Effects of blocking GABA degradation on corticotropin-releasing hormone gene expression in selected brain regions.
OBJECTIVE
The gamma-aminobutyric acid (GABA) degradation blocker gamma-vinyl-GABA (VGB) is used clinically to treat seizures in both adult and immature individuals. The mechanism by which VGB controls developmental seizures is not fully understood. Specifically, whether the anticonvulsant properties of VGB arise only from its elevation of brain GABA levels and the resulting activation of GABA receptors, or also from associated mechanisms, remains unresolved. Corticotropin-releasing hormone (CRH), a neuropeptide present in many brain regions involved in developmental seizures, is a known convulsant in the immature brain and has been implicated in some developmental seizures. In certain brain regions, it has been suggested that CRH synthesis and release may be regulated by GABA. Therefore we tested the hypothesis that VGB decreases CRH gene expression in the immature rat brain, consistent with the notion that VGB may decrease seizures also by reducing the levels of the convulsant molecule, CRH.


METHODS
VGB was administered to immature, 9-day-old rats in clinically relevant doses, whereas littermate controls received vehicle.


RESULTS
In situ hybridization histochemistry demonstrated a downregulation of CRH mRNA levels in the hypothalamic paraventricular nucleus but not in other limbic regions of VGB-treated pups compared with controls. In addition, VGB-treated pups had increased CRH peptide levels in the anterior hypothalamus, as shown by radioimmunoassay.


CONCLUSIONS
These findings are consistent with a reduction of both CRH gene expression and secretion in the hypothalamus, but do not support an indirect anticonvulsant mechanism of VGB via downregulation of CRH levels in limbic structures. However, the data support a region-specific regulation of CRH gene expression by GABA.
Tran
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Department of Pediatrics, University of California at Irvine, 92697-4475, USA.
Hatalski
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CG
Yan
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Baram
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TZ
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000679:Amygdala / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D015870:Gene Expression; D007031:Hypothalamus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology
D012333:RNA, Messenger; D005680:gamma-Aminobutyric Acid; D003346:Corticotropin-Releasing Hormone; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin