Modulation of thalamo-cortical activity by the NMDA receptor antagonists ketamine and phencyclidine in the awake freely-moving rat.

Non-competitive N-methyl-d-aspartate receptor antagonists mimic schizophrenia symptoms and produce immediate and persistent antidepressant effects. We investigated the effects of ketamine and phencyclidine (PCP) on thalamo-cortical network activity in awake, freely-moving male Wistar rats to gain new insight into the neuronal populations and brain circuits involved in the effects of NMDA-R antagonists. Single unit and local field potential (LFP) recordings were conducted in mediodorsal/centromedial thalamus and in medial prefrontal cortex (mPFC) using microelectrode arrays. Ketamine and PCP moderately increased the discharge rates of principal neurons in both areas while not attenuating the discharge of mPFC GABAergic interneurons. They also strongly affected LFP activity, reducing beta power and increasing that of gamma and high-frequency oscillation bands. These effects were short-lasting following the rapid pharmacokinetic profile of the drugs, and consequently were not present at 24 h after ketamine administration. The temporal profile of both drugs was remarkably different, with ketamine effects peaking earlier than PCP effects. Although this study is compatible with the glutamate hypothesis for fast-acting antidepressant action, it does not support a local disinhibition mechanism as the source for the increased pyramidal neuron activity in mPFC. The short-lasting increase in thalamo-cortical activity is likely associated with the rapid psychotomimetic action of both agents but could also be part of a cascade of events ultimately leading to the persistent antidepressant effects of ketamine. Changes in spectral contents of high-frequency bands by the drugs show potential as translational biomarkers for target engagement of NMDA-R modulators.

Lurasidone inhibits NMDA receptor antagonist-induced functional abnormality of thalamocortical glutamatergic transmission via 5-HT7 receptor blockade.

BACKGROUND AND PURPOSE: Lurasidone is an atypical mood-stabilizing antipsychotic with a unique receptor-binding profile, including 5-HT7 receptor antagonism; however, the detailed effects of 5-HT7 receptor antagonism on various transmitter systems relevant to schizophrenia, particularly the thalamo-insular glutamatergic system and the underlying mechanisms, are yet to be clarified. EXPERIMENTAL APPROACH: We examined the mechanisms underlying the clinical effects of lurasidone by measuring the release of l-glutamate, GABA, dopamine, and noradrenaline in the reticular thalamic nucleus (RTN), mediodorsal thalamic nucleus (MDTN) and insula of freely moving rats in response to systemic injection or local infusion of lurasidone or MK-801 using multiprobe microdialysis with ultra-HPLC. KEY RESULTS: Systemic MK-801 (0.5 mg·kg-1 ) administration increased insular release of l-glutamate, dopamine, and noradrenaline but decreased GABA release. Systemic lurasidone (1 mg·kg-1 ) administration also increased insular release of l-glutamate, dopamine, and noradrenaline but without affecting GABA. Local lurasidone administration into the insula (3 µM) did not affect MK-801-induced insular release of l-glutamate or catecholamine, whereas local lurasidone administration into the MDTN (1 µM) inhibited MK-801-induced insular release of l-glutamate and catecholamine, similar to the 5-HT7 receptor antagonist SB269970. CONCLUSIONS AND IMPLICATIONS: The present results indicate that MK-801-induced insular l-glutamate release is generated by activation of thalamo-insular glutamatergic transmission via MDTN GABAergic disinhibition resulting from NMDA receptor inhibition in the MDTN and RTN. Lurasidone inhibited this MK-801-evoked insular l-glutamate release through inhibition of excitatory 5-HT7 receptor in the MDTN. These effects on thalamo-insular glutamatergic transmission may contribute to the antipsychotic and mood-stabilizing actions of lurasidone.

Non-invasive transcutaneous auricular vagus nerve stimulation prevents postoperative ileus and endotoxemia in mice.

