Endogenous and exogenous serotonin, but not sumatriptan, ameliorate seizures and neuroinflammation in the pentylenetetrazole-induced seizure model in rats

ABSTRACT Background: Epilepsy has neuropsychiatric comorbidities such as depression, bipolar disorder, and anxiety. Drugs that target epilepsy may also be useful for its neuropsychiatric comorbidities. Objective: To investigate the effects of serotonergic modulation on pro-inflammatory cytokines and the seizures in pentylenetetrazole (PTZ)-induced seizure model in rats. Methods: Male Wistar rats were injected intraperitoneally with serotonin, selective serotonin reuptake inhibitor fluoxetine, 5-HT1B/D receptor agonist sumatriptan, or saline 30 min prior to PTZ treatment. Behavioral seizures were assessed by the Racine's scale. Concentrations of IL-1β, IL-6, and TNF-α in serum and brain tissue were determined by ELISA. Results: Serotonin and fluoxetine, but not sumatriptan, alleviated PTZ-induced seizures by prolonging onset times of myoclonic-jerk and generalized tonic-clonic seizures. The anti-seizure effect of fluoxetine was greater than that of serotonin. Likewise, serotonin and fluoxetine, but not sumatriptan, reduced PTZ-induced increases in the levels of IL-1β and IL-6 in both serum and brain tissue. None of the administered drugs including PTZ affected TNF-α concentrations. Conclusions: Our findings suggest that endogenous and exogenous serotonin exhibits anticonvulsant effects by suppressing the neuroinflammation. It seems that 5-HT1B/D receptors do not mediate anticonvulsant and anti-neuroinflammatory effects of serotonin.

Serotonergic Modulation of Orientation Tuning of Neurons in Primary Visual Cortex of Anesthetized Mice

Introduction: Sensory processing is profoundly regulated by brain neuromodulatory systems. One of the main neuromodulators is serotonin which influences higher cognitive functions such as different aspects of perceptual processing. So, malfunction in the serotonergic system may lead to visual illusion in psychiatric disorders such as autism and schizophrenia. In this work, we examined the serotonergic modulation of visual responses of neurons to stimulus orientation in the primary visual cortex. Methods: Eight-weeks old naive mice were anesthetized and craniotomy was done on the region of interest in primary visual cortex. Spontaneous and visual-evoked activities of neurons were recorded before and during the electrical stimulation of dorsal raphe nucleus using in vivo whole-cell patch-clamp recording. Square-wave grating of 12 orientations was presented. Data was analyzed and Wilcoxon signed-rank test, used in order to compare the data of two conditions that belong to the same neurons, with or without electrical stimulation. Results: The serotonergic system changed orientation tuning of about 60 % recorded neurons by decreasing the mean firing rate in two independent visual response components: gain and baseline response. It also increased mean firing rate in a small number of neurons (about 20%). Beyond that, it left the preferred orientation and sensitivity of neurons unchanged. Conclusion: However, serotonergic modulation showed a bi-directional effect; it seems to cause predominately divisive and subtractive decreases in the visual responses of the neurons in the primary visual cortex that can modify the balance between internal and external sensory signals and result in disorders.

Effects of Escitalopram and Relearning on Cortical and Subcortical Grey Matter in Healthy Humans

The antidepressant effect of selective serotonin reuptake inhibitors (SSRI) is related to increased neuroplasticity during relearning. Stress-induced dendritic atrophy in key brain areas for learning and memory such as the hippocampus and prefrontal cortex is reversed by SSRI treatment. This finding is accompanied by behavioral stabilization. The aim of this study was to investigated serotonergic modulation effects on structural neuroplasticity (cortical thickness, subcortical volumes) during relearning in healthy subjects. Participants performed daily associative learning tasks over 3 weeks followed by a 3-week relearning phase combined with intake of the SSRI escitalopram or placebo. Evidence suggests that SSRIs promote the brains susceptibility to change on the basis of environment factors. We found no effect of SSRI on grey matter measures during relearning. Here, non-findings might be a consequence of the implemented intensity and duration of study interventions. With sparse literature on healthy participants in this field, future studies will have to further elucidate SSRIs properties on relearning and structural neuroplasticity.

