Multimodal antidepressant vortioxetine increases frontal cortical oscillations unlike escitalopram and duloxetine--a quantitative EEG study in rats.

BACKGROUND AND PURPOSE: EEG studies show that 5-HT is involved in regulation of sleep-wake state and modulates cortical oscillations. Vortioxetine is a 5-HT3 , 5-HT7 , and 5-HT1D receptor antagonist, 5-HT1B partial agonist, 5-HT1A agonist, and 5-HT transporter inhibitor. Preclinical (animal) and clinical studies with vortioxetine show positive impact on cognitive metrics involving cortical function. Here we assess vortioxetine's effect on cortical neuronal oscillations in actively awake rats. EXPERIMENTAL APPROACH: Telemetric EEG recordings were obtained with the following treatments (mg·kg(-1) , s.c.): vehicle, vortioxetine (0.1, 1.0, 3.0, 10), 5-HT1A agonist flesinoxan (2.5), 5-HT3 antagonist ondansetron (0.30), 5-HT7 antagonist SB-269970-A (10), escitalopram (2.0), duloxetine (10) and vortioxetine plus flesinoxan. Target occupancies were determined by ex vivo autoradiography. KEY RESULTS: Vortioxetine dose-dependently increased wakefulness. Flesinoxan, duloxetine, ondansetron, but not escitalopram or SB-269970-A increased wakefulness. Quantitative spectral analyses showed vortioxetine alone and with flesinoxan increased θ (4-8 Hz), α (8-12 Hz) and γ (30-50 Hz) power. Duloxetine had no effect on θ and γ, but decreased α power, while escitalopram produced no changes. Ondansetron and SB-269970 (≈31-35% occupancy) increased θ power. Flesinoxan (≈41% occupancy) increased θ and γ power. CONCLUSIONS AND IMPLICATIONS: Vortioxetine increased wakefulness and increased frontal cortical activity, most likely because of its 5-HT7 and 5-HT3 antagonism and 5-HT1A agonism. Vortioxetine differs from escitalopram and duloxetine by increasing cortical θ, α and γ oscillations. These preclinical findings suggest a role of vortioxetine in modulating cortical circuits known to be recruited during cognitive behaviours and warrant further investigation as to their clinical impact.

The release and uptake of excitatory amino acids in rat brain: effect of aging and oxidative stress.

The excitatory amino acids (EAAs) L-aspartate and L-glutamate constitute the major neurotransmitters in the mammalian brain. This study established the influence of aging and oxidative stress on the release and uptake of EAAs. The high affinity uptake of D-[3H]aspartate in synaptosomal fractions of the neostriatum, hippocampus, and neocortex was not significantly different in Fisher 344/Norwegian Brown hybrid rats aged 3, 12, 24, and 37 months. Similarly, the K(+)-evoked efflux of endogenous aspartate and glutamate from neocortical minislices was also unaffected by age. To examine the possibility that EAA nerve terminals become more vulnerable to oxidative stress with age, the influence of an inhibitor of the electron transport chain (sodium cyanide) on EAA uptake and release was determined. Although cyanide inhibited D-[3H]aspartate uptake and potentiated the potassium-evoked efflux of aspartate and glutamate in a Ca(2+)-independent fashion, neither of these changes were influenced by age. Thus, the functional integrity of EAA nerve terminals and their vulnerability to oxidative stress are both preserved in normal aging. The potency of cyanide to inhibit D-[3H]aspartate uptake did, however, display regional variability: hippocampus > neocortex > neostriatum (IC50 = 1.2 +/- 0.2 mM, 1.9 +/- 0.1 mM and 2.7 +/- 0.2 mM, respectively), suggesting that EAA nerve terminals in the hippocampus may be selectively vulnerable to oxidative stress.