Tmod2 Is a Regulator of Cocaine Responses through Control of Striatal and Cortical Excitability and Drug-Induced Plasticity.

Drugs of abuse induce neuroadaptations, including synaptic plasticity, that are critical for transition to addiction, and genes and pathways that regulate these neuroadaptations are potential therapeutic targets. Tropomodulin 2 (Tmod2) is an actin-regulating gene that plays an important role in synapse maturation and dendritic arborization and has been implicated in substance abuse and intellectual disability in humans. Here, we mine the KOMP2 data and find that Tmod2 knock-out mice show emotionality phenotypes that are predictive of addiction vulnerability. Detailed addiction phenotyping shows that Tmod2 deletion does not affect the acute locomotor response to cocaine administration. However, sensitized locomotor responses are highly attenuated in these knock-outs, indicating perturbed drug-induced plasticity. In addition, Tmod2 mutant animals do not self-administer cocaine indicating lack of hedonic responses to cocaine. Whole-brain MR imaging shows differences in brain volume across multiple regions, although transcriptomic experiments did not reveal perturbations in gene coexpression networks. Detailed electrophysiological characterization of Tmod2 KO neurons showed increased spontaneous firing rate of early postnatal and adult cortical and striatal neurons. Cocaine-induced synaptic plasticity that is critical for sensitization is either missing or reciprocal in Tmod2 KO nucleus accumbens shell medium spiny neurons, providing a mechanistic explanation of the cocaine response phenotypes. Combined, these data, collected from both males and females, provide compelling evidence that Tmod2 is a major regulator of plasticity in the mesolimbic system and regulates the reinforcing and addictive properties of cocaine.

Androgens increase excitatory neurogenic potential in human brain organoids.

The biological basis of male-female brain differences has been difficult to elucidate in humans. The most notable morphological difference is size, with male individuals having on average a larger brain than female individuals1,2, but a mechanistic understanding of how this difference arises remains unknown. Here we use brain organoids3 to show that although sex chromosomal complement has no observable effect on neurogenesis, sex steroids-namely androgens-lead to increased proliferation of cortical progenitors and an increased neurogenic pool. Transcriptomic analysis and functional studies demonstrate downstream effects on histone deacetylase activity and the mTOR pathway. Finally, we show that androgens specifically increase the neurogenic output of excitatory neuronal progenitors, whereas inhibitory neuronal progenitors are not increased. These findings reveal a role for androgens in regulating the number of excitatory neurons and represent a step towards understanding the origin of sex-related brain differences in humans.

Relevance of 5-HT2A Receptor Modulation of Pyramidal Cell Excitability for Dementia-Related Psychosis: Implications for Pharmacotherapy.

Psychosis occurs across a wide variety of dementias with differing etiologies, including Alzheimer's dementia, Parkinson's dementia, Lewy body dementia, frontotemporal dementia, and vascular dementia. Pimavanserin, a selective serotonin 5-HT2A receptor (5-HT2AR) inverse agonist, has shown promising results in clinical trials by reducing the frequency and/or severity of hallucinations and delusions and the risk of relapse of these symptoms in patients with dementia-related psychosis. A literature review was conducted to identify mechanisms that explain the role of 5-HT2ARs in both the etiology and treatment of dementia-related psychosis. This review revealed that most pathological changes commonly associated with neurodegenerative diseases cause one or more of the following events to occur: reduced synaptic contact of gamma aminobutyric acid (GABA)-ergic interneurons with glutamatergic pyramidal cells, reduced cortical innervation from subcortical structures, and altered 5-HT2AR expression levels. Each of these events promotes increased pyramidal cell hyperexcitability and disruption of excitatory/inhibitory balance, facilitating emergence of psychotic behaviors. The brain regions affected by these pathological changes largely coincide with areas expressing high levels of 5-HT2ARs. At the cellular level, 5-HT2ARs are most highly expressed on cortical glutamatergic pyramidal cells, where they regulate pyramidal cell excitability. The common effects of different neurodegenerative diseases on pyramidal cell excitability together with the close anatomical and functional connection of 5-HT2ARs to pyramidal cell excitability may explain why suppressing 5-HT2AR activity could be an effective strategy to treat dementia-related psychosis.

