TAAR1 as an emerging target for the treatment of psychiatric disorders.

Trace amines, a group of amines expressed at the nanomolar level in the mammalian brain, can modulate monoamine transmission. The discovery of and the functional research on the trace amine-associated receptors (TAARs), especially the most well-characterized TAAR1, have largely facilitated our understanding of the function of the trace amine system in the brain. TAAR1 is expressed in the mammalian brain at a low level and widely distributed in the monoaminergic system, including the ventral tegmental area and substantial nigra, where the dopamine neurons reside in the mammalian brain. Growing in vitro and in vivo evidence has demonstrated that TAAR1 could negatively modulate monoamine transmission and play a crucial role in many psychiatric disorders, including schizophrenia, substance use disorders, sleep disorders, depression, and anxiety. Notably, in the last two decades, many studies have repeatedly confirmed the pharmacological effects of the selective TAAR1 ligands in various preclinical models of psychiatric disorders. Recent clinical trials of the dual TAAR1 and serotonin receptor agonist ulotaront also revealed a potential efficacy for treating schizophrenia. Here, we review the current understanding of the TAAR1 system and the recent advances in the elucidation of behavioral and physiological properties of TAAR1 agonists evaluated both in preclinical animal models and clinical trials. We also discuss the potential TAAR1-dependent signaling pathways and the cellular mechanisms underlying the inhibitory effects of TAAR1 activation on drug addiction. We conclude that TAAR1 is an emerging target for the treatment of psychiatric disorders.

Local tensile strain boosts the electrocatalytic ammonia oxidation reaction.

The introduction of local tensile strain in Ni(OH)2 nanosheets accelerates the Ni(OH)2-to-NiOOH transition and boosts the electrocatalytic ammonia oxidation reaction (EAOR), i.e., reducing the onset potential by 80 mV, doubling both the current density and N2 faradaic efficiency, and enabling 1000 hours of operation at 160 mA cm-2.

A natural carotenoid crocin exerts antidepressant action by promoting adult hippocampal neurogenesis through Wnt/ß-catenin signaling.

INTRODUCTION: Adult hippocampal neurogenesis (AHN) is acknowledged to play a critical role in depression. Emerging evidence suggests that the Wnt/ß-catenin pathway can modulate hippocampal neurogenesis. Crocin, a natural carotenoid, possesses antidepressant property. Yet, how it affects neurogenesis and exerts antidepressant response remains unknown. OBJECTIVE: To explore the role of AHN and Wnt/ß-catenin in the antidepressant action of crocin. METHODS: Depressive-related behaviors, including sucrose preference test (SPT), tail suspension test (TST), forced swimming test (FST), and sexual behaviors were performed following crocin treatment. Neurogenesis was characterized via immunohistochemistry, immunofluorescence, Golgi staining and electrophysiology approach. Wnt/ß-catenin signaling was examined with western blot analysis. The role of AHN Wnt/ß-catenin cascade in crocin's antidepressant response was assessed by conditional removal of glial fibrillary acidic protein (GFAP)-expressing newborn neural cells, temozolomide administration, microinfusion of Dkk1 or viral-mediated shRNA of Wnt3a. RESULTS: Crocin decreased the immobility duration in TST and FST without impairing the performance in sexual behaviors. Crocin boosted the proliferation and differentiation of progenitors, and promoted dendritic maturation and functional integration of hippocampal newborn neurons. Conditional removal of GFAP-expressing neural cells or temozolomide administration impaired the antidepressant response of crocin. Additionally, Wnt/ß-catenin signaling was promoted following crocin treatment. In chronic unpredictable mild stress (CUMS) murine model, crocin treatment displayed antidepressant response in SPT, FST and TST, and restored the neurogenesis levels and Wnt/ß-catenin signaling impaired by CUMS. Infusion of Dickkopf-1 (DKK1) or knockdown of Wnt3a in the hippocampus impaired the antidepressant response of crocin. CONCLUSION: Crocin exerted antidepressant response, which was dependent on enhancement of AHN and activation of the Wnt/ß-catenin pathway.

Selective TAAR1 agonists induce conditioned taste aversion.

