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 enzoylamino)ethyl]-4-(7-methoxynaphtyl)piperazine} and S 14671 oylamino)ethyl]-4[1-(7-methoxynaphtyl]piperazine}, potently reduced th e 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, th e prototypic 5-HT1A receptor agonist, 8-OH-DPAT [8-hydroxy-2-(di-n-pro pylamino)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 po tent 5-HT1A receptor antagonist, SDZ 216-525 2-yl)butyl]-1-piperazinyl }1H-indole-2-carboxylate} (0.63 mg/kg) and by the novel, selective 5-H T1A receptor antagonist, (+)-WAY 100,135 ertiobutyl-3-[4-(2-methoxyphe nyl)piperazinylphenyl propanamide): the effect of the latter was expre ssed dose dependently (Inhibitory Dose(50): 35 mg/kg). Similarly, in t he presence of (+)-WAY 100,135, S 14506 (0.63 mg/kg) failed to reduce immobility. Pretreatment with parachlorophenylalanine (3 X 300 mg/kg p er day, i.p.), which profoundly depleted cerebral pools of 5-HT, modif ied neither baseline immobility nor the actions of S 14506 and S 14671 . It is concluded that S 14506 and S 14671 possess exceptionally poten t activity in the forced swimming test and that their actions reflect the activation of postsynaptic 5-HT1A receptors.