Gamma-Hydroxybutyrate (GHB) is a naturally occurring metabolite of gamma-amino butyric acid (GABA) which has many properties indicating that it may be a neurotransmitter or neuromodulator. Also, this compound has the ability to produce absence-like seizure activity when given to animals. This renewal will seek to answer two fundamental questions about this phenomenon: 1. How does GHB produce petit mal-like seizures? 2. How does GABA exacerbate the GHB model and, for that matter, all models of generalized absence seizures? The data generated in the previous grant period suggest that these two questions intersect at the point of GHB-GABA interaction in the brain. This proposal therefore focuses upon the relationship between GHB and GABA and upon GABAergic mechanisms in the GHB model of absence seizures. As a means of addressing the above questions, a series of experiments are proposed to test the following four hypotheses: 1. GHB interacts with the GABA system at the postsynaptic level via the GABA/benzodiazepine/picrotoxinin (GABA/Bdz/Pctxn) chloride ionophore. II. GHB and GABA interact at the presynaptic level in brain. III. GHB-induced generalized absence-like seizures are caused by significant changes in the GHB and GABA systems, IV. The same perturbations of the GHB and GABAergic systems in brain that occur during the GHB-induced seizure are seen also in another model of petit mal, the pentylenetetrazole (PTZ) model. A variety of biochemical and pharmacological techniques will be used to assess the effect of GHB on binding, uptake, release, and turnover in the GABA system and vice versa in various brain regions both in vitro as well as at the onset of the PTZ induced, and various stages of the GHB-induced seizure state in the adult and developing animal. These studies have the potential clarify further the role of GHB in brain by defining the relationship or GHB to GABA, and to elucidate the basic underlying neurochemical mechanisms of generalized absence seizures.
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