RATIONALE: Trace amine-associated receptor 1 (TAAR1) is the best-studied receptor of trace amines, a group of biogenic amines expressed at a relatively low level in the mammalian brain. Growing evidence suggests that TAAR1 plays a critical role in various neuropsychiatric disorders. Given that selective TAAR1 agonists were shown to produce pro-cognition and antipsychotic-like effects as well as to suppress drug use and relapse, they have been proposed to be novel treatments for mental disorders such as schizophrenia and addiction. However, the aversive effects of selective TAAR1 agonists remain largely unknown. OBJECTIVES: Here, we evaluated whether the selective TAAR1 full agonist RO5166017 and partial agonist RO5263397 could induce conditioned taste aversion (CTA). RESULTS: We found that RO5166017 and RO5263397 produced significant aversions to both saccharin and NaCl taste novelty. Furthermore, RO5166017 produced CTA to saccharin in TAAR1 heterozygous knockout (taar1±) and wild-type rats but not in TAAR1 homozygous knockout rats (taar1-/-), suggesting that TAAR1 was sufficient for the taste aversive stimulus property of RO5166017. CONCLUSIONS: Taken together, our data indicate that selective TAAR1 agonists could produce strong CTA. Our study urges careful evaluations of the aversive effects of TAAR1 agonists before translating them to clinical use for the treatment of mental disorders.

Toll-Like Receptor 4: A Novel Target to Tackle Drug Addiction?

Drug addiction is a chronic brain disease characterized by compulsive drug-seeking and drug-taking behaviors despite the major negative consequences. Current well-established neuronal underpinnings of drug addiction have promoted the substantial progress in understanding this disorder. However, non-neuronal mechanisms of drug addiction have long been underestimated. Fortunately, increased evidence indicates that neuroimmune system, especially Toll-like receptor 4 (TLR4) signaling, plays an important role in the different stages of drug addiction. Drugs like opioids, psychostimulants, and alcohol activate TLR4 signaling and enhance the proinflammatory response, which is associated with drug reward-related behaviors. While extensive studies have shown that inhibition of TLR4 attenuated drug-related responses, there are conflicting findings implicating that TLR4 signaling may not be essential to drug addiction. In this chapter, preclinical and clinical studies will be discussed to further evaluate whether TLR4-based neuroimmune pharmacotherapy can be used to treat drug addiction. Furthermore, the possible mechanisms underlying the effects of TLR4 inhibition in modulating drug-related behaviors will also be discussed.

Trace amine-associated receptor 1 and drug abuse.

Trace amine-associated receptor 1 (TAAR1) is the best characterized receptor selectively activated by trace amines. It is broadly expressed in the monoaminergic system in the brain including ventral tegmental area (VTA), nucleus accumbens (NAc), dorsal raphe (DR) and substantial nigra (SN). Extensive studies have suggested that TAAR1 plays an important role in the modulation of monoaminergic system, especially dopamine (DA) transmission which may underlie the mechanisms by which TAAR1 interventions affect drug abuse-like behaviors. TAAR1 activation inhibits the rewarding and reinforcing effects of drugs from different classes including psychostimulants, opioid and alcohol as well as drug-induced increase in DA accumulation. The mechanisms of TAAR1's function in mediating drug abuse-like behaviors are not clear. However, it is hypothesized that TAAR1 interaction with DA transporter (DAT) and dopamine D2 receptor (D2) and the subsequent modulation of cellular cascades may contribute to the effects of TAAR1 in regulating drug abuse. Further studies are needed to investigate the role of TAAR1 in other drugs of abuse-related behaviors and its safety and efficacy for prolonged medications. Together, TAAR1 inhibits drug-induced DA transmission and drug abuse-related behaviors. Therefore, TAAR1 may be a promising therapeutic target for the treatment of drug addiction.

TAAR1 regulates drug-induced reinstatement of cocaine-seeking via negatively modulating CaMKIIα activity in the NAc.

Relapse remains a major challenge to the treatment of cocaine addiction. Recent studies suggested that the trace amine-associated receptor 1 (TAAR1) could be a promising target to treat cocaine addiction and relapse; however, the underlying mechanism remains unclear. Here, we aimed to investigate the neural mechanism underlying the role of TAAR1 in the drug priming-induced reinstatement of cocaine-seeking behavior in rats, an animal model of cocaine relapse. We focused on the shell subregion of nucleus accumbens (NAc), a key brain region of the brain reward system. We found that activation of TAAR1 by systemic and intra-NAc shell administration of the selective TAAR1 agonist RO5166017 attenuated drug-induced reinstatement of cocaine-seeking and prevented drug priming-induced CaMKIIα activity in the NAc shell. Activation of TAAR1 dampened the CaMKIIα/GluR1 signaling pathway in the NAc shell and reduced AMPAR-EPSCs on the NAc slice. Microinjection of the selective TAAR1 antagonist EPPTB into the NAc shell enhanced drug-induced reinstatement as well as potentiated CaMKIIα activity in the NAc shell. Furthermore, viral-mediated expression of CaMKIIα in the NAc shell prevented the behavioral effects of TAAR1 activation. Taken together, our findings indicate that TAAR1 regulates drug-induced reinstatement of cocaine-seeking by negatively regulating CaMKIIα activity in the NAc. Our findings elucidate a novel mechanism of TAAR1 in regulating drug-induced reinstatement of cocaine-seeking and further suggests that TAAR1 is a promising target for the treatment of cocaine relapse.

