Evidence that imipramine activates 5-HT 1C receptor function

Abstract

The anti-immobility effect of imipramine (15 mg/kg) in the forced swimming test in mice was antagonized by the non-selective 5-hydroxytryptamine (5-HT) antagonist, metitepine (0.5 mg/kg), by the 5-HT 1C/5-HT 2 antagonist, mesulergine (15 mg/kg), and by the dopamine D 2 antagonist, d,1-sulpiride (50 mg/kg). These three antagonists did not alter the behaviour of imipramine-treated mice in an open-field and did not reduce imipramine brain levels. The 5-HT 2 antagonist, ritanserin (0.06 mg/kg), the 5-HT 1A/5-HT B antagonist, 1-propranolol (20 mg/kg), and the 5-HT 3 antagonists, endo-2,3-dihydro-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)-2-oxo-1H-benzimidazole-1-carboxamide hydrochloride (DAU 6215; 0.1 mg/kg) and 1,2,3,9-tetrahydro-9-methyl-3 [(2-methyl-1H-imidazol-1-yl)methy]-4H-carbazol-4-one, HCl · 2H 2O) (GR 38032F; 0.1 mg/kg), failed to reduce imipramine-induced anti-immobility. Subthreshold doses of 8-hydroxy-2-(di-n-propylamino)tetralin hydrochloride (8-OH-DPAT; 0.5 mg/kg) and imipramine (7.5 mg/kg) did not synergizc in reducing immobility. d,l-Sulpiride, but not mesulergine, antagonized the effect of desipramine (15 mg/kg) in the forced swimming test. All compounds were administered i.p. 6 min before imipramine or desipramine, given i.p. 30 min before the testing. Imipramine produced 50% inhibition of [ 3H]mesulergine binding to 5-HT 1C receptors at 10 μM, a concentration below that obtained following i.p. imipramine administration. The results suggest a contribution of 5-HT 1C receptors in the mechanism of the imipramine effect in the forced swimming test.