Based on preclinical data, benzodiazepine (BZ) receptor alterations appear to be involved in both benzodiazepine dependence and cocaine abuse. Despite these data, we are unaware of any studies investigating BZ receptor alterations related to benzodiazepine dependence or cocaine abuse in human subjects. Over the past few years, our group has performed a series of careful BZ receptor brain imaging studies using the SPECT (single photon emission computed tomography) receptor ligand [123I]iomazenil in rodent, nonhuman primate, and human subjects - culminating in the demonstration that BZ receptor binding using this technique is quantifiable and reliable. These preliminary data, coupled with our group's extensive experience in clinical substance abuse studies, place us in a strong position to conduct the proposed studies of human BZ receptor alterations related to benzodiazepine use. The goals of this application are to determine whether the phenomena of BZ receptor downregulation, upregulation, and normalization occur in human subjects and whether these changes are associated with behavioral measurements of tolerance and withdrawal.
Aim #1 asks whether cortical BZ receptors are reduced during chronic benzodiazepine administration in human subjects. In the proposed study, a total of 25 healthy human subjects with a past history of casual benzodiazepine use but no history of substance abuse or dependence will be administered alprazolam 2 mg/d as outpatients. Equilibrium BZ receptor imaging using the SPECT receptor ligand [123I]iomazenil will be performed prior to alprazolam administration and again after 2 and 23 days treatment Comparison of the scans at baseline and after 2 days treatment will provide a measure of receptor occupancy caused by alprazolam. Comparison of scans at 2 and 23 days will provide a measure of receptor downregulation induced by chronic treatment. In addition, the first 10 subjects will be used to gather preliminary data on the time course of receptor downregulation and receive SPECT scans before and several times during alpraolam administration (2, 9, 16 and 23 days).
Aim #2 asks whether cortical BZ receptors increase during benzodiazepine abstinence in human subjects. In the proposed study, 25 patients with a history of daily chronic BZ use will be admitted to a NIDA funded inpatient research ward and stabilized on alprazolam 4 mg/d. Alprazolam will then be blindly discontinued by substitution of placebo. Equilibrium iomazenil imaging will be performed 2 and 23 days after alprazolam discontinuation. We predict that BZ receptors measured at 2 days will be upregulated (relative to baseline healthy subject values in Aim #1) and will decrease towards normal values on day 23. In addition, the first 10 subjects will be used to gather preliminary data on the time course of these changes and receive SPED scans at 2, 9, 16 and 23days.
| Fujita, M; Woods, S W; Verhoeff, N P et al. (1999) Changes of benzodiazepine receptors during chronic benzodiazepine administration in humans. Eur J Pharmacol 368:161-72 |
