The stimulus effects of 8-OH-DPAT: evidence for a 5-HT2A receptor-mediated component

Abstract

A previous investigation in our laboratory found that the stimulus effects of the 5-HT2A agonist, LSD, are potentiated by 5-HT1A receptor agonists including the prototypic agonist, 8-OH-DPAT. Also suggestive of behaviorally relevant interactions between 5-HT1A and 5-HT2A receptors are behavioral analyses of locomotor activity, head-twitch response, forepaw treading and production of the serotonin syndrome; in some instances effects are augmented, in other, diminished. These observations led us in the present investigation to test the hypothesis that stimulus control by 8-OH-DPAT [0.2 mg/kg; 15 min pretreatment time] is modulated by 5-HT2A ligands. Stimulus control was established with 8-OH-DPAT in a group of 10 rats. A two-lever, fixed ratio 10, positively reinforced task with saline controls was employed. As shown previously, stimulus control by 8-OH-DPAT and the generalization of 8-OH-DPAT to the 5-HT1A partial agonist, buspirone, was completely blocked by the selective 5-HT1A antagonist, WAY-100635. In contrast, antagonism by the selective 5-HT2A antagonist, M100907 [0.1 mg/kg; 30 min pretreatment time], of 8-OH-DPAT and of the generalization of 8-OH-DPAT to buspirone was statistically significant but less than complete. In light of our previous conclusions regarding the interactions of 5-HT1A agonists with LSD-induced stimulus control, the present data suggest that the interaction between 5-HT1A and 5-HT2A receptors is bidirectional in drug discrimination studies.

Figure 1

Dose-response relationship for 8-OH-DPAT alone and in combination with WAY-100,635. Circles represent the effects of 8-OH-DPAT alone in rats trained with 8-OH-DPAT as a discriminative stimulus (0.2 mg/kg; 15 min pretreatment time). Each point represents the mean of two determinations in each of 10 rats, with the exception of WAY-100,635 where a single determination is shown. The open hexagon represents the effects of WAY-100,635 (0.3 mg/kg 30 min. pretreatment) in combination with the training dose 8-OH-DPAT. The point at V is for vehicle controls.

Figure 2

Dose-response relationship for 8-OH-DPAT alone and in combination with M100907. Circles represent the effects of 8-OH-DPAT alone in rats trained with 8-OH-DPAT as a discriminative stimulus (0.2 mg/kg; 15 min pretreatment time). Each point represents the mean of two determinations in each of 10 rats, unless otherwise noted. Triangles represent the effects of M100907 (0.1 mg/kg 30 min. pretreatment) in combination with 8-OH-DPAT. The points at V are for either vehicle controls [circle] or M100907 alone [triangle]. The closed square represents the effects of buspirone (1.0 mg/kg 15 min pretreatment). The open square represents the effects of buspirone given in combination with M100907. The hexagon represents the effects of buspirone in combination with WAY-100,635. An asterisk indicates a statistically significant difference from 8-OH-DPAT given alone.