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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS017117-10
Application #
3397355
Study Section
Neurology A Study Section (NEUA)
Project Start
1981-04-01
Project End
1992-06-30
Budget Start
1991-07-31
Budget End
1992-06-30
Support Year
10
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
094878337
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
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Banerjee, P K; Snead 3rd, O C (1995) Presynaptic gamma-hydroxybutyric acid (GHB) and gamma-aminobutyric acidB (GABAB) receptor-mediated release of GABA and glutamate (GLU) in rat thalamic ventrobasal nucleus (VB): a possible mechanism for the generation of absence-like seizures induced by GH J Pharmacol Exp Ther 273:1534-43
Snead 3rd, O C (1995) Basic mechanisms of generalized absence seizures. Ann Neurol 37:146-57
Banerjee, P K; Snead 3rd, O C (1995) Thalamic NMDA receptors in the gamma-hydroxybutyrate model of absence seizures: a cerebral microinjection study in rats. Neuropharmacology 34:43-53
Banerjee, P K; Snead 3rd, O C (1994) Thalamic mediodorsal and intralaminar nuclear lesions disrupt the generation of experimentally induced generalized absence-like seizures in rats. Epilepsy Res 17:193-205

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