Effects of repeated treatment with 5-HT1A agonists on active avoidance responding in the rat.

The behavioural effects of the serotonin 1A receptor (5-HT1A) agonist anxiolytics are generally examined after acute administration. The present study examined the effects of these substances during repeated treatment in the two-way active avoidance (Conditioned Avoidance Response, CAR) procedure. Previously it has been found that the prototypical 5-HT1A receptor agonist, 8-OH-DPAT, increases avoidance, apparently by increasing general activity, after repeated administration but not on acute administration. In the present study, it was demonstrated that this increase in activity can be blocked by the 5-HT1A receptor antagonists (-)alprenolol (also beta adrenergic antagonist) and (S)-UH-301, but not by the non-selective 5-HT antagonist metergoline. The relatively full 5-HT1A agonist, flesinoxan, and the partial 5-HT1A agonist, ipsapirone, had qualitatively similar effects to 8-OH-DPAT, although the effect of ipsapirone was clearly smaller in magnitude. Buspirone, the 5-HT1A partial agonist/dopamine D2 antagonist, markedly decreased activity, and thus avoidance of the shocks, in a manner similar to the antipsychotic drug, haloperidol. However, when the hypothermic effects of these compounds were investigated after acute administration, buspirone induced a strong hypothermic response in rats, like 8-OH-DPAT, whereas haloperidol had no effect. With the exception of buspirone, the effectiveness of these compounds in increasing activity in the CAR test appears to be related to their agonist efficacy at the 5-HT1A receptor. Similarities between the effects of these compounds and previously reported results with serotonin-depleting agents (Tenen 1967; Breese et al. 1974) suggest that the net effect of 5-HT1A agonists after repeated administration is to produce a functional reduction in 5-HT activity. The activity suppressing action of buspirone indicates that the dopamine antagonist activity of buspirone predominates in this procedure.