The acute and late CNS glutamine response to benzodiazepine challenge: a pilot pharmacokinetic study using proton magnetic resonance spectroscopy.
Benzodiazepines (BZs), which are typically used as anxiolytics, act by modulating inhibitory signaling through gamma-aminobutyric acid A (GABA)(A) receptors. Functionally, the inhibitory effects of GABA may be counterbalanced by the excitatory effects of glutamate (Glu) as the two neurotransmitter systems are metabolically linked through their synthetic intermediate glutamine (Gln). The primary aim of this study was to determine whether the effects of different BZs on the GABA and Glu/Gln systems would vary according to the pharmacokinetics of the different drugs. Proton magnetic resonance spectroscopy ((1)H MRS) was used to measure GABA, Glu, and Gln levels in six healthy adult volunteers 1h and 10 h following immediate release alprazolam, extended release alprazolam, clonazepam, or placebo. Although there were no differences between 1 and 10 h when the drugs were examined individually, there was a trend level difference between the 1- and 10-h effects of BZs on Gln when the BZs were combined. In post-hoc comparisons, the difference in the Gln to creatine (Cr) ratio was 0.04 for the BZs versus placebo at 1h and 0.01 at 10h following the administration of drug (t(11)=2.49, P=0.03 1 h; t(10)=0.65, P=0.53 10 h; no correction for multiple comparisons). An increase in Gln/Cr at 1 h post-BZ is consistent with a functionally synergistic relationship between Glu/Gln and GABA in the brain. It also suggests that MRS may have sufficient sensitivity to detect acute drug effects.
Caritas St. Elizabeth's Medical Center, Department of Psychiatry, Boston, MA 02135, USA. michael.henry@caritaschristi.org
Michael E
ME
Henry
J Eric
JE
Jensen
Stephanie C
SC
Licata
Caitlin
C
Ravichandran
Michelle L
ML
Butman
Meghan
M
Shanahan
Tara L
TL
Lauriat
Perry F
PF
Renshaw
D000328:Adult; D000525:Alprazolam / Q000494:pharmacology; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D001569:Benzodiazepines / Q000494:pharmacology*; D001931:Brain Mapping; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism*; D002794:Choline / Q000378:metabolism; D002998:Clonazepam / Q000494:pharmacology; D003401:Creatine / Q000378:metabolism; D018592:Cross-Over Studies; D004311:Double-Blind Method; D018757:GABA Modulators / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D010865:Pilot Projects; D011522:Protons; D013997:Time Factors; D055815:Young Adult; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D011522:Protons; D005973:Glutamine; D001569:Benzodiazepines; D001224:Aspartic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D002998:Clonazepam; C000179:N-acetylaspartate; D003401:Creatine; D002794:Choline; D000525:Alprazolam