Escitalopram Administration, Neuroplastic Effects and Relearning: A Diffusion Tensor Imaging Study in Healthy Individuals

Background: Neuroplastic processes are influenced by selective serotonergic reuptake inhibitors, while learning in conjunction with the administration of serotonergic agents alters white matter microstructure in humans. The goal of this double-blind, placebo-controlled imaging study was to investigate the influence of escitalopram on white matter plasticity during (re)learning. Methods: Seventy-one healthy individuals (age = 25.6+/-5.0, 43 females) underwent 3 diffusion magnetic resonance imaging sessions: at baseline, after 3-weeks of associative learning (emotional/non-emotional content) and after relearning shuffled associations for an additional 3 weeks. During the relearning phase, subjects received daily escitalopram 10 mg or placebo orally. Data were analyzed using the FMRIB Software Library (FSL) and the implemented Tract-Based Spatial Statistics (TBSS) approach. Results: The TBSS analysis revealed widespread decreases in fractional anisotropy metrics in subjects that received escitalopram. In addition, axial diffusivity decreases were mainly found in the corpus callosum and in areas within the internal capsule. In subjects receiving placebo, we did not find such effects, nor did our results show diffusivity changes related to learning or relearning. Conclusion: Diffusivity changes were found within several tracts in the escitalopram group, while we observed no changes in the placebo group. Although previous studies examining the effects of SSRIs on white matter tracts in humans are underrepresented, our results suggest a relationship between serotonergic agents and diffusivity parameters. The findings of this study implicate that escitalopram may directly or indirectly impact white matter microstructures in healthy subjects. Nevertheless, we did not find a relationship between serotonergic modulation, neuroplastic effects and relearning.

Serotonergic Modulation of Persistent Inward Currents in Serotonergic Neurons of Medulla in ePet-EYFP Mice

Serotonergic (5-HT) neurons in the medulla play multiple functional roles associated with many symptoms and motor activities. The descending serotonergic pathway from medulla is essential for initiating locomotion. However, the ionic properties of 5-HT neurons in the medulla remain unclear. Using whole-cell patch-clamp technique, we studied the biophysical and modulatory properties of persistent inward currents (PICs) in 5-HT neurons of medulla in ePet-EYFP transgenic mice (P3–P6). PICs were recorded by a family of voltage bi-ramps (10-s duration, 40-mV peak step), and the ascending and descending PICs were mirrored to analyze the PIC hysteresis. PICs were found in 77% of 5-HT neurons (198/258) with no significant difference between parapyramidal region (n = 107) and midline raphe nuclei (MRN) (n = 91) in either PIC onset (−47.4 ± 10 mV and −48.7 ± 7 mV; P = 0.44) or PIC amplitude (226.9 ± 138 pA and 259.2 ± 141 pA; P = 0.29). Ninety-six percentage (191/198) of the 5-HT neurons displayed counterclockwise hysteresis and four percentage (7/198) exhibited the clockwise hysteresis. The composite PICs could be differentiated as calcium component (Ca_PIC) by bath application of nimodipine (25 μM), sodium component (Na_PIC) by tetrodotoxin (TTX, 2 μM), and TTX- and dihydropyridine-resistance component (TDR_PIC) by TTX and nimodipine. Ca_PIC, Na_PIC and TDR_PIC all contributed to upregulation of excitability of 5-HT neurons. 5-HT (15 μM) enhanced the PICs, including a 26% increase in amplitude of the compound currents of Ca_PIC and TDR_PIC (P < 0.001, n = 9), 3.6 ± 5 mV hyperpolarization of Na_PIC and TDR_PIC onset (P < 0.05, n = 12), 30% increase in amplitude of TDR_PIC (P < 0.01), and 2.0 ± 3 mV hyperpolarization of TDR_PIC onset (P < 0.05, n = 18). 5-HT also facilitated repetitive firing of 5-HT neurons through modulation of composite PIC, Na_PIC and TDR_PIC, and Ca_PIC and TDR_PIC, respectively. In particular, the high voltage-activated TDR_PIC facilitated the repetitive firing in higher membrane potential, and this facilitation could be amplified by 5-HT. Morphological data analysis indicated that the dendrites of 5-HT neurons possessed dense spherical varicosities intensively crossing 5-HT neurons in medulla. We characterized the PICs in 5-HT neurons and unveiled the mechanism underlying upregulation of excitability of 5-HT neurons through serotonergic modulation of PICs. This study provided insight into channel mechanisms responsible for the serotonergic modulation of serotonergic neurons in brainstem.