(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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA003117-13
Application #
2116697
Study Section
Drug Abuse Clinical and Behavioral Research Review Committee (DACB)
Project Start
1982-01-15
Project End
1997-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
13
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Rutgers University
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Lau, C E; Sun, L; Wang, Q et al. (2002) The effect of zolpidem on operant behavior and its relation to pharmacokinetics after intravenous and subcutaneous administration: concentration-effect relations. Behav Pharmacol 13:93-103
Simpao, A; Sun, L; Falk, J L et al. (2001) Spontaneous activity as a contingency-controlled behavior within an operant context: alprazolam concentration-effect relations after subcutaneous administration in rats. Psychopharmacology (Berl) 155:269-77
Lau, C E; Wang, Y; Sun, L et al. (2001) Negligible tolerance produced by chronic intravenous alprazolam administration: a low serum drug concentration effect. Exp Clin Psychopharmacol 9:110-6
Sun, L; Lau, C E (2000) Intravenous and oral clozapine pharmacokinetics, pharmacodynamics, and concentration-effect relations: acute tolerance. Eur J Pharmacol 398:225-38
Lobarinas, E; Falk, J L (2000) Comparison of benzodiazepines and the non-benzodiazepine agents zolpidem and zaleplon with respect to anxiolytic action as measured by increases in hypertonic NaCl-solution drinking in rats. Psychopharmacology (Berl) 149:176-80
Sun, L; Falk, J L; Nguyen, K N et al. (2000) Post-injection delays in experimental chambers, but not in home cages, produce both sensitization and tolerance of operant behaviour to midazolam: relation to pharmacokinetics. Behav Pharmacol 11:133-42
Wang, Y; Roy, A; Sun, L et al. (1999) A double-peak phenomenon in the pharmacokinetics of alprazolam after oral administration. Drug Metab Dispos 27:855-9
Wang, Q; Sun, L; Lau, C E (1999) Determination of zolpidem in serum microsamples by high-performance liquid chromatography and its application to pharmacokinetics in rats. J Chromatogr B Biomed Sci Appl 734:299-305
Smith, C; Ma, F; Lau, C E (1999) Dose independent pharmacokinetics of caffeine after intravenous administration under a chronic food-limited regimen. Drug Metabol Drug Interact 15:83-96
Lobarinas, E; Falk, J L (1998) Schedule-induced polydipsic consumption of hypertonic NaCl solutions: effects of chlordiazepoxide. Physiol Behav 63:419-23

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