BACKGROUND: The cholinergic anti-inflammatory pathway comprises the perception of peripheral inflammation by afferent sensory neurons and reflex activation of efferent vagus nerve activity to regulate inflammation. Activation of this pathway was shown to reduce the inflammatory response and improve outcome of postoperative ileus (POI) and sepsis in rodents. Herein, we tested if a non-invasive auricular electrical transcutaneous vagus nerve stimulation (tVNS) affects inflammation in models of POI or endotoxemia. METHODS: Mice underwent tVNS or sham stimulation before and after induction of either POI by intestinal manipulation (IM) or endotoxemia by lipopolysaccharide administration. Some animals underwent a preoperative right cervical vagotomy. Neuronal activation of the solitary tract nucleus (NTS) and the dorsal motor nucleus of the vagus nerve (DMV) were analyzed by immunohistological detection of c-fos+ cells. Gene and protein expression of IL-6, MCP-1, IL-1ß as well as leukocyte infiltration and gastrointestinal transit were analyzed at different time points after IM. IL-6, TNFα, and IL-1ß serum levels were analyzed 3 hours after lipopolysaccharide administration. RESULTS: tVNS activated the NTS and DMV and reduced intestinal cytokine expression, reduced leukocyte recruitment to the manipulated intestine segment, and improved gastrointestinal transit after IM. Endotoxemia-induced IL-6 and TNF-α release was also reduced by tVNS. The protective effects of tVNS on POI and endotoxemia were abrogated by vagotomy. CONCLUSION: tVNS prevents intestinal and systemic inflammation. Activation of the DMV indicates an afferent to efferent central circuitry of the tVNS stimulation and the beneficial effects of tVNS depend on an intact vagus nerve. tVNS may become a non-invasive approach for treatment of POI.

Site selective activation of lateral hypothalamic mGluR1 and R5 receptors elicits feeding in rats.

Recent findings from our lab indicate that metabotropic glutamate receptor (mGluR) activation elicits eating, and the goal of the current study was to specify whether the lateral hypothalamus (LH) is the actual brain site mediating this effect. To examine this issue we injected the selective mGluR group I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) unilaterally into the LH and surrounding regions (n=5-8 subjects/brain site) of satiated adult male Sprague-Dawley rats and measured elicited feeding. We determined that 1.0 nmol elicited food intake only within the LH. Increasing the dose to 10 or 25 nmol produced a more sustained effect in the LH, and also elicited eating in several other brain sites. These results, demonstrating that the LH mediates the eating elicited by low doses of DHPG, suggest that the LH may contain mGluR whose activation can produce eating behavior.

Systemic pregabalin attenuates facial hypersensitivity and noxious stimulus-evoked release of glutamate in medullary dorsal horn in a rodent model of trigeminal neuropathic pain.

Pregabalin is effective in treating many neuropathic pain conditions. However, the mechanisms of its analgesic effects remain poorly understood. The aim of the present study was to determine whether pregabalin suppresses facial mechanical hypersensitivity and evoked glutamate release in the medullary dorsal horn (MDH) in a rodent model of trigeminal neuropathic pain. Nociceptive mechanical sensitivity was assessed pre-operatively, and then post-operatively 1h following pregabalin or vehicle (saline) treatment on post-operative days 2 and 5 following infraorbital nerve transection (IONX). In addition, an in vivo microdialysis probe was inserted into the exposed medulla post-operatively and dialysate samples were collected. Glutamate release was then evoked by mustard oil (MO) application to the tooth pulp, and the effects of pregabalin or vehicle were examined on the MDH glutamate release. Glutamate concentrations in the dialysated samples were determined by HPLC, and data analyzed by ANOVA. IONX animals (but not control animals) showed facial mechanical hypersensitivity for several days post-operatively. In addition, tooth pulp stimulation with MO evoked a transient release of glutamate in the MDH of IONX animals. Compared to vehicle, administration of pregabalin significantly attenuated the facial mechanical hypersensitivity as well as the MO-evoked glutamate release in MDH. This study provides evidence in support of recent findings pointing to the usefulness of pregabalin in the treatment of orofacial neuropathic pain.

Neuron-immune interactions in the sensitized thalamus induced by mustard oil application to rat molar pulp.