Spike Activity in the Ventromedial Nucleus of Rat Hypothalamus during Aging.

Spike activity of neurons in the ventromedial nucleus (VMN) of the hypothalamus in adult (6-8 months) and aged (2 years) male rats was studied by the in vivo extracellular method using stereotaxic insertion of microelectrodes. In all animals, firing frequency of most VMN neurons increased in response to glucose administration. However, in aged rats, the mean baseline and glucose-induced spike frequencies of VMN neurons were lower than in adult animals. These results support the hypothesis that aging is associated with a decrease in the functional activity of hypothalamic neurons.

Dosage-Dependent Impact of Acute Serotonin Enhancement on Transcranial Direct Current Stimulation Effects.

BACKGROUND: The serotonergic system has an important impact on basic physiological and higher brain functions. Acute and chronic enhancement of serotonin levels via selective serotonin reuptake inhibitor administration impacts neuroplasticity in humans, as shown by its effects on cortical excitability alterations induced by non-invasive brain stimulation, including transcranial direct current stimulation (tDCS). Nevertheless, the interaction between serotonin activation and neuroplasticity is not fully understood, particularly considering dose-dependent effects. Our goal was to explore dosage-dependent effects of acute serotonin enhancement on stimulation-induced plasticity in healthy individuals. METHODS: Twelve healthy adults participated in 7 sessions conducted in a crossover, partially double-blinded, randomized, and sham-controlled study design. Anodal and cathodal tDCS was applied to the motor cortex under selective serotonin reuptake inhibitor (20 mg/40 mg citalopram) or placebo medication. Motor cortex excitability was monitored by single-pulse transcranial magnetic stimulation. RESULTS: Under placebo medication, anodal tDCS enhanced, and cathodal tDCS reduced, excitability for approximately 60-120 minutes after the intervention. Citalopram enhanced and prolonged the facilitation induced by anodal tDCS regardless of the dosage while turning cathodal tDCS-induced excitability diminution into facilitation. For the latter, prolonged effects were observed when 40 mg was administrated. CONCLUSIONS: Acute serotonin enhancement modulates tDCS after-effects and has largely similar modulatory effects on motor cortex neuroplasticity regardless of the specific dosage. A minor dosage-dependent effect was observed only for cathodal tDCS. The present findings support the concept of boosting the neuroplastic effects of anodal tDCS by serotonergic enhancement, a potential clinical approach for the treatment of neurological and psychiatric disorders.

Cortical excitability threshold can be increased by the AMPA blocker Perampanel in amyotrophic lateral sclerosis.

INTRODUCTION/AIMS: Cortical hyperexcitability is a feature of amyotrophic lateral sclerosis (ALS) and cortical excitability can be measured using transcranial magnetic stimulation (TMS). Resting motor threshold (MT) is a measure of cortical excitability, largely driven by glutamate. Perampanel, a glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker, is predicted to increase the cortical excitability threshold. This study aimed to evaluate TMS to functionally assess target engagement in a study of perampanel in ALS. METHOD: We studied the MT of ALS patients randomized to a single dose of perampanel or placebo 5:1 hourly for 4 h. Twelve patients participated at 4 mg and 7 returned for dosing and retesting at 8 mg. The study was terminated in April 2020 due to coronavirus disease 2019-related restrictions, after 7 out of 12 planned patients had received the 8 mg dose. Serum concentrations were also measured. RESULTS: Ten patients received the 4 mg dose (2 received placebo) and 5 received the 8 mg dose (2 received placebo). Motor Threshold increased at 2 h after dosing in the combined treatment group +7% of maximal stimulator output (P < .01). Change could be detected in the larger 4 mg group (P = .02), but not in the smaller 8 mg dose group (P = .1). No side effects were reported after single dose exposure. DISCUSSION: This study shows that perampanel effects the physiology of upper motor neurons. Studies aiming at gauging the effect of perampanel on ALS disease progression are already ongoing. Motor threshold may serve as a marker of biological target engagement.

IGF-1 facilitates extinction of conditioned fear.

