Esketamine accelerates emergence from isoflurane general anaesthesia by activating the paraventricular thalamus glutamatergic neurones in mice.

BACKGROUND: Delayed emergence from general anaesthesia poses a significant perioperative safety hazard. Subanaesthetic doses of ketamine not only deepen anaesthesia but also accelerate recovery from isoflurane anaesthesia; however, the mechanisms underlying this phenomenon remain elusive. Esketamine exhibits a more potent receptor affinity and fewer adverse effects than ketamine and exhibits shorter recovery times after brief periods of anaesthesia. As the paraventricular thalamus (PVT) plays a pivotal role in regulating wakefulness, we studied its role in the emergence process during combined esketamine and isoflurane anaesthesia. METHODS: The righting reflex and cortical electroencephalography were used as measures of consciousness in mice during isoflurane anaesthesia with coadministration of esketamine. The expression of c-Fos was used to determine neuronal activity changes in PVT neurones after esketamine administration. The effect of esketamine combined with isoflurane anaesthesia on PVT glutamatergic (PVTGlu) neuronal activity was monitored by fibre photometry, and chemogenetic technology was used to manipulate PVTGlu neuronal activity. RESULTS: A low dose of esketamine (5 mg kg-1) accelerated emergence from isoflurane general anaesthesia (474 [30] s vs 544 [39] s, P=0.001). Esketamine (5 mg kg-1) increased PVT c-Fos expression (508 [198] vs 258 [87], P=0.009) and enhanced the population activity of PVTGlu neurones (0.03 [1.7]% vs 6.9 [3.4]%, P=0.002) during isoflurane anaesthesia (1.9 [5.7]% vs -5.1 [5.3]%, P=0.016) and emergence (6.1 [6.2]% vs -1.1 [5.0]%, P=0.022). Chemogenetic suppression of PVTGlu neurones abolished the arousal-promoting effects of esketamine (459 [33] s vs 596 [33] s, P<0.001). CONCLUSIONS: Our results suggest that esketamine promotes recovery from isoflurane anaesthesia by activating PVTGlu neurones. This mechanism could explain the rapid arousability exhibited upon treatment with a low dose of esketamine.

Laser-Induced Apoptosis of Corticothalamic Neurons in Layer VI of Auditory Cortex Impact on Cortical Frequency Processing.

Corticofugal projections outnumber subcortical input projections by far. However, the specific role for signal processing of corticofugal feedback is still less well understood in comparisonto the feedforward projection. Here, we lesioned corticothalamic (CT) neurons in layers V and/or VI of the auditory cortex of Mongolian gerbils by laser-induced photolysis to investigate their contribution to cortical activation patterns. We have used laminar current-source density (CSD) recordings of tone-evoked responses and could show that, particularly, lesion of CT neurons in layer VI affected cortical frequency processing. Specifically, we found a decreased gain of best-frequency input in thalamocortical (TC)-recipient input layers that correlated with the relative lesion of layer VI neurons, but not layer V neurons. Using cortical silencing with the GABA a -agonist muscimol and layer-specific intracortical microstimulation (ICMS), we found that direct activation of infragranular layers recruited a local recurrent cortico-thalamo-cortical loop of synaptic input. This recurrent feedback was also only interrupted when lesioning layer VI neurons, but not cells in layer V. Our study thereby shows distinct roles of these two types of CT neurons suggesting a particular impact of CT feedback from layer VI to affect the local feedforward frequency processing in auditory cortex.

(S)-[18F]THK5117 brain uptake is associated with Aß plaques and MAO-B enzyme in a mouse model of Alzheimer's disease.

The mouse model of beta-amyloid (Aß) deposition, APP/PS1-21, exhibits high brain uptake of the tau-tracer (S)-[18F]THK5117, although no neurofibrillary tangles are present in this mouse model. For this reason we investigated (S)-[18F]THK5117 off-target binding to Aß plaques and MAO-B enzyme in APP/PS1-21 transgenic (TG) mouse model of Aß deposition. APP/PS1-21 TG and wild-type (WT) control mice in four different age groups (2-26 months) were imaged antemortem by positron emission tomography with (S)-[18F]THK5117, and then brain autoradiography. Additional animals were used for immunohistochemical staining and MAO-B enzyme blocking study with deprenyl pre-treatment. Regional standardized uptake value ratios for the cerebellum revealed a significant temporal increase in (S)-[18F]THK5117 uptake in aged TG, but not WT, brain. Immunohistochemical staining revealed a similar increase in Aß plaques but not endogenous hyper-phosphorylated tau or MAO-B enzyme, and ex vivo autography showed that uptake of (S)-[18F]THK5117 co-localized with the amyloid pathology. Deprenyl hydrochloride pre-treatment reduced the binding of (S)-[18F]THK5117 in the neocortex, hippocampus, and thalamus. This study's findings suggest that increased (S)-[18F]THK5117 binding in aging APP/PS1-21 TG mice is mainly due to increasing Aß deposition, and to a lesser extent binding to MAO-B enzyme, but not hyper-phosphorylated tau.

