NEUROPSYCHOPHARMACOLOGICAL PROFILE IN RODENTS OF SR 57746A, A NEW, POTENT 5-HT(1A) RECEPTOR AGONIST

The effect of the 5-HT1A agonist SR 57746A (1-[2-(naphth-2-yl) ethyl]- 4-(3-trifluoromethylphenyl))-1,2,5,6 tetrahydropyridine hydrochloride) , was evaluated in a variety of psychopharmacological tests in rodents . In the approach-avoidance conflict test in rats, orally administered SR 57746A significantly increased punished responding at doses as low as 3 mg/kg, while unpunished responding was only reduced at 30 mg/kg. SR 57746A was active for at least 4 hours in this test. SR 57746A sig nificantly antagonised the lithium-induced taste aversion in rats at d oses of 3 and 10 mg/kg po. In the staircase test in mice, SR 57746A re duced rearing at doses which did not reduce the number of steps climbe d. In the two-compartment exploratory model in mice, SR 57746A increas ed the latency to the first entry into the dark compartment (at 2 to 8 mg/kg po), and reduced the time spent in the dark compartment (at 8 m g/kg po) but had no effect on the total number of transitions. SR 5774 6A potently reduced aggressive behaviour in isolated mice, the dose of 1 mg/kg po produced over 80% inhibition of fighting in this test. SR 57746A was also active in the behavioural despair test of depression i n mice and rats, and reversed learned helpless behaviour in rats. SR 5 7746A dose-dependently generalised to the cue produced by 8-OH-DPAT in rats, but produced only a very weak serotonergic syndrome. Like 8-OH- DPAT and ipsapirone, SR 57746A reduced body temperature in mice, but o nly at a high dose (10 mg/kg po). SR 57746A reversed haloperidol-induc ed catalepsy in rats with an ED(50) of 3.85 mg/kg po, but was unable t o antagonise the stereotypy induced by apomorphine in this species. SR 57746A was inactive or only very weakly active in a series of tests t ypical of benzodiazepine-like activity, including antagonism of pentet razol-induced seizures, reduction of muscle tone and locomotor activit y, impairment of motor co-ordination, and potentiation of the effects of centrally-acting sedative-hypnotics. SR 57746A was also inactive as an analgesic in the PBQ writhing test. Thus, SR 57746A is active in a number of tests indicative of 5-HT1A receptor stimulation in vivo, an d, more particularly, in a number of tests predictive of anxiolytic, a nti-aggressive and antidepressant activities. SR 57746A is as potent a s diazepam in anxiolytic tests, and more potent than imipramine in ant idepressant tests, whereas it is devoid of neuroleptic potential. In v iew of this profile of activity, SR 57746A merits evaluation as a pote ntial anxiolytic and antidepressant in humans.