Insulin-like growth factor-1 (IGF-1) plays a key role in synaptic plasticity, spatial learning, and anxiety-like behavioral processes. While IGF-1 regulates neuronal firing and synaptic transmission in many areas of the central nervous system, its signaling and consequences on excitability, synaptic plasticity, and animal behavior dependent on the prefrontal cortex remain unexplored. Here, we show that IGF-1 induces a long-lasting depression of the medium and slow post-spike afterhyperpolarization (mAHP and sAHP), increasing the excitability of layer 5 pyramidal neurons of the rat infralimbic cortex. Besides, IGF-1 mediates a presynaptic long-term depression of both inhibitory and excitatory synaptic transmission in these neurons. The net effect of this IGF-1-mediated synaptic plasticity is a long-term potentiation of the postsynaptic potentials. Moreover, we demonstrate that IGF-1 favors the fear extinction memory. These results show novel functional consequences of IGF-1 signaling, revealing IGF-1 as a key element in the control of the fear extinction memory.

The roles of caffeine and corticosteroids in modulating cortical excitability after paired associative stimulation (PAS) and transcranial alternating current stimulation (tACS) in caffeine-naïve and caffeine-adapted subjects.

The modulatory effects of non-invasive brain stimulation (NIBS) are highly variable between subjects. This variability may be due to uncontrolled caffeine consumption and circadian rhythms. Therefore, here we studied if caffeine consumption, systemically available caffeine measured in saliva, and daytime have effects on the excitability and plasticity of the motor cortex. Since both, time of the day and caffeine may mediate their effects via cortisol, we also quantified corticosteroids in saliva. Experiment 1 was performed in caffeine-naïve participants (n = 30) and compared the effects of PAS or tACS with different stimulation intensities on the motor cortex with or without caffeine 200 mg administered in a double-blind fashion. Experiment 2 was performed in regular caffeine consumers (n = 30) and compared the influence of time of day on the effects of tACS (true or sham) on the motor cortex also with or without caffeine administered in a double-blind fashion. Caffeine increased the saliva corticosteroid concentrations in both experimental groups, and corticosteroid concentrations were higher in the morning in caffeine consumers. Gender also affected corticosteroid concentrations. There was a positive correlation between caffeine concentrations and baseline cortical excitability in caffeine-adapted participants, and a negative correlation between poststimulation caffeine concentrations and motor evoked potential (MEP) amplitudes after sham stimulation in caffeine-naïve subjects. No correlations were found between poststimulation caffeine or corticosteroid concentrations, and plasticity aftereffects. PAS and tACS did not elicit changes in the corticosteroid concentrations. We conclude that moderate caffeine consumption alters cortical excitability but not plasticity aftereffects. This study was registered in the ClinicalTrials.gov with these registration IDs: 1) NCT03720665 https://clinicaltrials.gov/ct2/results?cond=NCT03720665&term=&cntry=&state=&city=&dist= 2) NCT04011670 https://clinicaltrials.gov/ct2/results?cond=&term=NCT04011670&cntry=&state=&city=&dist=.

Inhibition of ATP-sensitive potassium channels exacerbates anoxic coma in Locusta migratoria.

Under extreme environmental conditions, many insects enter a protective coma associated with a spreading depolarization (SD) of neurons and glia in the central nervous system (CNS). Recovery depends on the restoration of ion gradients by mechanisms that are not well understood. We investigated the effects of glybenclamide, an ATP-sensitive K+ (KATP) channel inhibitor, and pinacidil, a KATP activator, on the mechanisms involved in anoxic coma induction and recovery in Locusta migratoria. KATP channels allow for the efflux of K+ when activated, thereby linking cellular metabolic state to membrane potential. In intact locusts, we measured the time to enter a coma after water immersion and the time to recover the righting reflex after returning to normoxia. In semi-intact preparations, we measured the time to SD in the metathoracic ganglion after flooding the preparation with saline or exposing it to 100% N2 gas, and the time for the transperineurial potential to recover after removal of the saline or return to air. Glybenclamide decreased the time to coma induction, whereas pinacidil increased induction times. Glybenclamide also lengthened the time to recovery and decreased the rate of recovery of transperineurial potential after SD. These results were not the same as the effects of 10-2 M ouabain on N2-induced SD. We conclude that glybenclamide affects the CNS response to anoxia via inhibition of KATP channels and not an effect on the Na+/K+-ATPase.NEW & NOTEWORTHY We demonstrate the involvement of ATP-sensitive K+ (KATP) channels during recovery from spreading depolarization (SD) induced via anoxic coma in locusts. KATP inhibition using glybenclamide impaired ion homeostasis across the blood-brain barrier resulting in a longer time to recovery of transperineurial potential following SD. Comparison with ouabain indicates that the effects of glybenclamide are not mediated by the Na+/K+-ATPase but are a result of KATP channel inhibition.

