BEHAVIORAL PROFILE OF 2 POTENTIAL ANTIDEPRESSANT PYRIDAZINE DERIVATIVES INCLUDING ARYLPIPERAZINYL MOIETIES IN THEIR STRUCTURE, IN MICE

The potential antidepressant effects of two pyridazine derivatives, 5- benzyl 6-methyl 2-[4-(3-trifluoromethyl phenyl) piperazin-1-yl] methyl pyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) pipe razin-1-yl] methylpyridazin-3-one (PC13), were evaluated using classic al psychopharmacological tests in mice. The intraperitoneal LD50 value s of PC4 and PC13 were respectively 1125.8 and 429.6 mg kg(-1). Only a t intraperitoneal doses of 100 mg kg(-1) did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5-20 mg kg(-1), i.p.) re duced the duration of immobility of mice in the forced swimming test, antagonized reserpine (2.5 mg kg(-1), i,p.)-induced ptosis, and potent iated reserpine (2 5 mg kg(-1), i.p.)-induced hypothermia. PC4 and PC1 3 (20 mg kg(-1) i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg(-1), s.c.) but were less effective for higher dos es of apomorphine (16 mg kg(-1), s.c.). At 200 mg kg(-1), intraperiton eal PC13 enhanced the toxic effects of yohimbine (30 mg kg(-1), s.c.) while PC4 was inactive. Head twitches produced either by L-5-hydroxytr yptophan (4 mg kg(-1), i.p.) in mice pretreated with pargyline (100 mg kg(-1) i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 m g kg(-1), i.p.) were antagonized by both pyridazine derivatives (20 mg kg(-1) i.p.). PC4 and PC13 showed analgesic properties in the phenylb enzoquinone-induced abdominal constriction test (5.0 < ED50 < 5.5 mg k g(-1) i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg(-1), i.p.). These antinociceptive effects were not significantly d iminished by naloxone (1 mg kg(-1),i.p.). Furthermore, acute intraperi toneal administration of both compounds (20 mg kg(-1) for PC4 and 5 mg kg(-1) for PC13) potentiated morphine (7.5 mg kg(-1), s.c.) analgesia in the hot-plate test. Thus, these results suggest that PC4 and PC13 possess potential antidepressant effects related to different aminergi c mechanisms, especially at the 5-HT2 receptor level.