor agonist BW 723C86 had no effect. Intracerebroventricular injection of imipramine also elevated plasma glucose levels, which is enhanced by SB 206 553. Hyperglycemia elicited by central injection of imipramine was abolished by adrenalectomy. These results suggest that imipramine-induced hyperglycemia in mice is related to its inhibition of the central 5-HT_2C receptor. Moreover, our results indicate that adrenaline release is related to imipramine-induced hyperglycemia.

Key words

Imipramine - 5-HT (5-hydroxytryptamine, serotonin) - 5-HT_2C/2B Receptor - Glucose - Antidepressants

References

• 1 Chaouloff F, Jeanrenaud B. 5-HT_1A and alpha-2 adrenergic receptors mediate the hyperglycemic and hypoinsulinemic effects of 8-hydroxy-2-(di-n-propylamino)tetralin in the conscious rat.  J Pharmacol Exp Ther. 1987;  243 1159-1166
• 2 Bouhelal R, Loubatieres-Mariani M M, Mir A K. Investigation of the mechanism(s) of 8-OH-DPAT-mediated inhibition of plasma insulin in spontaneously hypertensive rats.  Br J Pharmacol. 1990;  100 173-179
• 3 Durcan M J, Wozniak K M, Linnoila M. Modulation of the hypothermic and hyperglycaemic effects of 8-OH-DPAT by a-α₂-adrenoceptor antagonists.  Br J Pharmacol. 1991;  102 222-226
• 4 Critchley D V, Middlefell V C, Liddle C W, Foden N D, Dourish C T. Effects of the selective 5-HT_1A receptor antagonist WAY100135 and its enantiomers on 8-OH-DPAT-induced hyperglycemia in conscious rats.  Eur J Pharmacol. 1994;  254 133-139
• 5 Chaouloff F, Baudrie V, Laude D. Evidence that the 5-HT_1A receptor agonists buspirone and ipsapirone activate adrenaline release in the conscious rat.  Eur J Pharmacol. 1990;  177 107-110
• 6 Sugimoto Y, Yamada J, Kimura I, Watanabe Y, Horisaka K. The Effects of the serotonin_1A receptor agonist buspirone on the blood glucose and pancreatic hormones in rats.  Jpn J Pharmacol. 1992;  60 145-148
• 7 Baudrie V, Chaouloff F. Mechanisms involved in the hyperglycemic effect of the 5-HT_1C/5-HT₂ receptor agonist DOI.  Eur J Pharmacol. 1992;  213 41-46
• 8 Sugimoto Y, Yamada J, Yoshikawa T, Horisaka K. Effects of the 5-HT_2C/2B receptor agonist 1-(3-chlorophenyl)piperazine on the plasma glucose levels of rats.  Eur J Pharmacol. 1996;  307 75-80
• 9 Montgomery S A. Clinical efficacy of 5-HT uptake inhibitors.  Neuropharmacology. 1990;  13 285-286
• 10 Hyttel J. Pharmacological characterization of the selective serotonin reuptake inhibitors(SSRI's).  Int J Pharmacol. 1994;  9 19-26
• 11 Sugimoto Y, Inoue K, Yamada J. Involvement of serotonin in zimelidine-induced hyperglycemia in mice.  Biol Pharm Bull. 1999;  22 1240-1241
• 12 Yamada J, Sugimoto Y, Inoue K. Selective serotonin reuptake inhibitors fluoxetine and fluvoxamine induce hyperglycemia by different mechanisms.  Eur J Pharmacol. 1999;  382 211-215
• 13 Briley M, Moret C. Neurobiological mechanisms involved in antidepressant therapies.  J Clin Neuropharmacol. 1993;  16 24-35
• 14 Kaplan S M, Mass J W, Pixley J M, Ross W D. Use of imipramine in diabetes.  J Am Med Assooc. 1960;  174 511-517
• 15 Gupta B, Awasthi A, Jaju B P. Effect of acute & chronic imipramine treatment on glucose homeostasis.  Indian J Med Res. 1992;  96 65-71
• 16 Haley T J, McCormick W G. Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse.  J Pharmacol. 1957;  12 12-15
• 17 Katz L M, Fochtman L F, Pato M T. Clomipramine, fluoxetine and glucose control.  Ann Clin Psychiatry. 1991;  3 271-274
• 18 Palvimaki E P, Roth B L, Majasuo H, Laakso A, Kuoppamaki M, Syvalahti E, Hietala J. Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT_2C receptor.  Psychopharmacology. 1996;  126 234-240
• 19 Borsini F, Cesana R, Vidi A, Mennini T. Evidence that imipramine activates 5-HT_1C receptor function.  Eur J Pharmacol. 1991;  203 359-363
• 20 Redrobe J P, Bourin M. Partial role of 5-HT₂ and 5-HT₃ receptors in the activity of antidepressants in the mouse forced swimming test.  Eur J Pharmacol. 1997;  325 129-135
• 21 Yamada J, Sugimoto Y. Effects of 5-HT₂ receptor antagonists on the anti-immobility effects of imipramine in the forced swimming test with mice.  Eur J Pharmacol. 2001;  427 221-225
• 22 Baxter G, Kennett G A, Blaney F, Blackburn T. 5-HT₂ receptor subtypes: a family re-united?.  Trends Pharmacol Sci. 1995;  16 105-110
• 23 Groenink L, van der Gugten J, Verdouw P M, Maes R A, Olivier B. The anxiolytic effects of flesinoxan, a 5-HT_1A receptor agonist, are not related to its neuroendocrine effects.  Eur J Pharmacol. 1995;  280 185-193
• 24 Groenink L, van der Gugten J, Zethof T J, van der Heyden J A, Olivier B. Neuroendocrine effects of diazepam and flesinoxan in the stress-induced hyperthermia test in mice.  Pharmacol Biochem Behav. 1996;  54 249-254
• 25 Bouhelal R, Mir A K. Role of the adrenal medulla in the metabolic and pressor actions of 8-OH-DPAT.  Br J Pharmacol. 1992;  105 159-163
• 26 Chaouloff F, Laude D, Baudrie V. Ganglionic transmission is a prerequisite for the adrenaline-releasing and hyperglycemic effects of 8-OH-DPAT.  Eur J Pharmacol. 1990;  185 11-18
• 27 Gaut Z N. Influence of various substances which induce and inhibit aggregation on the uptake of deoxyglucose by human blood platelets.  J Pharmacol Exp Ther. 1974;  190 180-186
• 28 Pinkofsky H B, Dwyer D S, Bradley R J. The inhibition of GLUT1 glucose transport and cytochalasin B binding activity by tricyclic antidepressants.  Life Sci. 2000;  66 271-278