There is concern about the abuse and long term use of benzodiazepine anxiolytic/hypnotic drugs by polydrug abusers and patients. One of the most insidious adverse effects of benzodiazepines is a profound impairment in the ability to form memories of personally experienced events (episodic memory encoding). This project will characterize the changes in brain activity reliably associated with benzodiazepine-induced impairment of episodic memory encoding by parametrically manipulating the level of impairment, and will examine the pharmacological and neurochemical mechanisms underlying these changes. Three double blind, placebo-controlled, within-subject outpatient studies in healthy volunteers are proposed, employing well-established methods in cognitive neuroscience. Following acute drug administration, brain activity associated with performance of a verbal episodic memory encoding task will be measured by regional cerebral blood flow (rCBF) using positron emission tomography (PET) with 15O-H20. Experiment 1 will manipulate the level of encoding impairment via administration of three dose levels of the benzodiazepine hypnotic triazolam. Experiment 2 will manipulate the level of encoding impairment via conjoint administration of triazolam and the benzodiazepine receptor specific antagonist flumazenil, which has been shown to reverse benzodiazepine-induced amnesia; this experiment will also provide information about the pharmacological mechanisms underlying benzodiazepine-induced changes in rCBF during encoding. Experiment 3 will provide information about the neurochemical specificity of benzodiazepine-induced changes in rCBF during encoding by comparing the pattern of rCBF changes produced by triazolam to that produced by scopolamine, a compound which induces comparable decrements in episodic memory encoding but which acts via different receptor site/neurochemical mechanisms. Results of this project will enhance the understanding of the brain mechanisms underlying a serious adverse effect of a widely prescribed and abused class of drugs. Ultimately, data from this research may contribute to the development of new classes of anxiolytic/hypnotic compounds with reduced memory impairing potential, as well as compounds which act to reverse the memory-impairing effects of benzodiazepines. Results of the proposed research also will enhance the understanding of the functional neuroanatomy of basic human memory processes.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA014101-02
Application #
6523320
Study Section
Special Emphasis Panel (ZDA1-MXV-P (04))
Program Officer
Schnur, Paul
Project Start
2001-09-30
Project End
2004-07-31
Budget Start
2002-08-01
Budget End
2003-07-31
Support Year
2
Fiscal Year
2002
Total Cost
$327,000
Indirect Cost
Name
Johns Hopkins University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Mintzer, Miriam Z; Kuwabara, Hiroto; Alexander, Mohab et al. (2006) Dose effects of triazolam on brain activity during episodic memory encoding: a PET study. Psychopharmacology (Berl) 188:445-61