EFFECTS OF y-AMINOBUTYRIC ACID AGONIST AND ANTAGONIST DRUGS ON LOCAL CERERR.AL GLUCOSE UTILIZATION1

The [‘“C]%deoxy-D-glucose method of Sokoloff et al. (Sokoloff, L., M. Reivich, C. Kennedy, M. H. Des Rosiers, C. S. Patlak, K. D. Pettigrew, 0. Sakurada, and M. Shinohara (1977) J. Neurochem. 28: 897-916) was used to study local cerebral glucose utilization (LCGU) in rats treated with yaminobutyric acid (GABA) agonist (muscimol and 4,5,6,7-tetrahydroisoxazolo[5,4-Clpyridin-3-01, THIP) and antagonist (bicuculline) drugs. It was of interest to determine if the pattern of LCGU responses to GABA agonists and antagonists administered systemically in uiuo would reflect the known distributions of markers for central GABAergic synapses. The patterns of LCGU responses to muscimol and THIP generally were similar. Most brain regions showed dose-dependent decreases in LCGU; others showed no effects; but the red nucleus showed an increase. The GABA antagonist bicuculline produced convulsions and variable LCGU responses, depending on the time of administration. Bicuculline also partially antagonized the depressant effects of muscimol on LCGU. The magnitudes and distribution of in viva cerebral metabolic responses to specific GABA agonists were not correlated simply with markers for GABAergic synapses. This lack of correlation indicates that additional factors, such as neural circuitry, regulate the LCGU responses to GABAergic drugs. y-Aminobutyric acid (GABA), which is considered to be an important neuronal inhibitor, is the neurotransmitter for up to 40% of the neurons in the mammalian nervous system (Bloom and Iversen, 1971). Many aspects of GABA biosynthesis, storage, release, catabolism, and postsynaptic effects are widely documented (Roberts et al., 1976; Krogsgaard-Larsen et al., 1979a). Recent techniques for immunocytochemical localization of the GABA biosynthetic enzyme, L-glutamic acid decarboxylase (Ribak et al., 1979), and for light microscopic localization of high affinity GABA receptors (Palacios et al., 1980, 1981b) have provided considerable information on the distribution of GABAergic synapses. ’ We wish to thank H. Holloway, S. Nespor, P. Mahone, and N. Taylor for excellent technical assistance. Portions of this research were supported by United States Public Health Service Grant DA00266. J. M. P. is the recipient of International Research Fellowship TW02583. M. J. K. is the recipient of Research Career Development Type II Award MH-00053 from the National Institute of Mental Health. ’ Present address: Sandoz, Ltd., Preclinical Research 360/604, Base1