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Changes in Glutamate Levels Measured by Glutamate Changes in glutamate levels measured by glutamate voltammetry in the rat medial prefrontal cortex after treatment with N-methyl-D-aspartate receptor antagonists (P.1.g.023) Irina Ionescu, Kelly Allers, Roberto Arban, Cornelia Dorner-Ciossek and Lothar Kussmaul Boehringer Ingelheim, CNS Diseases Research Background Hypothesized antidepressant MoA of NMDA-R antagonists: Disinhibition of glutamatergic neurons in the PFC N-methyl-D-aspartate receptor (NMDA-R) have been described as potential novel treatment options in the therapy of treatment-reistant depression (TRD). A single sub-anesthetic dose of the noncompetitive NMDA-R antagonist GABA ketamine has been shown to exert rapid-onset and long-lasting antidepressant Glutamate Glutamate NMDA-R effects in TRD patients; these effects were accompanied by brief psychotic Increased glutamate release episodes. Fast-onset antidepressant effects without psychotic side effects have also been described in the clinic for the NR2B-selective negative allosteric modulator (NAM) traxoprodil. However, other unspecific NMDA-R blockers, Synaptic plasticity such as lanicemine, failed to show fast-onset long-lasting antidepressant NMDA-R antagonists (ketamine, traxoprodil) effects in the clinic after single application. Here, we used glutamate AMPA-R AMPA-R voltammetry in rats in order to identify a preclinical predictor of clinical efficacy The increase in glutamate release as proof of circuit by circuit engagement in the prefrontal cortex (PFC). engagement and antidepressant activity can be measured by glutamate voltammetry. Using glutamate voltammetry to show circuit engagement by clinically active NMDA-R antagonists in the PFC Glutamate biosensor (Pinnacle Technology Inc., USA) Advantages of glutamate voltammetry Experimental design - fast response time Experiments were performed in Wistar Han rats implanted with Recording site: PFC - fast sampling time (1 Hz) guide cannulae at the specified coordinates. On the day prior to the Coordinates: AP: +2.7 - high sensitivity experiment, sensors were implanted via the guide cannulae and ML: +0.5 DV (from dura): -1.3 - low analyte consumption allowed to equilibrate in vivo over night. Recordings were - no sample post-processing performed in the animals‘ home cages. A baseline was recorded for at least 30 min and the animals were subsequently treated by PrL fmi intraperitoneal injection (i.p.) with the compounds or with vehicle. IL Treatment-elicited changes in glutamate levels were recorded for aca at least 1 h post-treatment. Glutamate voltammetry shows glutamate increase to be the efficacy-associated MoA for NMDA-R antagonists S-ketamine Traxoprodil Lanicemine To investigate the relationship between Vehicle (n=10) Vehicle (n=10) Vehicle (n=8) Ketamine 3 mg/kg (n=8) Traxoprodil 2 mg/kg (n=8) circuit engagement and clinical efficacy, Lanicemine 10 mg/kg (n=7) Ketamine 10 mg/kg (n=8) Traxoprodil 6 mg/kg (n=8) Lanicemine 30 mg/kg (n=10) S-ketamine and traxoprodil, which have Ketamine 30 mg/kg (n=8) Traxoprodil 20 mg/kg (n=8) Lanicemine 90 mg/kg (n=9) Traxoprodil 60 mg/kg (n=8) 600 shown clinical efficacy, were compared with 600 600 lanicemine, which failed in the clinic. Doses 400 400 400 were selected by PK/PD modeling to mirror 200 0.3fold, 1fold and 3fold clinically efficacious 200 200 0 Cmax in patients. All data were analyzed Glutamate [nM] Glutamate [nM] Glutamate [nM] using 2way ANOVA of repeated measures 0 0 -200 (treatment and time). Upper panels: time -400 -200 course of glutamate changes (bins of 10 -200 (normalized to 10 min bin before injection) 0 0 0 n 0 0 0 0 0 0 3 2 1 o 1 2 3 4 5 6 (normalized to 10 min bin before injection) 0 