This is a proposal to renew an ongoing, productive human laboratory research project directed toward identification and development of medications for treatment of cocaine dependence. The project has developed and will use an efficient and sensitive human laboratory screening procedure to assess the effects of potential pharmacotherapeutic approaches. The goal is to identify medications that modulate the abuse liability of cocaine or craving for cocaine. Within a residential laboratory volunteer experienced cocaine abusers will be challenged with intravenous cocaine. Challenge sessions consist of a series of ascending doses of i.v. cocaine at one-hr intervals, yielding a dose-effect characterization of the profile and time course of cocaine's subjective and physiological effects. Potential pharmacotherapies are evaluated by superimposing the cocaine challenge test procedure on a schedule of chronic ascending-dose administration (and then discontinuation) of the potential pharmacotherapy -- yielding a dose-effect characterization of the effects of the pharmacotherapy alone, and of its modulation of or interaction with the cocaine response. Medications that alter cocaine response may have potential as anti-cocaine pharmacotherapies, or may help identify mechanisms relevant to developing such pharmacotherapies. Assessment will be multidimensional, including subjective, behavioral, and physiological. Intensive electrocardiologic recordings will assess for potential cardiologic effects relevant to safety of the test medications, including disturbances of autonomic balance as indicated by heart rate variability indices. Potential pharmacotherapeutic approaches to be tested include: oral cocaine (testing the feasibility of an agonist-substitution approach to cocaine dependence pharmacotherapy); the neuroleptic and dopamine partial agonist (+)UH232; the serotonergic agent tryptophan; a dopamine D-1 antagonist; a blocker of cocaine binding at the dopamine transporter; the combination of phentermine and fenfluramine, which combines dopaminergic and serotonergic activities; and/or other promising agents that become available for human testing during the term of this project. These studies will provide valuable data concerning both the safety and the potential efficacy of the tested pharmacotherapies alone and in combination with cocaine. This may be an efficient procedure for identifying pharmacotherapies sufficiently promising to warrant outpatient therapeutic trials. By testing in the laboratory some pharmacotherapies that also receive outpatient clinical trial evaluation, this project will help to address the relative merits of human laboratory studies versus outpatient clinical trials as strategies for drug abuse medications development research.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA005196-12S1
Application #
6027755
Study Section
Human Development Research Subcommittee (NIDA)
Project Start
1987-09-30
Project End
2002-12-31
Budget Start
1999-01-15
Budget End
1999-12-31
Support Year
12
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Donny, Eric C; Bigelow, George E; Walsh, Sharon L (2006) Comparing the physiological and subjective effects of self-administered vs yoked cocaine in humans. Psychopharmacology (Berl) 186:544-52
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Donny, Eric C; Bigelow, George E; Walsh, Sharon L (2004) Assessing the initiation of cocaine self-administration in humans during abstinence: effects of dose, alternative reinforcement, and priming. Psychopharmacology (Berl) 172:316-23
Donny, Eric C; Bigelow, George E; Walsh, Sharon L (2003) Choosing to take cocaine in the human laboratory: effects of cocaine dose, inter-choice interval, and magnitude of alternative reinforcement. Drug Alcohol Depend 69:289-301
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Nann-Vernotica, E; Donny, E C; Bigelow, G E et al. (2001) Repeated administration of the D1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine. Psychopharmacology (Berl) 155:338-47
Spanbauer, A C; Moody, D E; Foltz, R L et al. (2000) A gas chromatographic-positive ion chemical ionization-mass spectrometric method for determination of cocaine, benzoylecgonine, ecgonine methyl ester, and norcocaine in plasma: detection of norcocaine in plasma after oral administration of cocaine. J Anal Toxicol 24:453-5
Walsh, S L; Haberny, K A; Bigelow, G E (2000) Modulation of intravenous cocaine effects by chronic oral cocaine in humans. Psychopharmacology (Berl) 150:361-73
Stitzer, M L; Walsh, S L (1997) Psychostimulant abuse: the case for combined behavioral and pharmacological treatments. Pharmacol Biochem Behav 57:457-70
Preston, K L; Sullivan, J T; Strain, E C et al. (1996) Enhancement of cocaine's abuse liability in methadone maintenance patients. Psychopharmacology (Berl) 123:15-25

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