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 (1H MRS) was used to measure GABA, Glu, and Gln levels in six healthy adult volunteers 1 h 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 1 h and 0.01 at 10 h following the administration of drug (t11 = 2.49, P = 0.03 1 h; t10 = 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.