DEVELOPMENT OF TOLERANCE TO 8-OH-DPAT INDUCED BLOCKADE OF ACQUISITIONOF A PASSIVE-AVOIDANCE RESPONSE

We examined the effects of manipulating 5-HT1A receptors on the perfor mance of a passive avoidance task in rats. Firstly, we studied the eff ect of racemic 8-OH-DPAT and compared it to the pure enantiomers (subc utaneous 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-induc ed disruption of acquisition. Thirdly, we examined whether tolerance o ccurs to the effects of 8-OH-DPAT on passive avoidance acquisition. Fi nally, we examined the effects (s.c.) of the selective NMDA receptor a ntagonist dizocilpine, 11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imin e], on this tolerance development. Different doses of racemic 8-OH-DPA T were injected 10 min before rats were exposed to the acquisition pha se of a step through passive avoidance response. When tested for reten tion 24 h later, 8-OH-DPAT-pretreated rats failed to exhibit any avoid ance. R(+) and S(-)-8-OH-DPAT were also active with the R(+)-isomer be ing 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 fai led to show any indication of an avoidance response. Furthermore, the pretreatment dose of 8-OH-DPAT, given 24 hr before the challenge dose, failed to affect the response to the challenge dose of 8-OH-DPAT. Oth er rats were pretreated with 1 mg/kg of 8-OH-DPAT for 5 consecutive da ys. These rats developed a complete tolerance to the effects of a chal lenge dose of 8-OH-DPAT. Co-administration of MK-801 prior to each of the 5 pretreatment doses blocked the development of tolerance to a cha llenge dose of 8-OH-DPAT. Thus, tolerance develops to the inhibitory e ffects of 8-OH-DPAT on passive avoidance acquisition and this toleranc e development can be blocked by treatment with an NMDA receptor antago nist.