patent or program Cooperation Treaty worldwide program Zero

patent or program Cooperation Treaty worldwide program Zero. energy creation, as shown by 13C glutamate enrichment. During ketamine infusion, the ratio of 13C glutamate/glutamine enrichments, a putative measure of neurotransmission strength, was correlated with the Clinician-Administered Dissociative States Scale ( em r /em ?=??0.54, em p /em ?=?0.048). These findings provide the most direct evidence in humans to date that ketamine increases glutamate release in the prefrontal Mdk cortex, a mechanism previously linked to schizophrenia pathophysiology and implicated in the induction of rapid antidepressant effects. Introduction The discovery C527 [1] and replication [2] of the antidepressant effects of ketamine, and the implication of N-methyl-D-aspartate receptor (NMDAR) hypofunction in the pathophysiology of schizophrenia [3] have generated considerable excitement about the potential of targeting glutamate neurotransmission to develop safe, effective, and rapid acting antidepressants (RAADs) [4], as well as to develop glutamate-based antipsychotics to treat the often resistant cognitive deficits and negative symptoms in schizophrenia [5, 6]. However, to date not a single RAAD or glutamate-based antipsychotic has been approved to treat depression or schizophrenia, although two decades have passed since the RAAD and psychotomimetic effects of ketamine were first reported in the 1990s [3, 7]. A major obstacle in this field is the lack of biomarkers that directly reflect synaptic glutamate neurotransmission. Such markers would serve to (1) test ketamines RAAD and psychotomimetic mechanisms in humans and (2) C527 permit expedited screening and optimization of putative novel glutamate-based RAAD and antipsychotic agents. Carbon-13 magnetic resonance spectroscopy (13C MRS) is a unique, noninvasive method to measure neurotransmitter cycling and cell-specific neuroenergetics [8C10]. In the current study, we implemented a 13C MRS pharmacoimaging paradigm, using a novel method [11C13] to conduct quantitative 13C MRS acquisition in the human frontal lobea region closely related to psychopathology that was not initially accessible in 13C MRS studies. We aimed to determine ketamines effect on glutamateCglutamine cycling and to investigate the association between changes in neurotransmission and the psychotomimetic effects of ketamine. 13C MRS is presently the only method that provides direct dynamic measurements of glutamateCglutamine cycling in the human brain [10]. Briefly, labeled 13C-glucose is infused intravenously over 120?min during the MRS acquisition. The incorporation of the 13C in glutamate and glutamine generates unique signals on the 13C spectrum (Fig.?1). Metabolites of 13C-glucose enter the tricarboxylic acid (TCA; also known as Krebs) cycle, which in turn label glutamate. Then, as 13C-glutamate is released into the synaptic cleft, astrocytes take it up and convert it to 13C-glutamine (Fig.?2). The glutamate and glutamine 13C enrichments rise rapidly in the first 20C30?min of 13C-glucose infusion and reach a steady-state in the last 40C60?min (Fig.?S1). Accordingly, the glutamate enrichment primarily reflects oxidative energy production through the TCA cycle, while the rate of glutamine enrichment primarily reflects glutamate neurotransmitter cycling [8, 10]. Open in a separate window Fig. 1 Prefrontal 13C magnetic resonance spectroscopy (MRS) acquisition and 13C spectrum. Sagittal (a) and axial (b) view of the region of interestbased on the radius of the carbon coilprimarily rostral Brodmann Area 10. c 13C magnetic C527 resonance spectrum acquired at 4?T from the prefrontal region of a study participant during infusion of [U 13C]-glucose. Color code: blueraw; redfitted; greenresidual. Abbreviations: GluC45 13C-Glutamate C45, GlnC45 13C-Glutamine C45, and AspC34 13C-Aspartate C34 Open in a separate window Fig. 2 Carbon-13 (13C) labeling of glutamate C527 and glutamine via the TCA and glutamateCglutamine cycle. Following glycolysis, 13C-Glucose (13C-Glc) metabolites (i.e., acetyl-CoA) enter the mitochondrial tricarboxylic acid (TCA) cycle (also known as Krebs cycle) and subsequently label glutamate through exchange with -ketoglutarate. Next, 13C-glutamate is released into the.