Interleukin-1 receptor-associated kinase 4 (IRAK4) in the nucleus accumbens regulates opioid-seeking behavior in male rats.

Opioid addiction remains a severe health problem. While substantial insights underlying opioid addiction have been yielded from neuron-centric studies, the contribution of non-neuronal mechanisms to opioid-related behavioral adaptations has begun to be recognized. Toll-like receptor 4 (TLR4), a pattern recognition receptor, has been widely suggested in opioid-related behaviors. Interleukin-1 receptor-associated kinase 4 (IRAK4) is a kinase essential for TLR4 responses, However, the potential role of IRAK4 in opioid-related responses has not been examined. Here, we explored the role of IRAK4 in cue-induced opioid-seeking behavior in male rats. We found that morphine self-administration increased the phosphorylation level of IRAK4 in the nucleus accumbens (NAc) in rats; the IRAK4 signaling remained activated after morphine extinction and cue-induced reinstatement test. Both systemic and local inhibition of IRAK4 in the NAc core attenuated cue-induced morphine-seeking behavior without affecting the locomotor activity and cue-induced sucrose-seeking. In addition, inhibition of IRAK4 also reduced the cue-induced reinstatement of fentanyl-seeking. Our findings suggest an important role of IRAK4 in opioid relapse-like behaviors and provide novel evidence in the association between innate immunity and drug addiction.

Activation of trace amine-associated receptor 1 attenuates nicotine withdrawal-related effects.

Nicotine addiction is a leading avoidable brain disorder globally. Although nicotine induces a modest reinforcing effect, which is important for the initial drug use, the transition from nicotine use to nicotine addiction involves the mechanisms responsible for the negative consequences of drug abstinence. Recent study suggested that trace amine-associated receptor 1 (TAAR1) is a promising pharmacological target for the modulation of positive reinforcing effects of nicotine. However, whether TAAR1 plays a part in the negative reinforcement of nicotine withdrawal remains to be determined. Here, using a long-access (LA) self-administration model, we investigated whether LA rats show increased nicotine intake and withdrawal symptoms in comparison with saline and ShA rats and then tested the effect of TAAR1 partial agonist RO5263397 on nicotine withdrawal effects. We found that rats from long-access group showed significant abstinence-induced anxiety-like behaviour, mechanic hypersensitivity, increased number of precipitated withdrawal signs and higher motivation for the drug, while rats from short-access did not differ from saline group. TAAR1 partial agonist RO5263397 significantly reduced the physical and motivational withdrawal effects of nicotine in LA rats, as reflected by increased time spent on the open arm in the elevated plus maze (EPM) test, normalized paw withdrawal threshold, decreased withdrawal signs and motivation to self-administer nicotine. This study indicates that activation of TAAR1 attenuates the negative-reinforcing effects of nicotine withdrawal and further suggests TAAR1 as a promising target to treat nicotine addiction.

Potential of Ligands for Trace Amine-Associated Receptor 1 (TAAR1) in the Management of Substance Use Disorders.

Trace amines, including ß-phenylethylamine (ß-PEA), p-tyramine (TYR), tryptamine (TRP), and p-octopamine (OCT), represent a group of amines expressed at low levels in the mammalian brain. Given the close structural similarities to traditional monoamines, links between trace amines and the monoaminergic system have long been suspected. Trace amine-associated receptor 1 (TAAR1), the most well characterized receptor in the TAAR family, has been shown to be potently activated by trace amines such as TYR and PEA. Further, catecholamine metabolites and amphetamine analogs are also potent agonists of TAAR1, implicating the receptor in mediating the monoaminergic system and in substance use disorders. In the central nervous system, TAAR1 is expressed in brain regions involved in dopaminergic, serotonergic, and glutamatergic transmission, and genetic animal models and electrophysiological studies have revealed that TAAR1 is a potent modulator of the monoaminergic system. Selective and potent engineered TAAR1 ligands, including full (RO5166017 and RO5256390) and partial (RO5203648, RO5263397 and RO5073012) agonists and the antagonist EPPTB (N-(3-ethoxyphenyl)-4-(1-pyrrolidinyl)-3-(trifluoromethyl) benzamide, RO5212773), serve as invaluable tools for the investigation of TAAR1 functions and display significant potential for the development of TAAR1-based pharmacotherapies for the treatment of substance use disorders. Despite a number of advances that have been made, more clinical studies are warranted in order to test the potential and efficacy of TAAR1 ligands in the treatment of psychiatric disorders, including substance use disorders.

