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Cellular compartments of GABA in brain and their relationship to anticonvulsant activity

  • Chapter
The Biological Effects of Glutamic Acid and Its Derivatives

Part of the book series: Developments in Molecular and Cellular Biochemistry ((DMCB,volume 1))

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Summary

The effects of GABA-elevating agents were examined with respect to the cellular compartments in which GABA increases occurred and the brain region(s) that mediate the anticonvulsant activity of these compounds. Changes in GABA occurring in the presence and absence of GABAergic nerve terminals were estimated in vivo using rats in which the GABA projection to the substantia nigra (SN) was destroyed on one side of the brain. One week post-operatively, the GABA concentration in the denervated SN was 10–20% of control. The net increase in GABA content of the denervated SN was compared to that of the intact SN after intraperitoneal injection of amino-oxacetic acid (AOAA), di-n-propylacetate (DPA) and γ-vinyl GABA (GVG). In the intact SN, all drugs produced significant increases in GABA. In the denervated SN, both AOAA and GVG produced marked increases in GABA (nearly equivalent to those obtained in the intact SN) whereas DPA was without effect. It therefore appears that the DPA-induced elevation of GABA depends upon the presence of GABAergic nerve terminals whereas AOAA and GVG primarily elevate GABA in non-nerve terminal compartments. An increase in GABA associated with nerve terminals was obtained with GVG only after a latency of more than 12 h following a single injection. The time course of elevation of nerve terminal-associated GABA coincided with the time course of anticonvulsant action of GVG; both effects were maximal at 60 h after a single injection. Taken together, our results indicate that the ability of DPA, AOAA and GVG to protect against chemically- and electrically-induced seizures is directly correlated with increases in nerve terminal GABA and not related to increases in other GABA compartments.

Localization of the anatomical site that mediates anticonvulsant activity was examined using intracerebral injections of GVG into fore-, mid- and hindbrain areas. Blockade of tonic hindlimb extension in the maximal electroshock test and blockade of tonic and clonic seizures produced by pentylenetetrazol and bicuculline was obtained by microinjection of GVG (10 µg) into the ventral tegmental area of the midbrain. Injections of GVG (10–40 /µg) into forebrain areas (striatum, thalamus) or into hindbrain (pontine tegmentum) were without anticonvulsant activity. Anticonvulsant effects of midbrain GVG were correlated with GABA elevation (3–4 fold) within a 1.5 mm radius of the injection site; these effects were obtained within 6 h and lasted three to four days after a single treatment. After four days seizure activity returned to control. No changes in spontaneous motor activity or reflexes accompanied the GVG injections. Similar but shorter lasting anticonvulsant effects were obtained with the direct GABA receptor agonist muscimol (50 ng) injected into the midbrain site. On the other hand, doses of muscimol up to 500 ng placed in the rostral pontine tegmentum were without anticonvulsant effect, despite the appearance of marked sedation.

The time to peak anticonvulsant activity after midbrain microinjection of GVG (6 h) was considerably more rapid than that after intraperitoneal injection (60 h). Compartmental analysis revealed that nerve terminal associated GABA was elevated by 6 h after GVG when the direct microinjection route was used. These results suggest that GABAergic synapses in the midbrain may be critically involved in the control of seizure propagation.

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Author notes

  1. Michael J. Iadarola

    Present address: Duke VA Neurology Research Laboratory, VA Hospital, Durham, NC, USA

Authors and Affiliations

  1. Dept. of Pharmacology, Georgetown University Schools of Medicine and Dentistry, Washington, D.C., USA

    Michael J. Iadarola & Karen Gale

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  1. Michael J. Iadarola
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  2. Karen Gale
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V. A. Najjar

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© 1981 Martinus Nijhoff/Dr W. Junk Publishers, The Hague

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Iadarola, M.J., Gale, K. (1981). Cellular compartments of GABA in brain and their relationship to anticonvulsant activity. In: Najjar, V.A. (eds) The Biological Effects of Glutamic Acid and Its Derivatives. Developments in Molecular and Cellular Biochemistry, vol 1. Springer, Dordrecht. https://doi.org/10.1007/978-94-009-8027-3_20

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  • DOI: https://doi.org/10.1007/978-94-009-8027-3_20

  • Publisher Name: Springer, Dordrecht

  • Print ISBN: 978-94-009-8029-7

  • Online ISBN: 978-94-009-8027-3

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