Differentiation of 5-HT1A receptor ligands by drug discrimination.

Pigeons were trained to discriminate 0.64 mg/kg (high dose) of 8-OH-DPAT (8-hydroxy-(2-di-n-propylamino)tetralin) from saline or were retrained to discriminate 0.16 mg/kg (low dose) of 8-OH-DPAT from saline. This resulted in a decrease of the ED50 for recognition of the 8-OH-DPAT cue from 0.14 to 0.04 mg/kg. Partial agonists for the 5-HT1A receptor (e.g., buspirone) were generalized fully in the low dose condition, but only partially in the high dose condition. Full antagonists, such as N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY-100635), antagonized the 8-OH-DPAT cue in both groups without producing generalization in either group. (-)-Pindolol produced full generalization in the low dose group, but antagonized the high dose stimulus cue. The behavioral effects of other compounds with 5-HT1A receptor activities (4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-pyridinyl-benz ami de hydrochloride (p-MPPI): (-)-1-(1H-indol-4-yloxy)-3-(cyclohexylamino)-2-propanol maleate ((-)-LY206130); racemic pindolol and idazoxan) also differed between groups. Comparing results obtained using differing training doses in the drug discrimination paradigm simplifies determination of the full agonist, partial agonist, or antagonist properties of compounds.