Effect of psychotropic drugs on cortical excitability of patients with major depressive disorders: A transcranial magnetic stimulation study.

Transcranial magnetic stimulation (TMS) can be used to evaluate the effects of pharmacological interventions. The aim of this study was to assess the impact of the selective serotonin reuptake inhibitor, sertraline, and the atypical antipsychotic drugs quetiapine and olanzapine, on cortical excitability in unmedicated patients with major depressive disorder (MDD). The study included 45 medication-free MDD patients diagnosed according to DSM V. They were divided randomly into three groups who received a single oral dose of one of the three drugs sertraline (50 mg), quetiapine (100 mg) and olanzapine (10 mg). Psychological evaluation was conducted using the Mini-Mental State Examination (MMSE) and Beck Depression Inventory Scale (BDI). Resting and active motor thresholds (rMT and aMT) together with contralateral and ipsilateral cortical silent periods (cSP, and iSP) were measured for each participant before and at the time of maximum concentration of drug intake. There was significant increase in excitability of motor cortex after sertraline without changes in GABAB neurotransmission. Quetiapine and olanzapine potentiated inhibitory GABAB neurotransmission (prolongation of cSP); olanzapine additionally prolonged the iSP. Thus TMS can differentiate between the impact of different psychotropic drugs on excitatory and inhibitory transmission in motor cortex.

Exposure to 1-bromopropane vapors during pregnancy enhances the development of hippocampal neuronal excitability in rat pups during lactation.

OBJECTIVES: Although 1-Bromopropane (1-BP) exposure has been reported to cause neurotoxicity in adult humans and animals, its effects on the development of the central nervous system remain unclear. Recently, we reported delayed developmental neurotoxicity (DNT) upon 1-BP exposure in rats. Here we aimed to study the effect of prenatal 1-BP exposure on the hippocampal excitability in the juvenile offspring. METHODS: Pregnant Wistar rats were exposed to vaporized 1-BP for 20 days (6 h/d) with concentrations of 0 (control), 400, or 700 ppm. Hippocampal slices were prepared from male offspring during postnatal days (PNDs) 13, 14, and 15. Field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded simultaneously from the CA1 region. RESULTS: In the exposed groups, the stimulation/response relationships of fEPSP slope and PS amplitude were enhanced more than in the control group at PND 14. Analysis of fEPSP-spike coupling demonstrated increased values of Top and Eslope50 in the exposed groups. Real-time PCR analysis showed a significant increase in the mRNA levels of the adult type Nav 1.1 Na+ channel subunit and the GluR1 glutamate receptor subunit in the hippocampus of the 700 ppm group at PND 14. CONCLUSIONS: Our results provide evidence that prenatal exposure to 1-BP accelerates developmental enhancement of hippocampal excitability in the pups before eye-opening. The current study suggests that our evaluation method of DNT is applicable to the industrial chemical 1-BP.

Cortical excitability in epilepsy and the impact of antiepileptic drugs: transcranial magnetic stimulation applications.

INTRODUCTION: Epileptic conditions are characterized by impaired cortical excitation/inhibition balance and interneuronal disinhibition. Transcranial magnetic stimulation (TMS) is a neurophysiological method that assesses brain excitation/inhibition. AREA COVERED: This review was written after a detailed search in PubMed, EMBASE, ISI web of science, SciELO, Scopus, and Cochrane Controlled Trials databases from 1990 to 2020. It summarizes TMS applications for diagnostic and therapeutic purposes in epilepsy. TMS studies help to distinguish different epilepsy conditions and explore the antiepileptic drugs' (AEDs') effects on neuronal microcircuits and plasticity mechanisms. Repetitive TMS studies showed that low-frequency rTMS (0.33-1 Hz) can reduce seizures' frequency in refractory epilepsy or pause ongoing seizures; however, there is no current approval for its use in such patients as adjunctive treatment to AEDs. EXPERT OPINION: There are variable and conflicting TMS results which reflect the distinct pathogenic mechanisms of each epilepsy condition, the dynamic epileptogenic process over the long disease course resulting in the development of recurrent spontaneous seizures and/or progression of epilepsy after it is established, and the differential effect of AEDs on cortical excitability. Future epilepsy research should focus on combined TMS/functional connectivity studies that explore the complex cortical excitability circuits and networks using different TMS parameters and techniques.