Blockade of corticotropin-releasing factor receptor 1 in the central amygdala prevents cocaine-seeking behaviour induced by orexin-A administered to the posterior paraventricular nucleus of the thalamus in male rats.

Background: Orexin-A (OrxA) administration in the posterior paraventricular nucleus of the thalamus (pPVT) reinstates extinguished cocaine-seeking behaviour following extended access to the drug (a model of dependence). The pPVT receives and integrates information associated with emotionally salient events and sends excitatory inputs to brain regions involved in the expression of emotional states, such as those driving cocaine-seeking behaviour (i.e., the nucleus accumbens, the central nucleus of the amygdala [CeA], the basolateral amygdala, the bed nucleus of the stria terminalis [BNST] and the prefrontal cortex). Methods: We monitored the activation pattern of these regions (measured by Fos) during cocaine-seeking induced by OrxA administered to the pPVT. The BNST and CeA emerged as being selectively activated. To test whether the functionality of these regions was pivotal during OrxA-induced cocaine-seeking behaviour, we transiently inactivated these regions concomitantly with OrxA administration to the pPVT. We then tested the participation of corticotropin-releasing factor receptors (CRF1) in the CeA during OrxA-induced cocaine-seeking using the CRF1 antagonist CP154526. Results: We observed selective activation of the CeA and BNST during cocaine-seeking induced by OrxA administered to the pPVT, but only transient inactivation of the CeA prevented cocaine-seeking behaviour. Administration of CP154526 to the CeA prevented OrxAinduced cocaine-seeking behaviour. Limitations: The use of only male rats could have been a limitation. Other limitations could have been the use of an indirect approach to test the hypothesis that administration of OrxA to the pPVT drives cocaine-seeking via CRF1 signalling in the CeA, and a lack of analysis of the participation of CeA subregions. Conclusion: Cocaine-seeking behaviour induced by OrxA administered to the pPVT is driven by activation of the CeA via CRF1 signalling.

Decreased thalamo-cortico connectivity during an implicit sequence motor learning task and 7 days escitalopram intake.

Evidence suggests that selective serotonin reuptake inhibitors (SSRIs) reorganize neural networks via a transient window of neuroplasticity. While previous findings support an effect of SSRIs on intrinsic functional connectivity, little is known regarding the influence of SSRI-administration on connectivity during sequence motor learning. To investigate this, we administered 20 mg escitalopram or placebo for 1-week to 60 healthy female participants undergoing concurrent functional magnetic resonance imaging and sequence motor training in a double-blind randomized controlled design. We assessed task-modulated functional connectivity with a psycho-physiological interaction (PPI) analysis in the thalamus, putamen, cerebellum, dorsal premotor, primary motor, supplementary motor, and dorsolateral prefrontal cortices. Comparing an implicit sequence learning condition to a control learning condition, we observed decreased connectivity between the thalamus and bilateral motor regions after 7 days of escitalopram intake. Additionally, we observed a negative correlation between plasma escitalopram levels and PPI connectivity changes, with higher escitalopram levels being associated with greater thalamo-cortico decreases. Our results suggest that escitalopram enhances network-level processing efficiency during sequence motor learning, despite no changes in behaviour. Future studies in more diverse samples, however, with quantitative imaging of neurochemical markers of excitation and inhibition, are necessary to further assess neural responses to escitalopram.

Determining the effect of aging, recovery time, and post-stroke memantine treatment on delayed thalamic gliosis after cortical infarct.

