Gamma-vinyl GABA increases nonvesicular release of GABA and glutamate in the nucleus accumbens in rats via action on anion channels and GABA transporters.
BACKGROUND
gamma-Amino butyric acid (GABA) is a well-characterized inhibitory neurotransmitter in the central nervous system, which may also stimulate nonvesicular release of other neurotransmitters under certain conditions. We have recently reported that gamma-vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, elevates extracellular GABA but fails to alter dopamine release in the nucleus accumbens (NAc).


OBJECTIVE
Here, we investigated the mechanism(s) by which GVG elevates extracellular GABA levels and whether GVG also alters glutamate release in the NAc.


METHODS
In vivo microdialysis was used to simultaneously measure extracellular NAc GABA and glutamate before and after GVG administration in freely moving rats.


RESULTS
Systemic administration of GVG or intra-NAc local perfusion of GVG significantly increased extracellular NAc GABA and glutamate. GVG-enhanced GABA was completely blocked by intra-NAc local perfusion of 5-nitro-2, 3-(phenylpropylamino)-benzoic acid (NPPB), a selective anion channel blocker and partially blocked by SKF89976A, a type 1 GABA transporter inhibitor. GVG-enhanced glutamate was completely blocked by NPPB or SKF89976A. Tetrodotoxin, a voltage-dependent Na(+)-channel blocker, failed to alter GVG-enhanced GABA and glutamate.


CONCLUSIONS
These data suggest that GVG-enhanced extracellular GABA and glutamate are mediated predominantly by the opening of anion channels and partially by the reversal of GABA transporters. Enhanced extracellular glutamate may functionally attenuate the pharmacological action of GABA and prevent enhanced GABA-induced excess inhibition.
Peng
Xiao-Qing
XQ
Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.
Gardner
Eliot L
EL
Xi
Zheng-Xiong
ZX
D000818:Animals; D004347:Drug Interactions; D058805:GABA Uptake Inhibitors / Q000494:pharmacology*; D018698:Glutamic Acid / Q000378:metabolism*; D007473:Ion Channels / Q000037:antagonists & inhibitors*; D008297:Male; D017551:Microdialysis / Q000379:methods; D008845:Microinjections; D009557:Nipecotic Acids / Q000008:administration & dosage / Q000494:pharmacology; D009579:Nitrobenzoates / Q000008:administration & dosage / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D009435:Synaptic Transmission / Q000187:drug effects; D013572:Synaptic Vesicles / Q000187:drug effects*; D013779:Tetrodotoxin / Q000008:administration & dosage / Q000494:pharmacology; D020888:Vigabatrin / Q000008:administration & dosage / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D058805:GABA Uptake Inhibitors; D007473:Ion Channels; D009557:Nipecotic Acids; D009579:Nitrobenzoates; C058176:5-nitro-2-(3-phenylpropylamino)benzoic acid; D018698:Glutamic Acid; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C045598:N-(4,4-diphenyl-3-butenyl)nipecotic acid; D020888:Vigabatrin