DIFFERENTIAL REINFORCEMENT OF LOW-RATE PERFORMANCE, PHARMACOKINETICS AND PHARMACOKINETIC-PHARMACODYNAMIC MODELING - INDEPENDENT INTERACTIONOF ALPRAZOLAM AND CAFFEINE

To investigate the interaction between alprazolam and caffeine, perfor mance on a differential reinforcement of low-rate behavior schedule an d the respective pharmacokinetics (PK) were explored in concurrent stu dies. Alprazolam PK was not altered by caffeine, but alprazolam retard ed caffeine absorption indirectly, as inferred by the lack of i.v. dru g administration PK interaction, thereby decreasing serum methylxanthi ne concentrations. Inasmuch as alprazolam was more potent and short-li ved than caffeine in decreasing the reinforcement rate (consonant with their respective t(1/2) values, 0.44 and 3.1 hr), the alprazolam/caff eine potency ratio decreased across the session time, which determined the expression of the combined effects. Thus, the decreased methylxan thine level yielded slightly less disruption in performance for the ob served combined effect, compared to the expected calculated effect, on ly near the end of a session. The interaction was PK linked and mainly not distinguishable from independence as indicated by the Poch dose-r esponse curve method and the integration of PK and pharmacodynamics. T he sigmoid maximal effect-link pharmacodynamic model indicated that ca ffeine did not alter the concentration at half of the maximal effect v alue of alprazolam and suggested that the interaction is not competiti ve, but independent. Although the nature of the benzodiazepine-methylx anthine interaction has been controversial in other behavioral studies , as is the role of PK in determining behavior, this and our previous study make it evident that the interaction is independent not only acr oss doses and routes of administration, but also with respect to two i ndices of differential reinforcement of low rate performance.