0 0 n 0 0 0 0 0 0 - - - i 0 0 0 n 0 0 0 0 0 0 (normalized to 10 min bin before injection) 3 2 1 o 1 2 3 4 5 6 t -3 -2 -1 io 1 2 3 4 5 6 - - - ti c t c je min). Lower panels: AUC. c je in je n . in i p . i. p .p i. Time (10 min bins) i Time (10 min bins) Time (10 min bins) S-ketamine treatment led to significantly increased glutamate levels in rats at 1fold *** clinically efficacious Cmax (10 mg/kg), a *** 400 400 *** dose which also shows efficacy in the 400 *** ** 300 forced-swim test (FST) and leads to 300 *** 300 increased locomotor activity (LA) in mice, 200 200 mirroring psychotic effects in patients. 200 100 Traxoprodil treatment significantly increased 100 100 0 glutamate levels in rats at 3fold clinically Glutamate [nM] Glutamate [nM] Glutamate [nM] 0 efficacious Cmax (20 mg/kg), a dose -100 0 showing efficacy in the FST but no -100 -200 (normalized to 10 min bin before injection) -100 (normalized to 10 min bin before injection) psychotomimetic effects in LA in mice. (normalized to 10 min bin before injection) Lanicemine, the clinically inactive Vehicle baselineVehicle injection Vehicle baselineVehicle injection compound, failed to increase glutamate Vehicle baselineVehicle injection S-ket 3 mg/kgS-ket 3baseline mg/kg injection S-ket 10S-ket mg/kg 10 baseline mg/kg injectionS-ket 30S-ket mg/kg 30 baseline mg/kg injection levels in rats at up to 30fold clinically Traxoprodil 2 mg/kg baselineTrayoprodil 6 mg/kg baseline Traxoprodil 2 mg/kg injectionTraxoprodil 6 Traxoprodilmg/kg injection 20 mg/kg baselineTraxoprodil 60 mg/kg baseline Traxoprodil 20 mg/kg injectionTraxoprodil 60 mg/kg injection LanicemineLanicemine 10 mg/kg baseline 10 mg/kgLanicemine injectionLanicemine 30 mg/kg baseline 30 mg/kgLanicemine injection 90Lanicemine mg/kg baseline 90 mg/kg injection achieved exposures (90 mg/kg). Differentiating between contribution of glutamate increase to Conclusions psychotomimetic side effects and antidepressant-like effects of NMDA-R Here, we show for the first time, using glutamate voltammetry as a antagonists Increase in glutamate levels was observed with both S-ketamine, which elicits surrogate marker, that prefrontal disinhibition correlates with the clinical psychotic side effects in patients and efficacy of NMDA-R antagonists. Circuit engagement in the PFC occurs psychotomimetic effects in rodents at the only in the case of clinically efficacious NMDA-R antagonists such as clinically efficaious Cmax, and traxoprodil, which does not. Therefore, we investigated S-ketamine and traxoprodil, and is absent in the case of the clinically the effects of (2R,2S)-hydroxynorketamine inefficacious NMDA-R antagonist lanicemine. (HNK), a metabolite of ketamine which was Furthermore, we show that the glutamate increase observed in the PFC of described to have α-amino-3-hydroxy-5-methyl-4-isoxazole- rats upon treatment with clinically efficacious NMDA-R antagonists is most propionic acid receptor (AMPA-R) likely not related to psychotomimetic side effects, but to antidepressant-like Time (10 min bins) activation-dependent effects in rodents in effects, as it is present in the case of traxoprodil and HNK, but absent in the the FST, but not in LA, on glutamate levels case of lanicemine, none of which elicit psychotomimetic side effects. at the effective dose from literature. HNK led to significant increase in glutamate levels, Taken together, the increase in glutamate levels in the PFC by clinically which could be blocked by the AMPA-R efficacious NMDA-R antagonists described here may be a valid predictor of antagonist NBQX. antidepressant effects in patients. Conflict of interest: All authors are employees of Boehringer Ingelheim. Contact details: [email protected].
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