S-Ketamine's Effect Changes the Cortical Electrophysiological Activity Related to Semantic Affective Dimension of Pain: A Placebo- Controlled Study in Healthy Male Individuals.

BACKGROUND: Previous studies using the electroencephalogram (EEG) technique pointed out that ketamine decreases the amplitude of cortical electrophysiological signal during cognitive tasks, although its effects on the perception and emotional-valence judgment of stimuli are still unknown. OBJECTIVE: We evaluated the effect of S-ketamine on affective dimension of pain using EEG and behavioral measures. The hypothesis was that S-ketamine would be more effective than placebo, both within and between groups, to attenuate the EEG signal elicited by target and non-target words. METHODS: This double-blind parallel placebo-controlled study enrolled 24 healthy male volunteers between 19 and 40 years old. They were randomized to receive intravenous S-ketamine (n = 12) at a plasmatic concentration of 60 ng/ml or placebo (n = 12). Participants completed a computerized oddball paradigm containing written words semantically related to pain (targets), and non-pain related words (standard). The volunteers had to classify the words either as "positive," "negative" or "neutral" (emotional valence judgment). The paradigm consisted in 6 blocks of 50 words each with a fixed 4:1 target/non-target rate presented in a single run. Infusion started during the interval between the 3rd and 4th blocks, for both groups. EEG signal was registered using four channels (Fz, Pz, Pz, and Oz, according to the 10-20 EEG system) with a linked-earlobe reference. The area under the curve (AUC) of the N200 (interval of 100-200 ms) and P300 (300-500 ms) components of event-related potentials (ERPs) was measured for each channel. RESULTS: S-ketamine produced substantial difference (delta) in the AUC of grand average ERP components N200 (P = 0.05) and P300 (P = 0.02) at Pz during infusion period when compared to placebo infusion for both targets and non-targets. S-ketamine was also associated with a decrease in the amount of pain-related words judged as negative from before to after infusion [mean = 0.83 (SD = 0.09) vs. mean = 0.73 (SD = 0.11), respectively; P = 0.04]. CONCLUSION: Our findings suggest that S-ketamine actively changed the semantic processing of written words. There was an increase in electrophysiological response for pain-related stimuli and a decrease for standard stimuli, as evidenced by the increased delta of AUCs. Behaviorally, S-ketamine seems to have produced an emotional and discrimination blunting effect for pain-related words. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT03915938.

Methylglyoxal can mediate behavioral and neurochemical alterations in rat brain.

Diabetes is associated with loss of cognitive function and increased risk for Alzheimer's disease (AD). Advanced glycation end products (AGEs) are elevated in diabetes and AD and have been suggested to act as mediators of the cognitive decline observed in these pathologies. Methylglyoxal (MG) is an extremely reactive carbonyl compound that propagates glycation reactions and is, therefore, able to generate AGEs. Herein, we evaluated persistent behavioral and biochemical parameters to explore the hypothesis that elevated exogenous MG concentrations, induced by intracerebroventricular (ICV) infusion, lead to cognitive decline in Wistar rats. A high and sustained administration of MG (3µmol/µL; subdivided into 6days) was found to decrease the recognition index of rats, as evaluated by the object-recognition test. However, MG was unable to impair learning-memory processes, as shown by the habituation in the open field (OF) and Y-maze tasks. Moreover, a single high dose of MG induced persistent alterations in anxiety-related behavior, diminishing the anxiety-like parameters evaluated in the OF test. Importantly, MG did not alter locomotion behavior in the different tasks performed. Our biochemical findings support the hypothesis that MG induces persistent alterations in the hippocampus, but not in the cortex, related to glyoxalase 1 activity, AGEs content and glutamate uptake. Glial fibrillary acidic protein and S100B content, as well as S100B secretion (astroglial-related parameters of brain injury), were not altered by ICV MG administration. Taken together, our data suggest that MG interferes directly in brain function and that the time and the levels of exogenous MG determine the different features that can be seen in diabetic patients.

Increase of extracellular glutamate concentration increases its oxidation and diminishes glucose oxidation in isolated mouse hippocampus: reversible by TFB-TBOA.

Glutamate concentration at the synaptic level must be kept low in order to prevent excitotoxicity. Astrocytes play a key role in brain energetics, and also astrocytic glutamate transporters are responsible for the vast majority of glutamate uptake in CNS. Experiments with primary astrocytic cultures suggest that increased influx of glutamate cotransported with sodium at astrocytes favors its flux to the tricarboxylic acid cycle instead of the glutamate-glutamine cycle. Although metabolic coupling can be considered an emergent field of research with important recent discoveries, some basic aspects of glutamate metabolism still have not been characterized in brain tissue. Therefore, the aim of this study was to investigate whether the presence of extracellular glutamate is able to modulate the use of glutamate and glucose as energetic substrates. For this purpose, isolated hippocampi of mice were incubated with radiolabeled substrates, and CO2 radioactivity and extracellular lactate were measured. Our results point to a diminished oxidation of glucose with increasing extracellular glutamate concentration, glutamate presumably being the fuel, and might suggest that oxidation of glutamate could buffer excitotoxic conditions by high glutamate concentrations. In addition, these findings were reversed when glutamate uptake by astrocytes was impaired by the presence of (3S)-3-[[3-[[4-(trifluoromethyl)benzoyl]amino]phenyl]methoxy]-L-aspartic acid (TFB-TBOA). Taken together, our findings argue against the lactate shuttle theory, because glutamate did not cause any detectable increase in extracellular lactate content (or, presumably, in glycolysis), because the glutamate is being used as fuel instead of going to glutamine and back to neurons.

Effects of chronic administration of tryptophan with or without concomitant fluoxetine in depression-related and anxiety-like behaviors on adult rat.

Depression and anxiety play an important role in decreasing quality of life worldwide. Since tryptophan is a serotonin precursor and low levels of serotonin seems to be related to depression, the effect of oral tryptophan has been investigated for possible potentiation of the action of antidepressant drugs. We investigated the effects of chronically administered tryptophan (50mg/kg/day, p.o.) with or without concomitant fluoxetine (10mg/kg/day, s.c.) on adult rats regarding depression-related and anxiety-like behaviors. Tryptophan levels in cerebrospinal fluid (CSF) were measured 4h after a single administration of daily dosages of chronic treatments. We found that tryptophan increased depressive-related behavior, but did not alter anxiety-like behavior. However, fluoxetine decreased depression-related behavior and was anxiogenic. Tryptophan with concomitant fluoxetine did not alter anxiety-like behavior. Moreover, our data suggests that the antidepressant effect of fluoxetine was not enhanced by concomitant administration of tryptophan, which could be associated with increased levels of tryptophan in CSF. Further investigations are needed to elucidate the related mechanisms.