Cortical excitability measured with transcranial magnetic stimulation in children with epilepsy before and after antiepileptic drugs.

AIM: To evaluate cortical excitability with transcranial magnetic stimulation (TMS) in children with new-onset epilepsy before and after antiepileptic drugs (AEDs). METHOD: Fifty-five drug-naïve patients (29 females, 26 males; 3-18y), with new-onset epilepsy were recruited from 1st May 2014 to 31st October 2017 at the Child Neurology Department, Queen Silvia's Children's Hospital, Gothenburg, Sweden. We performed TMS in 48 children (23 females, 25 males; mean [SD] age 10y [3y], range 4-15y) with epilepsy (27 generalized and 21 focal) before and after the introduction of AEDs. We used single- and paired-pulse TMS. We used single-pulse TMS to record resting motor thresholds (RMTs), stimulus-response curves, and cortical silent periods (CSPs). We used paired-pulse TMS to record intracortical inhibition and facilitation at short, long, and intermediate intervals. RESULTS: There were no differences in cortical excitability between children with generalized and focal epilepsy at baseline. After AED treatment, RMTs increased (p=0.001), especially in children receiving sodium valproate (p=0.005). CSPs decreased after sodium valproate was administered (p=0.050). As in previous studies, we noted a negative correlation between RMT and age in our study cohort. Paired-pulse TMS could not be performed in most children because high RMTs made suprathreshold stimulation impossible. INTERPRETATION: Cortical excitability as measured with RMT decreased after the introduction of AEDs. This was seen in children with both generalized and focal epilepsy who were treated with sodium valproate, although it was most prominent in children with generalized epilepsy. We suggest that TMS might be used as a prognostic tool to predict AED efficacy. WHAT THIS PAPER ADDS: Resting motor threshold (RMT) correlated negatively with age in children with epilepsy. No differences in cortical excitability were noted between patients with generalized and focal epilepsy. Treatment with antiepileptic drugs decreased cortical excitability as measured with transcranial magnetic stimulation (TMS). Decreased cortical excitability with increased RMT was recorded, especially after sodium valproate treatment. Paired-pulse TMS was difficult to perform because of high RMTs in children.

Medición de la excitabilidad cortical con estimulación magnética transcraneal en niños con epilepsia antes y después de los fármacos antiepilépticos OBJETIVO: Evaluar la excitabilidad cortical con estimulación magnética transcraneal (EMT) en niños con epilepsia de nueva aparición antes y después del uso de un fármaco antiepiléptico (FAE). MÉTODO: Cincuenta y cinco pacientes sin tratamiento previo (29 mujeres, 26 varones; de 3-18 años), con epilepsia de nueva aparición fueron reclutados del 1 de mayo de 2014 al 31 de octubre de 2017 en el Departamento de Neurología Infantil del Hospital de Niños Queen Silvia, en Gotemburgo, Suecia. Se realizó EMT en 48 niños (23 mujeres, 25 varones; media [DE] de 10 años [3 años], rango 4-15 años) con epilepsia (27 generalizada y 21 focal) antes y después de la introducción de los FAE. Usamos EMT de pulso único y de pulso emparejado. Utilizamos EMT de pulso único para registrar umbrales motores en reposo (UMR), curvas de estímulo-respuesta y períodos silenciosos corticales (PSC). Usamos EMT de pulso emparejado para registrar la inhibición y la facilitación intracorticales a intervalos cortos, largos e intermedios. RESULTADOS: No hubo diferencias en la excitabilidad cortical entre niños con epilepsia generalizada y focal al inicio. Después del tratamiento con FAE, los UMR aumentaron (p.0,001), especialmente en niños que recibieron valproato de sodio (p.0,005). Los PSC disminuyeron después de la administración del valproato sódico (p.0,050). Como en estudios anteriores, observamos una correlación negativa entre UMR y edad en nuestra cohorte de estudio. La EMT de pulso emparejado no se pudo realizar en la mayoría de los niños porque los UMR altos hacían imposible la estimulación supraumbral. INTERPRETACIÓN: La excitabilidad cortical medida con UMR disminuyó después de la introducción de los FAE. Esto se vio en niños con epilepsia generalizada y focal que fueron tratados con valproato de sodio, fue más prominente en niños con epilepsia generalizada. Sugerimos que EMT podría utilizarse como una herramienta de pronóstico para predecir la eficacia de la FAE.

