The effect of BIMT 17, a new potential antidepressant, in the forced swimming test in mice.

BIMT 17 inhibits cortical electrical activity through the activation of cortical 5-HT(1A) receptors combined with the antagonism of 5-HT(2) receptors. The aim of this study was to evaluate the potential antidepressant activity of BIMT 17 and its mechanism of action by using the forced swimming test in mice. BIMT 17, when administered i.p. (16mg/kg), s.c. (8mg/kg) and orally (32mg/kg), increased the struggling time in mice forced to swim. With i.p. administration, BIMT 17 did not alter locomotor activity. The effect of BIMT 17 seems to be mediated by 5-HT(1A) receptors since it was antagonised by WAY 100135 (10mg/kg i.p.), a selective 5-HT(1A) antagonist. The 5-HT(2) component does not seem to modulate BIMT 17 activity since the administration of DOI (1mg/kg i.p.), a 5-HT(2A/2C) agonist, did not modify the BIMT 17 effect. Antagonism of BIMT 17 was also produced by buspirone (30mg/kg p.o.), alpha-methyl-p-tyrosine (250mg/kg i.p.) and sulpiride (50mg/kg i.p.) but not by pindolol (20mg/kg i.p.). Neither the reduction of 5-HT synthesis brought about by p-chlorophenylalanine nor the selective destruction of 5-HT containing neurons by 5,7-dihydroxytryptamine reduced the BIMT 17 effect, suggesting that BIMT 17 acts postsynaptically in increasing struggling behaviour.

Mesulergine antagonism towards the fluoxetine anti-immobility effect in the forced swimming test in mice.

The anti-immobility effect of fluoxetine (40 mg kg-1) in the forced swimming test in mice was antagonized by the 5-HT1c/2 antagonist mesulergine (7.5 mg kg-1) and the dopamine D2 antagonist (+/-)-sulpiride (12.5 mg kg-1) but not by the 5-HT2/1C antagonist ritanserine (2 mg kg-1), the 5-HT1A/1B antagonist (-)-propranolol (20 mg kg-1) or the 5-HT3 antagonist DAU 6215 (0.1 mg kg-1). All compounds were administered intraperitoneally (i.p.) 6 min before fluoxetine, given i.p. 30 min before testing. The anti-immobility effect of fluoxetine was also prevented by pretreatment with p-chlorophenylalanine (300 mg kg-1 twice daily for 3 days) which produced an 80% reduction of 5-HT in brain. The results suggest that fluoxetine reduces immobility time in mice forced to swim, by acting indirectly through a mesulergine-sensitive site, probably the 5-HT1C receptor.

Pharmacology of mifentidine, a novel H2-receptor antagonist.

N1-[(4-Imidazolyl)-phenyl]-N2-isopropylformamidine (mifentidine, DA 4577 is a potent and selective H2 antagonist, representative of a new class of compounds, the imidazolylphenyl-formamidines, characterized by a semi-rigid structural conformation. Mifentidine appeared to be a specific and competitive antagonist of several histamine-mediated responses. Thus, in isolated guinea pig atria and ventricles it antagonized histamine chronotropic and dimaprit inotropic effects in a competitive manner providing affinity estimates (pA2) of 7.66 and 7.74, respectively. Mifentidine exerted potent antisecretory effects in: the isolated mouse stomach where it antagonized the acid promoting activity of histamine (EC50 3.28 mumol/l) but not that of bethanechol or db-cAMP (adenosine 3',5'-monophosphate); the lumen perfused stomach of the anaesthetized rat, inhibiting histamine (ED50 0.1 mumol/kg i.v.) and pentagastrin (ED50 0.2 mumol/kg i.v.) stimulated secretion; the pylorus ligated rat (ED50 1.35 mumol/kg i.v.); the gastric fistula dog, reducing the secretagogue effect of pentagastrin (ED50 96 nmol/kg i.v.); the conscious dog equipped with the Heidenhain pouch, where it was effective both following intravenous (ED50 119.7 nmol/kg) and oral administration (ED50 323.8 nmol/kg) in antagonizing histamine action. Mifentidine antisecretory effect, examined in the dog, appeared to last for a significantly longer time than that of ranitidine. Mifentidine was free of cardiovascular effects (on aortic blood pressure and heart rate) when administered repeatedly to the conscious dog at doses far above those needed to suppress acid secretion.