DOSE-DEPENDENT DISCRIMINATIVE STIMULUS PROPERTIES OF 8-OH-DPAT

Separate groups of rats were trained to discriminate either 0.1 mg/kg (tow dose; L) or 2.5 mg/kg (high dose; H) of 8-OH-DPAT from saline, in a standard operant task. Both cues were found to be dose, time and ro ute dependent and generalized completely to the 5-HT1A agonists ipsapi rone and flesinoxan. Buspirone substituted completely for 8-OH-DPAT in L and partially in H, whereas the 5-HT1A/1B receptor agonist eltopraz ine substituted completely for 8-OH-DPAT in H but only partially in L. The 5-HT1A/1B receptor agonist RU24969, the 5-HT1B/2C/1A receptor ago nist TFMPP and the 5-HT reuptake blocker fluvoxamine did not completel y mimic the effect of 8-OH-DPAT in either L or H and the 5-HT1A mixed agonists/antagonists BMY 7378 and NAN-190 produced partial generalizat ion in L, but no generalization in H. In antagonism tests, NAN-190 and BMY 7378 only partially blocked the 8-OH-DPAT cue in both groups. The non-selective 5-HT receptor antagonist methysergide did not completel y block the 8-OH-DPAT cue in L or H. However,in generalization studies , it completely mimicked the 8-OH-DPAT cue in L and produced partial g eneralization in H. The beta-adrenergic/5-HT1A/1B receptor antagonist pindolol completely blocked the 8-OH-DPAT cue in L and H and did not m imic the 8-OH-DPAT cue in either condition. The alpha(2)-adrenoceptor blocker yohimbine substituted fully for the 8-OH-DPAT cue in L and par tially in H. Idazoxan did not substitute for the cue of 8-OH-DPAT in H , but produced nearly 80% generalization in L. The dopamine receptor a ntagonist pimozide neither blocked nor mimicked the cue of 8-OH-DPAT i n either group. A number of other drugs (i.e. m-CPP, S(-)-propranolol, DOI, ketanserin, clonidine and apomorphine) were only tested in H.S(- )-Propranolol blocked the 8-OH-DPAT cue but the other compounds produc ed neither stimulus generalization nor antagonism. The present study d emonstrates that the cues produced by the low and the high training do se of 8-OH-DPAT are quantitatively different and mediated by the agoni stic activity of 8-OH-DPAT at 5-HT1A receptors. Although the results s uggest that the 8-OH-DPAT cue (both L and H) is mediated via postsynap tic 5-HT1A receptors, the involvement of presynaptic 5-HT1A receptors cannot yet be ruled out.