Excitabilidade cortical medida com estimulação magnética transcraniana em crianças com epilepsia antes e após drogas antiepilépticas OBJETIVO: Avaliar a excitabilidade cortical com estimulação magnética transcraniana (TMS) em crianças com epilepsia de início recente antes e após drogas antiepilépticas (DAEs). MÉTODO: Cinquenta e cinco pacientes não expostos a drogas (29 do sexo feminino, 26 do sexo masculino; 3-18a), com epilepsia de início recente foram recrutadas de 1 de maio de 2014a a 31 de outubro de 2017 no Departamento de Neurologia Infantil, Hospital Rainha Silvia, Gothenburg, Suécia. Aplicamos TMS em 48 crianças (23 do sexo feminino, 25 do sexo masculino; média [DP] de idade 10a [3a], variação 4-15a) com epilepsia (27 generalizada e 21 focal) antes e após a introdução de DAEs. Usamos TMS de pulso único e pareado. O TMS de pulso único foi usado para registrar os limiares motores de repouso (LMR), curvas de estímulo-resposta, e períodos de silêncio cortical (PSC). Usamos TMS de pulsos pareados para registrar inibição e facilitação intracortical nos intervalos curto, longo e intermediário. RESULTADOS: Não houve diferenças na excitabiildade cortical entre crianças com epilepsia generalizada e focal na linha de base. Após o tratamento com DAE, o LMR aumentou (p=0,001), especialmente em crianças recebendo valproato de sódio (p=0,005). Os PSCs diminuíram após o valproato de sódio ser (p=0,050). Como em estudos prévios, notamos correlação negativa entre LMR e idade em nossa coorte. TMS de pulso pareado não pôde ser realizado na maioria das crianças porque os altos LMRs tornaram a estimulação supra-limiar impossível. INTERPRETAÇÃO: A excitabilidade cortical mensurada por LMR diminuiu após a introdução de DAEs. Isso foi visto em crianças com epilepsia generalizada e focal tratadas com valproato de sódio, embora tenha sido mais proeminente naquelas com epilepsia generalizada. Sugerimos que o TMS pode ser usada como ferramenta prognóstica para predizer a eficácia da DAE.

Chlorpromazine binding to the PAS domains uncovers the effect of ligand modulation on EAG channel activity.

Ether-a-go-go (EAG) potassium selective channels are major regulators of neuronal excitability and cancer progression. EAG channels contain a Per-Arnt-Sim (PAS) domain in their intracellular N-terminal region. The PAS domain is structurally similar to the PAS domains in non-ion channel proteins, where these domains frequently function as ligand-binding domains. Despite the structural similarity, it is not known whether the PAS domain can regulate EAG channel function via ligand binding. Here, using surface plasmon resonance, tryptophan fluorescence, and analysis of EAG currents recorded in Xenopus laevis oocytes, we show that a small molecule chlorpromazine (CH), widely used as an antipsychotic medication, binds to the isolated PAS domain of EAG channels and inhibits currents from these channels. Mutant EAG channels that lack the PAS domain show significantly lower inhibition by CH, suggesting that CH affects currents from EAG channels directly through the binding to the PAS domain. Our study lends support to the hypothesis that there are previously unaccounted steps in EAG channel gating that could be activated by ligand binding to the PAS domain. This has broad implications for understanding gating mechanisms of EAG and related ERG and ELK K+ channels and places the PAS domain as a new target for drug discovery in EAG and related channels. Up-regulation of EAG channel activity is linked to cancer and neurological disorders. Our study raises the possibility of repurposing the antipsychotic drug chlorpromazine for treatment of neurological disorders and cancer.

