The potent activity of the 5-HT1A receptor agonists, S 14506 and S 14671, in the rat forced swim test is blocked by novel 5-HT1A receptor antagonists

The high efficacy methoxynaphtylpiperazine 5-HT1A receptor agonists, S 14506 (1-[2-(4-fluorobenzoylamino)ethyl]-4-(7-methoxynaphtyl)piper azine) and S 14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7-methoxynaphtyl]piperazin e), potently reduced the duration of immobility in the forced swimming test in rats [minimal effective dose (MED): 0.01 mg/kg, s.c., in each case]; in contrast, the prototypic 5-HT1A receptor agonist, 8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide], was much less potent (MED: 0.63 mg/kg). The action of S 14671 (0.16 mg/kg) was completely blocked by the potent 5-HT1A receptor antagonist, SDZ 216-525 (4-(4-[4-(1,1,3-trioxo-2H-1,2-benzoisothiazol-2- yl)butyl]-1-piperazinyl)1H-indole-2-carboxylate) (0.63 mg/kg) and by the novel, selective 5-HT1A receptor antagonist, (+)-WAY 100,135 (N-tertiobutyl-3-[4-(2-methoxyphenyl)piperazinylphenyl propanamide): the effect of the latter was expressed dose dependently (Inhibitory Dose50: 35 mg/kg). Similarly, in the presence of (+)-WAY 100,135, S 14506 (0.63 mg/kg) failed to reduce immobility. Pretreatment with parachlorophenylalanine (3 x 300 mg/kg per day, i.p.), which profoundly depleted cerebral pools of 5-HT, modified neither baseline immobility nor the actions of S 14506 and S 14671. It is concluded that S 14506 and S 14671 possess exceptionally potent activity in the forced swimming test and that their actions reflect the activation of postsynaptic 5-HT1A receptors.