We investigated whether the interoceptive cues mediated by the anxiolytic benzodiazepine receptor agonist alprazolam and the anxiogenic serotonin (5-HT)(1B/2C) receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) in rats are related to anxiety. mCPP-induced anxiety in humans can be blocked with alprazolam, and if mCPP drug discrimination is to be used as a model of anxiety, mCPP's stimulus should be blocked by alprazolam. Therefore, two groups of rats were trained to discriminate either alprazolam (2 mg/kg, PO) or mCPP (2 mg/kg, PO) from vehicle in a two-level operant drug discrimination procedure. Cross antagonism tests were performed with alprazolam and mCPP. mCPP did not antagonize alprazolam's stimulus to any extent, but disrupted responding severely. Low and intermediate doses of alprazolam (1.0-4.0 mg/kg, PO) did not antagonize the mCPP discriminative stimulus; only a high dose of 8.0 mg/kg (PO) partially antagonized mCPP but disrupted responding in most of the animals. We conclude that, at best, there is only weak evidence to suggest that the interoceptive cues of alprazolam and mCPP are mediated by modulation of anxiety processes, and that the mCPP drug discrimination as a model for anxiety is unreliable. Copyright (C) 1999 Elsevier Science Inc.