Chronic ethanol exposure alters prelimbic prefrontal cortical Fast-Spiking and Martinotti interneuron function with differential sex specificity in rat brain.

Chronic ethanol exposure results in numerous neurobiological adaptations that promote deficits in medial prefrontal cortical (mPFC) function associated with blunted inhibitory control and elevated anxiety during withdrawal. Studies exploring alcohol dependence-related changes in this region have largely investigated adaptations in glutamatergic signaling, with inhibitory neurotransmission remaining relatively understudied. To address this, we used biochemical and electrophysiological methods to evaluate the effects of ethanol on the activity of deep-layer prelimbic mPFC Fast-Spiking (FS) and Martinotti interneurons after chronic ethanol exposure in male and female rats. We report that chronic alcohol exposure significantly impairs FS neuron excitability in both males and females. Interestingly, we observed a marked sex difference in the baseline activity of Martinotti cells that furthermore displayed differential sex-specific responses to alcohol exposure. In addition, alcohol effects on Martinotti neuron excitability negatively correlated with hyperpolarization-activated currents mediated by hyperpolarization-activated cyclic nucleotide gated (HCN) channels, indicative of a causal relationship. Analysis of HCN1 protein expression also revealed a substantial sex difference, although no effect of ethanol on HCN1 protein expression was observed. Taken together, these findings further elucidate the complex adaptations that occur in the mPFC after chronic ethanol exposure and reveal fundamental differences in interneuron activity between sexes. Furthermore, this disparity may reflect innate differences in intracortical microcircuit function between male and female rats, and offers a tenable circuit-level explanation for sex-dependent behavioral responses to alcohol.

Application of oxytocin with low-level laser irradiation suppresses the facilitation of cortical excitability by partial ligation of the infraorbital nerve in rats: An optical imaging study.

The effects of current treatments for neuropathic pain are limited. Oxytocin is a novel candidate substance to relieve neuropathic pain, as demonstrated in various animal models with nerve injury. Low-level laser therapy (LLLT) is another option for the treatment of neuropathic pain. In this study, we quantified the effects of oxytocin or LLLT alone and the combination of oxytocin and LLLT on cortical excitation induced by electrical stimulation of the dental pulp using optical imaging with a voltage-sensitive dye in the neuropathic pain model with partial ligation of the infraorbital nerve (pl-ION). We applied oxytocin (OXT, 0.5 µmol) to the rat once on the day of pl-ION locally to the injured nerve. LLLT using a diode laser (810 nm, 0.1 W, 500 s, continuous mode) was performed daily via the skin to the injured nerve from the day of pl-ION to 2 days after pl-ION. Cortical responses to electrical stimulation of the mandibular molar pulp under urethane anesthesia were recorded 3 days after pl-ION. Both the amplitude and area of excitation in the primary and secondary somatosensory and insular cortices in pl-ION rats were larger than those in sham rats. The larger amplitude of cortical excitation caused by pl-ION was suppressed by OXT or LLLT. The expanded area of cortical excitation caused by pl-ION was suppressed by OXT with LLLT but not by OXT or LLLT alone. These results suggest that the combined application of OXT and LLLT is effective in relieving the neuropathic pain induced by trigeminal nerve injury.

Cortical Excitability by Transcranial Magnetic Stimulation as Biomarkers for Seizure Controllability in Temporal Lobe Epilepsy.

