(1) The initiation of oral reinforcing efficacy for benzodiazepines (BZs) will be studied in animals at abusive intake levels using a drug preference procedure under schedule-induced polydipsia conditions. A possible decrease in the reinforcing threshold of oral BZs by psychomotor stimulants, particularly caffeine, a threshold shift by the BZ antagonist flumazenil, as well as the serum pharmacokinetics relevant to oral BZ reinforcing function, will be studied. (2) The synergistic action of combined midazolam and caffeine injections in disrupting fine- motor task performance will be analyzed using a variety of spontaneous and programmed motor measures. These studies may implicate caffeine (and other stimulants) in motor problems of the elderly (specifically falling) that involve BZs and are not reducible to BZ sedative action. The behavioral and pharmacologic generality of BZ-xanthine synergism will be characterized. (3) The behavioral implications of the increase in apparent clearance of serum caffeine that results from chronic exposure to midazolam will be explored with the possibility that part of the BZ discontinuance syndrome may be attributable to caffeinism. (4) Clarification of the acute and chronic pharmacokinetics of BZ-stimulant combinations will parallel behavioral studies in the delineation of the mechanism of BZ-xanthine synergism. (5) There will be study of a alprazolam-caffeine interactions for a possible synergistic disruption of fine-motor control, which might be relevant to triggering or worsening panic disorder. Also, the effect of BZs on theophylline's behavioral effects will be noted in relation to tremor produced by therapeutic doses of theophylline, particularly by the oral route.
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