Secondary injury following cortical stroke includes delayed gliosis and eventual neuronal loss in the thalamus. However, the effects of aging and the potential to ameliorate this gliosis with NMDA receptor (NMDAR) antagonism are not established. We used the permanent distal middle cerebral artery stroke model (pdMCAO) to examine secondary thalamic injury in young and aged mice. At 3 days post-stroke (PSD3), slight microgliosis (IBA-1) and astrogliosis (GFAP) was evident in thalamus, but no infarct. Gliosis increased dramatically through PSD14, at which point degenerating neurons were detected. Flow cytometry demonstrated a significant increase in CD11b+/CD45int microglia (MG) in the ipsilateral thalamus at PSD14. CCR2-RFP reporter mouse further demonstrated that influx of peripheral monocytes contributed to the MG/Mϕ population. Aged mice demonstrated reduced microgliosis and astrogliosis compared with young mice. Interestingly, astrogliosis demonstrated glial scar-like characteristics at two years post-stroke, but not by 6 weeks. Lastly, treatment with memantine (NMDAR antagonist) at 4 and 24 h after stroke significantly reduced gliosis at PSD14. These findings expand our understanding of gliosis in the thalamus following cortical stroke and demonstrate age-dependency of this secondary injury. Additionally, these findings indicate that delayed treatment with memantine (an FDA approved drug) provides significant reduction in thalamic gliosis.

Chronic Administrations of Guanfacine on Mesocortical Catecholaminergic and Thalamocortical Glutamatergic Transmissions.

It has been established that the selective α2A adrenoceptor agonist guanfacine reduces hyperactivity and improves cognitive impairment in patients with attention-deficit/hyperactivity disorder (ADHD). The major mechanisms of guanfacine are considered to involve the activation of the postsynaptic α2A adrenoceptor of glutamatergic pyramidal neurons in the frontal cortex, but the effects of chronic guanfacine administration on catecholaminergic and glutamatergic transmissions associated with the orbitofrontal cortex (OFC) are yet to be clarified. The actions of guanfacine on catecholaminergic transmission, the effects of acutely local and systemically chronic (for 7 days) administrations of guanfacine on catecholamine release in pathways from the locus coeruleus (LC) to OFC, the ventral tegmental area (VTA) and reticular thalamic-nucleus (RTN), from VTA to OFC, from RTN to the mediodorsal thalamic-nucleus (MDTN), and from MDTN to OFC were determined using multi-probe microdialysis with ultra-high performance liquid chromatography. Additionally, the effects of chronic guanfacine administration on the expression of the α2A adrenoceptor in the plasma membrane fraction of OFC, VTA and LC were examined using a capillary immunoblotting system. The acute local administration of therapeutically relevant concentrations of guanfacine into the LC decreased norepinephrine release in the OFC, VTA and RTN without affecting dopamine release in the OFC. Systemically, chronic administration of therapeutically relevant doses of guanfacine for 14 days increased the basal release of norepinephrine in the OFC, VTA, RTN, and dopamine release in the OFC via the downregulation of the α2A adrenoceptor in the LC, OFC and VTA. Furthermore, systemically, chronic guanfacine administration did not affect intrathalamic GABAergic transmission, but it phasically enhanced thalamocortical glutamatergic transmission. The present study demonstrated the dual actions of guanfacine on catecholaminergic transmission-acute attenuation of noradrenergic transmission and chronic enhancement of noradrenergic transmission and thalamocortical glutamatergic transmission. These dual actions of guanfacine probably contribute to the clinical effects of guanfacine against ADHD.

Neural effects of propofol-induced unconsciousness and its reversal using thalamic stimulation.

The specific circuit mechanisms through which anesthetics induce unconsciousness have not been completely characterized. We recorded neural activity from the frontal, parietal, and temporal cortices and thalamus while maintaining unconsciousness in non-human primates (NHPs) with the anesthetic propofol. Unconsciousness was marked by slow frequency (~1 Hz) oscillations in local field potentials, entrainment of local spiking to Up states alternating with Down states of little or no spiking activity, and decreased coherence in frequencies above 4 Hz. Thalamic stimulation 'awakened' anesthetized NHPs and reversed the electrophysiologic features of unconsciousness. Unconsciousness is linked to cortical and thalamic slow frequency synchrony coupled with decreased spiking, and loss of higher-frequency dynamics. This may disrupt cortical communication/integration.

A single dose of escitalopram blunts the neural response in the thalamus and caudate during monetary loss.

Background: Selective serotonin reuptake inhibitors (SSRIs) show acute effects on the neural processes associated with negative affective bias in healthy people and people with depression. However, whether and how SSRIs also affect reward and punishment processing on a similarly rapid time scale remains unclear. Methods: We investigated the effects of an acute and clinically relevant dose (20 mg) of the SSRI escitalopram on brain response during reward and punishment processing in 19 healthy participants. In a doubleblind, placebo-controlled study using functional MRI, participants performed a well-established monetary reward task at 3 time points: at baseline; after receiving placebo or escitalopram; and after receiving placebo or escitalopram following an 8-week washout period. Results: Acute escitalopram administration reduced blood-oxygen-level-dependent (BOLD) response during punishment feedback in the right thalamus (family-wise error corrected [FWE] p = 0.013 at peak level) and the right caudate head (pFWE = 0.011 at peak level) compared to placebo. We did not detect any significant BOLD changes during reward feedback. Limitations: We included only healthy participants, so interpretation of findings are limited to the healthy human brain and require future testing in patient populations. The paradigm we used was based on monetary stimuli, and results may not be generalizable to other forms of reward. Conclusion: Our findings extend theories of rapid SSRI action on the neural processing of rewarding and aversive stimuli and suggest a specific and acute effect of escitalopram in the punishment neurocircuitry.

Input-selective adenosine A1 receptor-mediated synaptic depression of excitatory transmission in dorsal striatum.

The medial (DMS) and lateral (DLS) dorsal striatum differentially drive goal-directed and habitual/compulsive behaviors, respectively, and are implicated in a variety of neuropsychiatric disorders. These subregions receive distinct inputs from cortical and thalamic regions which uniquely determine dorsal striatal activity and function. Adenosine A1 receptors (A1Rs) are prolific within striatum and regulate excitatory glutamate transmission. Thus, A1Rs may have regionally-specific effects on neuroadaptive processes which may ultimately influence striatally-mediated behaviors. The occurrence of A1R-driven plasticity at specific excitatory inputs to dorsal striatum is currently unknown. To better understand how A1Rs may influence these behaviors, we first sought to understand how A1Rs modulate these distinct inputs. We evaluated A1R-mediated inhibition of cortico- and thalamostriatal transmission using in vitro whole-cell, patch clamp slice electrophysiology recordings in medium spiny neurons from both the DLS and DMS of C57BL/6J mice in conjunction with optogenetic approaches. In addition, conditional A1R KO mice lacking A1Rs at specific striatal inputs to DMS and DLS were generated to directly determine the role of these presynaptic A1Rs on the measured electrophysiological responses. Activation of presynaptic A1Rs produced significant and prolonged synaptic depression (A1R-SD) of excitatory transmission in the both the DLS and DMS of male and female animals. Our findings indicate that A1R-SD at corticostriatal and thalamostriatal inputs to DLS can be additive and that A1R-SD in DMS occurs primarily at thalamostriatal inputs. These findings advance the field's understanding of the functional roles of A1Rs in striatum and implicate their potential contribution to neuropsychiatric diseases.

Effects of the noncompetitive AMPA receptor antagonist perampanel on thalamo-cortical excitability: A study of high-frequency oscillations in somatosensory evoked potentials.

OBJECTIVE: Wedesignedalongitudinalcohortstudyon People with Epilepsy (PwE) with the aimofassessingthe effect of Perampanel (PER) oncortico-subcortical networks, as measured by high-frequency oscillations of somatosensory evoked potentials (SEP-HFOs). SEP-HFOs measure the excitability of both thalamo-corticalprojections(early HFOs) and intracortical GABAergic synapses (late HFOs), thus they could be used to study the anti-glutamatergic action of PER, a selective antagonist of the AMPA receptor. METHODS: 15 PwE eligible for PER add-on therapy, were enrolled prospectively. Subjects underwent SEPs recording from the dominant hand at two times: PwET0 (baseline, before PER titration) and PwET1 (therapeutic dose of 4 mg). HFOs were obtained by filtering N20 scalp response in the 400-800 Hz range. Patients were compared with a normative population of 15 healthy controls (HC) matched for age and sex. RESULTS: We found a significant reduction ofTotal HFOs and mostly early HFOs area between PwET0 and PwET1 (p = 0.05 and p = 0.045 respectively) and between HC and PwET1 (p = 0.01). Furthermore, we found a significant reduction of P24/N24 Amplitude between PwET0 and HC and between PwET0 and PwET1 (p = 0.006 and p = 0.032, respectively). CONCLUSIONS: Introduction of PER as add-on therapy reduced the area of total HFOs, acting mainly on the early burst, related to thalamo-cortical pathways. Furthermore P24/N24 amplitude, which seems to reflect a form of cortico-subcortical integration, resulted increased in PwE at T0 and normalized at T1. SIGNIFICANCE: Our findings suggest that PER acts on cortico-subcortical excitability. This could explain the broad spectrum of PER and its success in forms of epilepsy characterized by thalamo-cortical hyperexcitability.

Lysergic acid diethylamide differentially modulates the reticular thalamus, mediodorsal thalamus, and infralimbic prefrontal cortex: An in vivo electrophysiology study in male mice.

BACKGROUND: The reticular thalamus gates thalamocortical information flow via finely tuned inhibition of thalamocortical cells in the mediodorsal thalamus. Brain imaging studies in humans show that the psychedelic lysergic acid diethylamide (LSD) modulates activity and connectivity within the cortico-striato-thalamo-cortical (CSTC) circuit, altering consciousness. However, the electrophysiological effects of LSD on the neurons in these brain areas remain elusive. METHODS: We employed in vivo extracellular single-unit recordings in anesthetized adult male mice to investigate the dose-response effects of cumulative LSD doses (5-160 µg/kg, intraperitoneal) upon reticular thalamus GABAergic neurons, thalamocortical relay neurons of the mediodorsal thalamus, and pyramidal neurons of the infralimbic prefrontal cortex. RESULTS: LSD decreased spontaneous firing and burst-firing activity in 50% of the recorded reticular thalamus neurons in a dose-response fashion starting at 10 µg/kg. Another population of neurons (50%) increased firing and burst-firing activity starting at 40 µg/kg. This modulation was accompanied by an increase in firing and burst-firing activity of thalamocortical neurons in the mediodorsal thalamus. On the contrary, LSD excited infralimbic prefrontal cortex pyramidal neurons only at the highest dose tested (160 µg/kg). The dopamine D2 receptor (D2) antagonist haloperidol administered after LSD increased burst-firing activity in the reticular thalamus neurons inhibited by LSD, decreased firing and burst-firing activity in the mediodorsal thalamus, and showed a trend towards further increasing the firing activity of neurons of the infralimbic prefrontal cortex. CONCLUSION: LSD modulates firing and burst-firing activity of reticular thalamus neurons and disinhibits mediodorsal thalamus relay neurons at least partially in a D2-mediated fashion. These effects of LSD on thalamocortical gating could explain its consciousness-altering effects in humans.

Modafinil Decreased Thalamic Activation in Auditory Emotional Processing: A Randomized Controlled Functional Magnetic Resonance Imaging Study.

BACKGROUND: Modafinil improves wakefulness and attention, is approved in Japan for treatment of narcolepsy, and was reported to be effective for attention-deficit/hyperactivity disorder. However, it was reported to induce emotional instability, including mania, depression, and suicidal ideation. Such side effects may be related to changes in cognitive behavior caused by the effects of modafinil on emotional recognition. However, the effects of modafinil on the neural basis of emotional processing have not been fully verified. We used functional magnetic resonance imaging to investigate the effects of modafinil on the neural basis of auditory emotional processing. METHODS: This study adopted a placebo-controlled within-subject crossover design. Data from 14 participants were analyzed. The effects of modafinil on cerebral activation and task performance during an emotional judgement task were analyzed. RESULTS: Task accuracy decreased significantly and response time of emotional judgement was significantly delayed by modafinil, as compared with placebo. Right thalamic activation in auditory emotional processing was significantly less in the modafinil condition than in the placebo condition. In addition, reduction of right thalamic activation by modafinil was positively correlated with accuracy of emotional judgement. CONCLUSIONS: Our findings suggest that modafinil acts on the right thalamus and changes behavior and brain function associated with auditory emotional processing. These results indicate that modafinil might change emotional recognition by reducing emotional activation related to social communication.

Structural alterations in cortical and thalamocortical white matter tracts after recovery from prefrontal cortex lesions in macaques.

Unilateral damage to the frontoparietal network typically impairs saccade target selection within the contralesional visual hemifield. Severity of deficits and the degree of recovery have been associated with widespread network dysfunction, yet it is not clear how these behavioural and functional brain changes relate with the underlying structural white matter tracts. Here, we investigated whether recovery after unilateral prefrontal cortex (PFC) lesions was associated with changes in white matter microstructure across large-scale frontoparietal cortical and thalamocortical networks. Diffusion-weighted imaging was acquired in four male rhesus macaques at pre-lesion, week 1, and week 8-16 post-lesion when target selection deficits largely recovered. Probabilistic tractography was used to reconstruct cortical frontoparietal fiber tracts, including the superior longitudinal fasciculus (SLF) and transcallosal fibers connecting the PFC or posterior parietal cortex (PPC), as well as thalamocortical fiber tracts connecting the PFC and PPC to thalamic nuclei. We found that the two animals with small PFC lesions showed increased fractional anisotropy in both cortical and thalamocortical fiber tracts when behaviour had recovered. However, we found that fractional anisotropy decreased in cortical frontoparietal tracts after larger PFC lesions yet increased in some thalamocortical tracts at the time of behavioural recovery. These findings indicate that behavioural recovery after small PFC lesions may be supported by both cortical and subcortical areas, whereas larger PFC lesions may have induced widespread structural damage and hindered compensatory remodeling in the cortical frontoparietal network.

Executive functioning-specific behavioral impairments in a rat model of human third trimester binge drinking implicate prefrontal-thalamo-hippocampal circuitry in Fetal Alcohol Spectrum Disorders.

Individuals diagnosed with Fetal Alcohol Spectrum Disorders (FASD) often display behavioral impairments in executive functioning (EF). Specifically, the domains of working memory, inhibition, and set shifting are frequently impacted by prenatal alcohol exposure. Coordination between prefrontal cortex and hippocampus appear to be essential for these domains of executive functioning. The current study uses a rodent model of human third-trimester binge drinking to identify the extent of persistent executive functioning deficits following developmental alcohol by using a behavioral battery of hippocampus- and prefrontal cortex-dependent behavioral assays in adulthood. Alcohol added to milk formula was administered to Long Evans rat pups on postnatal days 4-9 (5.25 g/kg/day of ethanol; intragastric intubation), a period when rodent brain development undergoes comparable processes to human third-trimester neurodevelopment. Procedural control animals underwent sham intubation, without administration of any liquids (i.e., alcohol, milk solution). In adulthood, male rats were run on a battery of behavioral assays: novel object recognition, object-in-place associative memory, spontaneous alternation, and behavioral flexibility tasks. Alcohol-exposed rats demonstrated behavioral impairment in object-in-place preference and performed worse when the rule was switched on a plus maze task. All rats showed similar levels of novel object recognition, spontaneous alternation, discrimination learning, and reversal learning, suggesting alcohol-induced behavioral alterations are selective to executive functioning domains of spatial working memory and set-shifting in this widely-utilized rodent model. These specific behavioral alterations support the hypothesis that behavioral impairments in EF following prenatal alcohol exposure are caused by distributed damage to the prefrontal-thalamo-hippocampal circuit consisting of the medial prefrontal cortex, thalamic nucleus reuniens, and CA1 of hippocampus.

Enhancement of morphine-induced antinociception after electroconvulsive shock in mice.

Electroconvulsive therapy (ECT) has been applied for chronic pain for decades. The amounts of opioids to treat pain are sometimes reduced after a series of ECT. The effect of ECT on morphine-induced analgesia and its mechanism underlying the reduction of morphine requirement has yet to be clarified. Therefore, we administered electroconvulsive shocks (ECS) to mice and investigated the antinociceptive effect of morphine in a hot plate test. We examined the expression level of µ-opioid receptor in the thalami of mice 25 h after administration of ECS compared to the thalami of mice without ECS administration using western blotting. ECS disturbed the development of a decrease in the percentage of maximal possible effect (%MPE), which was observed 24 h after a morphine injection, when ECS was applied 25, 23, 21, and 12 h before the second administration of morphine. We also examined the effect of ECS on the dose-response curve of %MPE to morphine-antinociception. Twenty-five hours after ECS, the dose-response curve was shifted to the left, and the EC50 of morphine given to ECS-pretreated mice decreased by 30.1% compared to the mice that were not pretreated with ECS. We also found that the expression level of µ-opioid receptors was significantly increased after ECS administration. These results confirm previous clinical reports showing that ECT decreased the required dose of opioids in neuropathic pain patients and suggest the hypothesis that this effect of ECT works through the thalamus.

Brain Structure and Function of Chronic Low Back Pain Patients on Long-Term Opioid Analgesic Treatment: A Preliminary Study.

Chronic low back pain (CLBP) is often treated with opioid analgesics (OA), a class of medications associated with a significant risk of misuse. However, little is known about how treatment with OA affect the brain in chronic pain patients. Gaining this knowledge is a necessary first step towards understanding OA associated analgesia and elucidating long-term risk of OA misuse. Here we study CLBP patients chronically medicated with opioids without any evidence of misuse and compare them to CLBP patients not on opioids and to healthy controls using structural and functional brain imaging. CLBP patients medicated with OA showed loss of volume in the nucleus accumbens and thalamus, and an overall significant decrease in signal to noise ratio in their sub-cortical areas. Power spectral density analysis (PSD) of frequency content in the accumbens' resting state activity revealed that both medicated and unmedicated patients showed loss of PSD within the slow-5 frequency band (0.01-0.027 Hz) while only CLBP patients on OA showed additional density loss within the slow-4 frequency band (0.027-0.073 Hz). We conclude that chronic treatment with OA is associated with altered brain structure and function within sensory limbic areas.

The effect of GABAergic neurotransmission on the seizure-related activity of the laterodorsal thalamic nuclei and the somatosensory cortex in a genetic model of absence epilepsy.

The present study aimed to investigate the alterations of the GABAergic system in the laterodorsal nucleus (LDN) of the thalamus and the somatosensory cortex (SC) in an experimental model of absence seizure. The effects of pharmacological manipulation of both GABAA and GABAB receptor subunits in the LDN on the generation of spike-wave discharges (SWD) were evaluated. The experiments were carried out in four groups of both WAG/Rij and Wistar rats with 2 and 6 months of age. The expressions of various GABA receptor subunits were studied in the LDN and SC. Furthermore, recordings of unit activity from the LDN and electrocorticography were simultaneously monitored before, during, and after the application of GABAA and GABAB antagonists in the LDN. The generation of SWD in the older WAG/Rij rats was associated with significant alterations in the expression of GABAARα1, GABAARß3, and GABABR2 subunits in the LDN as well as GABAARα1, GABAARß3, GABAARγ2, and GABABR2 subunits in the SC. Furthermore, the occurrence of SWD was associated with a significant reduction of gene expression of GABAARα1 and increase of GABAARß3 in the LDN as well as reduction of GABAARα1, GABAARß3, GABAARγ2, and GABABR2 in the SC. The microionthophoretic application of the GABAA antagonist bicuculline resulted in a significant increase in the population firing rate of LDN neurons as well as the mean number and duration of SWD. The application of the GABAB antagonist CGP35348 significantly increased the population firing rate of LDN neurons but decreased the mean number of SWD. Our data indicate the regulatory effect of the GABAergic system of the LDN and SC in absence seizures.

Effects of Subchronic Administrations of Vortioxetine, Lurasidone, and Escitalopram on Thalamocortical Glutamatergic Transmission Associated with Serotonin 5-HT7 Receptor.

The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram.

Propofol rather than Isoflurane Accelerates the Interstitial Fluid Drainage in the Deep Rat Brain.

Objective: Different anesthetics have distinct effects on the interstitial fluid (ISF) drainage in the extracellular space (ECS) of the superficial rat brain, while their effects on ISF drainage in the ECS of the deep rat brain still remain unknown. Herein, we attempt to investigate and compare the effects of propofol and isoflurane on ECS structure and ISF drainage in the caudate-putamen (CPu) and thalamus (Tha) of the deep rat brain. Methods: Adult Sprague-Dawley rats were anesthetized with propofol or isoflurane, respectively. Twenty-four anesthetized rats were randomly divided into the propofol-CPu, isoflurane-CPu, propofol-Tha, and isoflurane-Tha groups. Tracer-based magnetic resonance imaging (MRI) and fluorescent-labeled tracer assay were utilized to quantify ISF drainage in the deep brain. Results: The half-life of ISF in the propofol-CPu and propofol-Tha groups was shorter than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. The ECS volume fraction in the propofol-CPu and propofol-Tha groups was much higher than that in the isoflurane-CPu and isoflurane-Tha groups, respectively. However, the ECS tortuosity in the propofol-CPu and propofol-Tha groups was much smaller than that in isoflurane-CPu and isoflurane-Tha groups, respectively. Conclusions: Our results demonstrate that propofol rather than isoflurane accelerates the ISF drainage in the deep rat brain, which provides novel insights into the selective control of ISF drainage and guides selection of anesthetic agents in different clinical settings, and unravels the mechanism of how general anesthetics function.