OBJECTIVE: To investigate whether indicators of cortical excitability are good biomarkers of seizure controllability in temporal lobe epilepsy (TLE). MATERIALS AND METHODS: Three groups of subjects were recruited: those with poorly controlled (PC) TLE (N = 41), well-controlled (WC) TLE (N = 71), and healthy controls (N = 44). Short- and long-latency recovery curves were obtained by paired-pulse transcranial magnetic stimulation. Linear mixed effect models were used to study the effects of group, interstimulus interval (ISI), and antiepileptic drugs on long-interval intracortical inhibition (LICI) and short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). RESULTS: The mixed effect model that did not incorporate antiepileptic drugs showed that group and ISI were significant factors for LICI and SICI/ICF. LICI in the healthy control group was greater than in the two epilepsy groups, and the difference was significant at ISIs of 50, 150, and 200 msec. In contrast, SICI/ICF in the PC group was greater than in the healthy control and WC groups, and the difference was significant at an ISI of 15 msec. However, due to large variance, it was difficult to identify a cutoff value with both good sensitivity and good specificity. Incorporating the information of antiepileptic drugs to the mixed effect model did not change the overall results. CONCLUSIONS: Although LICI and SICI/ICF parameters were significantly different at the group level, they may not be suitable biomarkers for the controllability of TLE at the subject level.

Effect of chronic nicotine consumption on motor cortical excitability: A transcranial magnetic stimulation study.

OBJECTIVES: Transcranial magnetic stimulation (TMS) allows exploration of the mode of action of neuroactive substances in the human brain, and allows evaluation of neuronal networks, which might be involved in the action of nicotine. The aim of the present study was to explore motor cortex excitability in chronic smokers and non-smokers using TMS. METHODS: The study included 50 healthy subjects, of whom 25 were chronic smokers and 25 were age- and sex-matched non-smokers. Number of cigarettes per day and duration of smoking in years were documented. Serum level of cotinine was measured. Resting and active motor threshold (RMT, AMT) and input-output curves (I/O) were performed to assess corticospinal excitability. The duration of the contralateral silent period (cSP) at different ranges of stimulation intensities and ipsilateral silent period (iSP) were used as measures of inhibition. RESULTS: There were no significant differences either in RMT or AMT between groups. I/O curve showed a significant intensity×group interaction (P=0.008). This was attributable to significantly higher amplitudes of MEP among smokers than non-smokers especially at 130, 140 and 150% of RMT (P=0.0001 and P=0.03 and 0.02 respectively). The mean duration of the cSP at different intensities and iSP duration were similar in both groups. Nicotine level and smoking index were correlated respectively with rMT and iSP (P=0.03 and 0.01). CONCLUSION: The present results confirm previous findings by Grundey et al. (2013) that chronic nicotine consumption is characterized by hyperexcitability of corticospinal output. We speculate that it is a secondary adaptation to long-term nicotine use with high inter-individual variance.

TMS as a pharmacodynamic indicator of cortical activity of a novel anti-epileptic drug, XEN1101.

OBJECTIVE: Transcranial magnetic stimulation (TMS) produces characteristic deflections in the EEG signal named TMS-evoked EEG potentials (TEPs), which can be used to assess drug effects on cortical excitability. TMS can also be used to determine the resting motor threshold (RMT) for eliciting a minimal muscle response, as a biomarker of corticospinal excitability. XEN1101 is a novel potassium channel opener undergoing clinical development for treatment of epilepsy. We used TEPs and RMT to measure the effects of XEN1101 in the human brain, to provide evidence that XEN1101 alters cortical excitability at doses that might be used in future clinical trials. METHODS: TMS measurements were incorporated in this Phase I clinical trial to evaluate the extent to which XEN1101 modulates TMS parameters of cortical and corticospinal excitability. TEPs and RMT were collected before and at 2-, 4-, and 6-hours post drug intake in a double-blind, placebo-controlled, randomized, two-period crossover study of 20 healthy male volunteers. RESULTS: Consistent with previous TMS investigations of antiepileptic drugs (AEDs) targeting ion channels, the amplitude of TEPs occurring at early (15-55 msec after TMS) and at late (150-250 msec after TMS) latencies were significantly suppressed from baseline by 20 mg of XEN1101. Furthermore, the RMT showed a significant time-dependent increase that correlated with the XEN1101 plasma concentration. INTERPRETATION: Changes from baseline in TMS measures provided evidence that 20 mg of XEN1101 suppressed cortical and corticospinal excitability, consistent with the effects of other AEDs. These results support the implementation of TMS as a tool to inform early-stage clinical trials.

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action.

For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors. Drug development of non-D2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D2-based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D2 receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D2 signaling. SIGNIFICANCE STATEMENT: Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D2 receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D2 receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT1A receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders.