Discriminative stimulus properties of 8-OH-DPAT: relationship to affinity for 5HT1A receptors

Previous studies have shown that discriminative stimulus control established with the 5HT_1A receptor agonist, 8-OH-DPAT, generalises to other 5HT_1A agonists and partial agonists but also to the ₂-adrenoceptor antagonist, yohimbine. On the basis of these results it has been proposed that the 8-OH-DPAT cue may be produced by activity at more than one receptor. In the present study rats were trained to discriminate a dose of 8-OH-DPAT (0.05 mg/kg, SC) from saline. Substitution tests showed dose-dependent generalisation with the 5HT_1A compounds, buspirone, ipsapirone, MDL 72832 and MDL 73005EF, the ₂-adrenoceptor antagonists, yohimbine and idazoxan, and BMY 14802, which is usually described as a sigma ligand. The buspirone metabolite 1-pyrimidinyl piperazine (1-PP) which possesses mainly ₂-adrenoceptor antagonist properties produced only partial generalisation which was not dose related. Receptor binding studies showed that all the compounds which substituted for 8-OH-DPAT displaced [³H]-8-OH-DPAT binding to rat hippocampal membranes. Furthermore, there were statistically significant positive correlations between drug affinity for 5HT_1A sites and their ED₅₀ values for both substitution for 8-OH-DPAT and potency to decrease response rates. These results are consistent with the view that the 8-OH-DPAT cue, like the ability of the compounds tested to decrease rates of responding, is largely mediated by activity at 5HT_1A receptors.