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 GHB.
The ventrobasal nucleus of thalamus (VB) is considered to be intimately involved in the genesis of experimental absence-like seizures. Bilateral microinfusion of gamma-hydroxybutyric acid (GHB) into VB or systemic administration of gamma-butyrolactone, the pro-drug of GHB, induces generalized absence-like seizures in rats. In the present study, the basal and K(+)-evoked extracellular output of endogenous gamma-aminobutyric acid (GABA) and glutamate (GLU) in behaving rat VB nucleus was characterized 1) during unilateral GHB perfusion into VB and 2) during the course of generalized absence-like seizures induced by GHB. Although the basal extracellular release of GABA was inhibited by GHB (250-1500 microM) in a concentration-dependent manner, basal GLU levels remained unaltered. However, K(+)-evoked release of both GABA and GLU was significantly attenuated by GHB. During GHB-induced absence-like seizures, a similar decrease in basal GABA or K(+)-evoked GABA and GLU levels was observed. These effects of GHB were partially reversed by the specific GHB receptor antagonist NCS 382. (-)-Baclofen (10-50 microM) also produced a concentration-dependent decrease in basal and K(+)-evoked levels of GABA and GLU in this thalamic nucleus. The effects of either (-)-baclofen or GHB on the release of GABA and GLU were selectively antagonized by the GABAB receptor antagonists phaclofen (0.75-2 mM) and CGP 35348 (50-200 microM), respectively. These results suggest that by selectively modulating the basal and K(+)-evoked release of GABA and GLU, GHB induces, in the thalamic ventrobasal relay nucleus, an optimal "excitatory" environment conducive to the generation of absence seizures. Moreover, the data raise the possibility that a presynaptic GHB/GABAB receptor complex occurs in VB.
Banerjee
P K
PK
Department of Neurology, University of Southern California School of Medicine, Los Angeles, USA.
Snead
O C
OC
D000200:Action Potentials; D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D004832:Epilepsy, Absence / Q000139:chemically induced*; D005110:Extracellular Space / Q000378:metabolism; D058788:GABA-B Receptor Antagonists; D018698:Glutamic Acid / Q000378:metabolism*; D008297:Male; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011188:Potassium / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000378:metabolism; D018080:Receptors, GABA-B / Q000378:metabolism; D012978:Sodium Oxybate / Q000633:toxicity*; D013787:Thalamic Nuclei / Q000378:metabolism* / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
C039403:4-hydroxybutyric acid receptor; D058788:GABA-B Receptor Antagonists; D009943:Organophosphorus Compounds; D011956:Receptors, Cell Surface; D018080:Receptors, GABA-B; C052329:phaclofen; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D012978:Sodium Oxybate; C066430:CGP 35348; D001418:Baclofen; D011188:Potassium