ISSN:
1432-2072
Keywords:
GABA delivery system
;
Brain
;
Anxiolysis
;
CNS inhibitory neurotransmitter
Source:
Springer Online Journal Archives 1860-2000
Topics:
Medicine
Notes:
Abstract We evaluated the anxiolytic property of a brain-specific gamma-aminobutyric acid delivery system (GABA-CDS) in male rats by means of a drink-foot shock conflict procedure. Brain-specific delivery of the active compound was achieved by combination of GABA benzyl ester with an interconvertible dihydropyridine⇌pyridinium salt carrier, which is “locked in” to the brain upon its oxidation. Pharmacokinetic studies revealed that the hydrophilic pyridinium salt form (G-Q+) of the GABA-CDS formed in situ remained in the brain for 12 h but was cleared from the blood and other peripheral tissues by 0.5–4 h. While the lipophilic form (G-DH) of the GABA-CDS caused a marked and sustained anxiolytic response when administered systemically, GABA and the charged pyridinium salt (G-Q+ form) of the GABA-CDS were ineffective. G-DH was injected at either 0, 4, 10 or 25 mg/kg IV in DMSO after rats were water and food deprived. After either 0.5, 2, 4, 8 or 24 h, rats were permitted 10 s of shock-free drinking of 10% sucrose, then given a 35 mA (DC) current through the drinking tube. Drinking time was recorded for 3 min. All doses of G-DH caused a significant increase in anxiolysis over control levels through 8 h. An increase (4 to 7-fold) in anxiolytic activity was observed through the 10 mg/kg dose with the 25 mg/kg dose causing no additional increase. No sedation or analgesia was observed at 2 h with any anxiolytic-producing dose of G-DH. These results suggest that G-DH elicits anxiolysis with minimal sedation, through the local brain action the G-Q+ or subsequent to the release of GABA.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1007/BF00177908
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