Cocaine abuse and dependence continue to be significant public health concerns. The number of Americans that used cocaine in the past month, the percentage of 12th-, 10th- and 8th-graders that used cocaine in the past year, and the percentage of treatment admissions involving cocaine has remained stable in recent years. In 1996, cocaine use cost society over $45 billion due to medical consequences, lost productivity and crime. Because of the public-health concerns and costs associated with its abuse, identifying a pharmacotherapy for cocaine dependence is a priority with the National Institute on Drug Abuse (N.I.D.A.). A pharmacological adjunct for cocaine dependence has not yet been identified. The results of clinical trials suggest that agonist replacement therapies (e.g., d-amphetamine) may be effective for cocaine dependence. Because cf-amphetamine reduces cocaine use, these clinical findings can be used as a reference to identify human laboratory procedures for screening putative pharmacotherapies. Identifying procedures for assessing the efficacy ofputative pharmacotherapies is important because human laboratory studies can be conducted more rapidly/and/efficiently than clinical trials. The present project has two specific aims. The first specific aim is to demonstrate the sensitivity and predictive validity of human laboratory procedures commonly used to screen putative pharmacotherapies for cocaine dependence. To accomplish this aim, we will conduct two """"""""proof-of- concept"""""""" studies. We will first demonstrate the safety and tolerability of d-amphetamine-cocaine combinations (Exp. 1). We will then 'demonstrate that d-amphetamine maintenance attenuates the reinforcing effects of cocaine (Exp. 2). The ability to attenuate the reinforcing effects of cocaine may be an important characteristic of an effective pharmacotherapy. The results of these studies will help elucidate the optimal conditions (e.g., dose) under which d-amphetamine might be expected to be effective. The second specific aim is to determine the efficacy of atomoxetine (Strattera?) as a putative agonist replacement pharmacotherapy for cocaine dependence. To accomplish this aim, we will conduct two experiments to determine the effects of cocaine during atomoxetine maintenance. We will first demonstrate the safety and tolerability of atomoxetine-cocaine combinations (Exp. 3). Finally, we will determine the reinforcing effects of intranasal cocaine during atomoxetine maintenance (Exp. 4). Atomoxetine, a potent norepinephrine uptake blocker, was chosen for study because its pharmacological and behavioral effects overlap to some extent with those of d-amphetamine, but it appears to have less abuse potential. Identifying novel agonist replacement therapies is important because clinicians may be reluctant to use d-amphetamine because of its abuse potential.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA021155-03
Application #
7390340
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Oversby, Steven
Project Start
2006-06-01
Project End
2010-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$348,516
Indirect Cost
Name
University of Kentucky
Department
Psychology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Reynolds, Anna R; Bolin, B Levi; Stoops, William W et al. (2013) Relationship between drug discrimination and ratings of subjective effects: implications for assessing and understanding the abuse potential of D-amphetamine in humans. Behav Pharmacol 24:523-32
Stoops, William W; Rush, Craig R (2013) Agonist replacement for stimulant dependence: a review of clinical research. Curr Pharm Des 19:7026-35
Bolin, B Levi; Reynolds, Anna R; Stoops, William W et al. (2013) Relationship between oral D-amphetamine self-administration and ratings of subjective effects: do subjective-effects ratings correspond with a progressive-ratio measure of drug-taking behavior? Behav Pharmacol 24:533-42
Stoops, William W; Lile, Joshua A; Glaser, Paul E A et al. (2012) Alternative reinforcer response cost impacts cocaine choice in humans. Prog Neuropsychopharmacol Biol Psychiatry 36:189-93
Rush, Craig R; Stoops, William W (2012) Agonist replacement therapy for cocaine dependence: a translational review. Future Med Chem 4:245-65
Stanley, Matthew D; Poole, Mégan M; Stoops, William W et al. (2011) Amphetamine self-administration in light and moderate drinkers. Alcohol Clin Exp Res 35:443-53
Vansickel, Andrea R; Stoops, William W; Rush, Craig R (2010) Human sex differences in d-amphetamine self-administration. Addiction 105:727-31
Herin, David V; Rush, Craig R; Grabowski, John (2010) Agonist-like pharmacotherapy for stimulant dependence: preclinical, human laboratory, and clinical studies. Ann N Y Acad Sci 1187:76-100
Rush, Craig R; Stoops, William W; Hays, Lon R (2009) Cocaine effects during D-amphetamine maintenance: a human laboratory analysis of safety, tolerability and efficacy. Drug Alcohol Depend 99:261-71
Stoops, William W; Blackburn, John W; Hudson, David A et al. (2008) Safety, tolerability and subject-rated effects of acute intranasal cocaine administration during atomoxetine maintenance. Drug Alcohol Depend 92:282-5

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