A drug's abuse liability is an interactive function of its liability for abuse (i.e., it functions as reinforcer and maintains self-administration) and its liability of abuse (i.e., it produces adverse effects such as impaired performance and dependence). Benzodiazepines are among the most widely prescribed psychoactive drugs. While their abuse liability is low compared to other drugs of abuse, there is sufficient evidence documenting that benzodiazepines have some liability for abuse as well as significant liability of abuse. Moreover, various benzodiazepines, and benzodiazepine- like compounds, may differ in terms of their abuse. Moreover, various benzodiazepines, and benzodiazepine-like compounds, may differ in terms of their abuse liability. For example many clinicians believe high-potency benzodiazepine hypnotics, like triazolam, have a greater abuse liability than low-potency benzodiazepine hypnotics, like temazepam and flurazepam. Novel compounds like zolpidem may also have less abuse liability. This application consists of 5 laboratory experiments that aim to comprehensively assess the abuse liability of triazolam, a high potency benzodiazepine hypnotic; temazepam, a low-potency benzodiazepine hypnotic; and zolpidem, a novel imidazopyridine hypnotic that has a unique CNS binding profile. Experiments 103 will determine th abuse liability of these hypnotics in insomniacs (Exp. 1), elderly volunteers (Exp.2), and volunteers with a history of sedative abuse (Exp. 3) in order to begin to identify individuals in which the use of certain hypnotics may pose greater risks. Triazolam, temazepam and zolpidem will be administered chronically in Exp. 4 to determine if tolerance develops differentially. Determining whether tolerance develops differentially is important since it may lead to dose escalation and increased risk of dependence. Finally, Exp. 5 will determine if alcohol differentially exacerbates the deleterious effects of triazolam, temazepam and zolpidem. Determining differential interactions with alcohol is important since combining alcohol and hypnotics increases the magnitude of behavioral impairment, thereby increasing the risk to the individual and society. We propose to use insomniacs in Exp. 4 an 5, but elderly or drug abusing volunteers will be used if interesting between-drug differences are observed with these subject populations in Exp. 2 and 3. In addition to practical clinical information, testing a wide range of doses in these studies will begin to determine whether there are meaningful differences between the dose-response functions of high- and low- potency benzodiazepines. Including zolpidem, which has a unique CNS benzodiazepine-receptor binding profile relative to benzodiazepine hypnotics, will provide information concerning a drug's neuropharmacology and abuse liability. During the next several years, other compounds that have unique pharmacological profiles will become available for testing in human behavioral pharmacology studies. The availability of these drugs will allow the relationship between neuropharmacology and abuse liability to be further explored in various human populations. Thus, this FIRST Award will sere as a foundation for future R01 applications to study sedative hypnotic compounds with unique neuropharmacological profiles.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Special Emphasis Panel (SRCD (26))
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Lynch, Minda
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University of Kentucky
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United States
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Vansickel, Andrea R; Hays, Lon R; Rush, Craig R (2006) Discriminative-stimulus effects of triazolam in women and men. Am J Drug Alcohol Abuse 32:329-49
Stoops, William W; Rush, Craig R (2003) Differential effects in humans after repeated administrations of zolpidem and triazolam. Am J Drug Alcohol Abuse 29:281-99
Rush, Craig R; Kelly, Thomas H; Fillmore, Mark T et al. (2003) Discriminative-stimulus effects of triazolam in light and moderate drinkers. Alcohol Clin Exp Res 27:638-46
Simpson, Cathy A; Rush, Craig R (2002) Acute performance-impairing and subject-rated effects of triazolam and temazepam, alone and in combination with ethanol, in humans. J Psychopharmacol 16:23-34
Fillmore, M T; Rush, C R; Kelly, T H et al. (2001) Triazolam impairs inhibitory control of behavior in humans. Exp Clin Psychopharmacol 9:363-71
Fillmore, M T; Kelly, T H; Rush, C R et al. (2001) Retrograde facilitation of memory by triazolam: effects on automatic processes. Psychopharmacology (Berl) 158:314-21
Rush, C R; Baker, R W; Rowlett, J K (2000) Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans. Exp Clin Psychopharmacol 8:22-36
Rush, C R; Ali, J A (1999) A follow-up study of the acute behavioral effects of benzodiazepine-receptor ligands in humans: comparison of quazepam and triazolam. Exp Clin Psychopharmacol 7:257-65
Rush, C R; Baker, R W; Wright, K (1999) Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans. Psychopharmacology (Berl) 144:220-33
Rush, C R (1998) Behavioral pharmacology of zolpidem relative to benzodiazepines: a review. Pharmacol Biochem Behav 61:253-69

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