ONTOGENY OF GABA A RECEPTOR COMPLEX MEASURED WITH PET

Wayne State University, Detroit MI

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Abstract

DESCRIPTION: (Adapted from the applicant's Description) The overall aim of this application is to determine in vivo age-related changes of the GABAA receptor complex in children. A knowledge of GABAA receptor ontogeny is relevant in understanding the efficacy of pharmacological agents which bind to the GABAA receptor complex, as well as agents which alter brain GABA concentration. Changes in whole brain distribution of the GABAA receptor complex in vivo will be measured in children with epilepsy by applying positron emission tomography (PET) using the tracer [C-11]flumazenil (FMZ), a benzodiazepine antagonist which binds to the alpha subunit of the GABAA receptor complex. The studies are designed to extract normative data from FMZ PET studies being performed on epileptic children under evaluation for surgical treatment, since ethical guidelines prohibit the study of normal children with PET. Specific Aim 1 will determine the changes in brain values for FMZ volume of distribution (VD) with age in children with partial (focal) epilepsy. Specific Aim 2 will determine the effects of vigabatrin, an anticonvulsant which increases brain GABA levels, on values for FMZ VD with age in children with partial epilepsy. Specific Aim 3 will determine differences in the regional pattern of FMZ VD in the hemisphere contralateral to the epileptic focus in children with partial epilepsy as compared to normal adults. The hypotheses to be tested will increase our understanding of the ontogeny of the human GABA alpha receptor complex. In addition, these experiments will improve our understanding of how changes in GABA alpha receptors with age might affect the pharmacology of anitconvulsants, as well as the pharmacology of other therapeutic drugs and drugs of abuse acting at this receptor complex. Our studies will facilitate the application of PET studies of GABA alpha receptors in other pediatric patient groups, such as adolescents with alcohol abuse. For example, should we confirm our preliminary finding that the regional pattern of FMZ VD in children over 6 years of age does not differ from that in adults, this would facilitate the use of adult control subjects for analysis of regional differences of GABA alpha receptors in various pediatric disorders using statistical parametric mapping (SPM).