We have reported that mustard oil application to the rat dental pulp induces neuronal activation in the thalamus. To address the mechanisms involved in the thalamic changes, we performed neuronal responsiveness recording, immunohistochemistry, and molecular biological analysis. After mustard oil application, neuronal responsiveness was increased in the mediodorsal nucleus. When MK801 (an N-methyl-D-aspartate receptor antagonist) was applied to the mediodorsal nucleus, the enhanced responsiveness was decreased. N-methyl-D-aspartate receptor 2D, glial fibrillary acidic protein, and antigen-presenting cell-related gene mRNAs in the contralateral thalamus were up-regulated at 10 minutes after mustard oil application, but were down-regulated within 10 minutes after the antagonist application. OX6-expressing microglia and glial fibrillary acidic protein-expressing astrocytes did not increase until 60 minutes after mustard oil application. These results suggested that the thalamic neurons play some roles in regulating the glial cell activation in the mediodorsal nucleus via N-methyl-D-aspartate receptor 2D during pulp inflammation-induced central sensitization.

Neurotoxic lesions of the medial mediodorsal nucleus of the thalamus disrupt reinforcer devaluation effects in rhesus monkeys.

The mediodorsal thalamus is a major input to the prefrontal cortex and is thought to modulate cognitive functions of the prefrontal cortex. Damage to the medial, magnocellular part of the mediodorsal thalamus (MDmc) impairs cognitive functions dependent on prefrontal cortex, including memory. The contribution of MDmc to other aspects of cognition dependent on prefrontal cortex has not been determined. The ability of monkeys to adjust their choice behavior in response to changes in reinforcer value, a capacity impaired by lesions of orbital prefrontal cortex, can be tested in a reinforcer devaluation paradigm. In the present study, rhesus monkeys with bilateral neurotoxic MDmc lesions were tested in the devaluation procedure. Monkeys learned visual discrimination problems in which each rewarded object is reliably paired with one of two different food rewards and then were given choices between pairs of rewarded objects, one associated with each food. Selective satiation of one of the food rewards reduces choices of objects associated with that food in normal monkeys. Monkeys with bilateral neurotoxic lesions of MDmc learned concurrently presented visual discrimination problems as quickly as unoperated control monkeys but showed impaired reinforcer devaluation effects. This finding suggests that the neural circuitry for control of behavioral choice by changes in reinforcer value includes MDmc.

Comparative effects of injecting 5,6-dihydroxytryptamine in the dorsal or medial raphe nuclei on rat puberty.

The role played by the serotoninergic system in the control of puberty onset and first ovulation in rats is studied in this paper by analyzing the effects of injecting the neurotoxin 5,6-dihydroxytryptamine (5,6-DHT) into the dorsal (DRN) or medial (MRN) raphe nucleus of 30-day-old female rats. Complete lesion to the DRN resulted in the blockade of ovulation and a decrease in both the number of ovarian follicles and the serum concentration of follicle stimulating hormone (FSH). This treatment was also found to be associated with an increase in serotoninergic activity in the anterior and medial hypothalami. A lesion to the central portion of the DRN resulted in a significant decrease in the concentration of progesterone in serum and in the number of ova shed by ovulating animals. The lesion to the lateral portion of the DRN did not have an apparent effect on ovulation rate, the number of ova shed, nor in hormone serum concentration. The injection of propranolol to rats with a lesion to the DRN restored ovulation in 73% of treated animals and returned serotoninergic activity in the anterior hypothalamus to levels similar to those of sham-operated animals. In turn, in the medial hypothalamus, the increase in serotoninergic activity was not modified. The results presented herein suggest that serotoninergic inputs to the anterior hypothalamus have a direct influence on gonadotropin secretion and first ovulation, while the noradrenergic innervation exerts an indirect influence.

PET neuroimaging of clomipramine challenge in humans: focus on the thalamus.

PET neuroimaging of serotonin responsivity relied previously mainly on fenfluramine, but that drug has been withdrawn from the market. Therefore, we determined whether clomipramine, which stimulates serotonergic mechanisms by inhibiting serotonin reuptake, has reliable effects in the healthy human brain as measured by [15O]H2O PET. The clomipramine challenge markedly reduced the relative rate of blood flow in the selected region of interest, namely the dorsomedial nucleus of the thalamus, a limbic region rich in serotonin uptake sites. These findings show similarities between effects of fenfluramine and clomipramine in the healthy human brain, and support the use of the clomipramine challenge in conjunction with PET for studying cerebral serotonergic mechanisms.