In vivo evidence for reduced cortical glutamate–glutamine cycling in rats treated with the antidepressant/antipanic drug phenelzine

Converging evidence has indicated that hyperglutamatergic activity and GABAergic dysfunction may play important roles in the neurobiology and treatment of depression and other mood disorders. In this study, in vivo 1H[13C] magnetic resonance spectroscopy was used to quantify the effects of acute phenelzine administration on cortical energetics, glutamate neurotransmission, and GABA synthesis flux. The time-resolved kinetics of cortical [4-13C]glutamate, [4-13C]glutamine, and [2-13C]GABA turnover from i.v.-infused [1,6-13C2]glucose was measured at 11.7 T in alpha-chloralose anesthetized rats four hours after phenelzine treatment (10 mg/kg, i.p.) and in non-treated controls. The rate of the tricarboxylic acid cycle flux was not affected by phenelzine treatment compared with the non-treated group (0.46+/-0.05 vs. 0.50+/-0.05 micromol/g/min, respectively). The rate of the glutamate-glutamine cycling flux between neurons and glia in the phenelzine-treated group was significantly reduced (from 0.16+/-0.04 to 0.10+/-0.03 micromol/g/min), providing in vivo evidence that phenelzine attenuates glutamate neurotransmission. Following phenelzine treatment, the cortical GABA concentration increased significantly (from 1.02+/-0.17 to 2.30+/-0.26 micromol/g), while the GABA synthesis flux was unchanged (from 0.07+/-0.02 to 0.06+/-0.02 micromol/g/min). The possible role of augmented GABAergic function resulting from elevated GABA levels in the observed modulatory effect of phenelzine on the glutamate-glutamine cycling flux was discussed. The reduced glutamate-glutamine cycling flux observed in this study suggests that, in addition to its effects on monoaminergic and GABAergic systems, the attenuation of glutamate neurotransmission resulting from phenelzine administration may also contribute to its efficacy in the treatment of depression. This study is the first demonstration that the glutamate-glutamine cycling flux, which can be measured non-invasively in the human brain in vivo, was altered due to the action of a psychotropic drug.