Development of tolerance to 8-OH-DPAT induced blockade of acquisition of a passive avoidance response

We examined the effects of manipulating 5-HT1A receptors on the performance of a passive avoidance task in rats. Firstly, we studied the effect of racemic 8-OH-DPAT and compared it to the pure enantiomers (subcutaneous injection, s.c.). Secondly, we investigated the effect (s.c.) of the selective 5-HT1A receptor antagonist (S)-UH-301 [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin] both alone and on 8-OH-DPAT-induced disruption of acquisition. Thirdly, we examined whether tolerance occurs to the effects of 8-OH-DPAT on passive avoidance acquisition. Finally, we examined the effects (s.c.) of the selective NMDA receptor antagonist dizocilpine, (+)-MK-801[(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohe pten-5, 10-imine], on this tolerance development. Different doses of racemic 8-OH-DPAT were injected 10 min before rats were exposed to the acquisition phase of a step through passive avoidance response. When tested for retention 24 h later, 8-OH-DPAT-pretreated rats failed to exhibit any avoidance. R(+) and S(-)-8-OH-DPAT were also active with the R(+)-isomer being more active than the S(-)-isomer. The 5-HT1A antagonist (S)-UH-301 [(S)-5-fluoro-8-hydroxy-2-(dipropylamino)tetralin] was without effect on avoidance performance but antagonized the effect of 8-OH-DPAT. In a further experiment, rats were pretreated with racemic 8-OH-DPAT (0.3 mg/kg). Twenty four hours later, they received a challenge dose of 8-OH-DPAT and exposed to the acquisition phase of the avoidance response. When tested 24 hr later for retention, 8-OH-DPAT challenged rats failed to show any indication of an avoidance response.(ABSTRACT TRUNCATED AT 250 WORDS)