/ABTRACT Methamphetamine dependence is a significant public-health concern. Dopamine plays a prominent role in mediating the behavioral effects of methamphetamine. -Aminobutyric-acid (GABA) systems inhibit dopamine systems. Increasing GABA activity may result in greater inhibition of dopamine systems and thus attenuate the behavioral effects of methamphetamine thought to contribute to its abuse. Preclinical and human laboratory experiments have demonstrated that high-efficacy GABAA receptor modulators attenuate the behavioral effects of stimulants under a variety of behavioral arrangements. These findings suggest that GABAA receptor modulation might be a viable target for the development of medications to manage methamphetamine abuse. The overarching goal of this application is to demonstrate targeting GABAA receptor modulation is a viable strategy for the development of medications to manage methamphetamine dependence. This goal will be achieved through the conduct of two "proof-of-concept" experiments designed to accomplish two specific aims. The first specific aim is to demonstrate that a GABAA receptor modulator attenuates the reinforcing effects of methamphetamine. To accomplish this aim, we will determine the reinforcing effects of intranasal methamphetamine during maintenance on a high-efficacy GABAA receptor modulator using a progressive-ratio procedure (Exp. 1). The reinforcing effects of stimulants are central to their abuse potential. By inference, then, an effective pharmacotherapy for managing stimulant dependence will modify drug self-administration. The second specific aim is to demonstrate that a GABAA receptor modulator attenuates the discriminative-stimulus effects of methamphetamine. To accomplish this aim, we will teach volunteers to discriminate intranasal methamphetamine using a drug-discrimination procedure (Exp. 2). A range of doses of methamphetamine will then be tested during maintenance on a GABAA receptor modulator and placebo. The discriminative effects of methamphetamine may be involved in relapse to drug-taking behavior in that an initial dose (i.e., a lapse) may function as a discriminative stimulus signaling the availability of more drug. Pharmacotherapies that attenuate the discriminative-stimulus effects of methamphetamine may be effective for preventing relapse. The proposed research will provide initial clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications for methamphetamine abuse. In addition to the clinical information, the proposed research will provide basic-science and translational information. First, the inclusion of drug self-administration and discrimination measures, along with subjective-effect questionnaires, will provide information concerning the relationship between the reinforcing, discriminative and subjective effects of methamphetamine. Second, because GABAA receptor modulators have been tested as pharmacotherapies for stimulant dependence in laboratory animals using similar behavioral procedures, the proposed research will determine, albeit indirectly, the extent that findings from preclinical studies generalize to humans. PROJECTIVE NARRATIVE Methamphetamine dependence is a significant public health concern. The proposed research will provide important clinical information regarding the viability of targeting GABAA receptor modulation for the development of medications to manage methamphetamine dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA025591-04
Application #
8235917
Study Section
Special Emphasis Panel (ZDA1-MXH-H (22))
Program Officer
Hampson, Aidan
Project Start
2008-09-15
Project End
2013-06-28
Budget Start
2012-03-01
Budget End
2013-06-28
Support Year
4
Fiscal Year
2012
Total Cost
$351,710
Indirect Cost
$111,635
Name
University of Kentucky
Department
Psychology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Marks, Katherine R; Roberts, Walter; Stoops, William W et al. (2014) Fixation time is a sensitive measure of cocaine cue attentional bias. Addiction 109:1501-8
Pike, Erika; Stoops, William W; Hays, Lon R et al. (2014) Methamphetamine self-administration in humans during D-amphetamine maintenance. J Clin Psychopharmacol 34:675-81
Marks, Katherine R; Pike, Erika; Stoops, William W et al. (2014) Test-retest reliability of eye tracking during the visual probe task in cocaine-using adults. Drug Alcohol Depend 145:235-7
Marks, Katherine R; Lile, Joshua A; Stoops, William W et al. (2014) Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users. Psychopharmacology (Berl) 231:2741-50
Pike, Erika; Stoops, William W; Fillmore, Mark T et al. (2013) Drug-related stimuli impair inhibitory control in cocaine abusers. Drug Alcohol Depend 133:768-71
Lile, Joshua A; Stoops, William W; Glaser, Paul E A et al. (2011) Physiological and subjective effects of acute intranasal methamphetamine during extended-release alprazolam maintenance. Drug Alcohol Depend 119:187-93