The selective TAAR1 partial agonist RO5263397 promoted novelty recognition memory in mice.

RATIONALE: Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that has a particular role in regulating dopaminergic, serotonergic, and glutamatergic transmission. TAAR1 agonists have shown pro-cognitive activities. However, it remains largely unknown of the effects of TAAR1 agonists on memory performance. OBJECTIVES: Here, by using the mice novel object recognition (NOR) test, we examined the effects of the selective TAAR1 partial agonist RO5263397 on recognition memory. RESULTS: We found that RO5263397 significantly enhanced the retrieval of short-term memory (STM; 20 min after training) both in male and female mice. RO5263397 promoted the retrieval of STM in the wild-type (WT) littermates but not TAAR1-KO mice, indicating that the effects of RO5263397 were dependent on TAAR1. Interestingly, compared to their WT litters, TAAR1-KO mice showed similar levels of STM, suggesting that genetic deletion of taar1 gene did not affect the STM retrieval. Furthermore, RO5263397 also promoted the retrieval of long-term NOR memory (24 h after training). CONCLUSIONS: These results indicate that TAAR1 activation promotes NOR memory retrieval. Consistent with previous studies, our finding further suggests that TAAR1 agonists have pro-cognitive properties.

Activation of trace amine-associated receptor 1 selectively attenuates the reinforcing effects of morphine.

BACKGROUND AND PURPOSE: Trace amine-associated TA1 receptors play critical roles in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of TA1 receptors modulates addiction-like behaviours associated with psychostimulants. However, little is known about whether TA1 receptor modulation would regulate the behavioural effects of opioids. EXPERIMENTAL APPROACH: Effects of the selective TA1 receptor partial agonist RO5263397 on the addiction-related and antinociceptive effects of morphine were systematically assessed in male rats and mice. KEY RESULTS: RO5263397 attenuated the expression of morphine-induced behavioural sensitization in wildtype but not TA1 receptor knockout mice. RO5263397 shifted the dose-effect curve of morphine self-administration downward and reduced the breakpoint in a progressive ratio schedule of reinforcement but did not affect food self-administration in rats. RO5263397 decreased the cue- and drug-induced reinstatement of morphine-seeking behaviour in rats. RO5263397 alone did not trigger reinstatement of morphine-seeking behaviour or change locomotor activity in rats with a history of morphine self-administration. However, RO5263397 did not affect the expression of morphine-induced conditioned place preference in mice or rats. RO5263397 did not affect naltrexone-precipitated jumping behaviour or naltrexone-induced conditioned place aversion in morphine-dependent mice. Furthermore, RO5263397 did not affect the analgesic effects of morphine in an acute nociception model in mice and a chronic pain model in rats. CONCLUSION AND IMPLICATIONS: These results indicated that TA1 receptor activation selectively attenuated the reinforcing, but not withdrawal or antinociceptive effects of morphine, suggesting that selective TA1 receptor agonists might be useful to combat opioid addiction, while sparing the analgesic effects.

A Unique Double-Layered Carbon Nanobowl-Confined Lithium Borohydride for Highly Reversible Hydrogen Storage.

Poor reversibility and high desorption temperature restricts the practical use of lithium borohydride (LiBH4 ) as an advanced hydrogen store. Herein, a LiBH4 composite confined in unique double-layered carbon nanobowls prepared by a facile melt infiltration process is demonstrated, thanks to powerful capillary effect under 100 bar of H2 pressure. The gradual formation of double-layered carbon nanobowls is witnessed by transmission electron microscopy (TEM) observation. Benefiting from the nanoconfinement effect and catalytic function of carbon, this composite releases hydrogen from 225 °C and peaks at 353 °C, with a hydrogen release amount up to 10.9 wt%. The peak temperature of dehydriding is lowered by 112 °C compared with bulk LiBH4 . More importantly, the composite readily desorbs and absorbs ≈8.5 wt% of H2 at 300 °C and 100 bar H2 , showing a significant reversibility of hydrogen storage. Such a high reversible capacity has not ever been observed under the identical conditions. The usable volumetric energy density reaches as high as 82.4 g L-1 with considerable dehydriding kinetics. The findings provide insights in the design and development of nanosized complex hydrides for on-board applications.

Effects of a trace amine-associated receptor 1 agonist RO 5263397 on ethanol-induced behavioral sensitization.

BACKGROUND: Alcohol dependence is a chronic and severe health problem which puts a heavy burden on society. Alcohol activates mesolimbic dopamine circuity to achieve its reinforcing effect. While TAAR1 is critically involved in the modulation of dopamine, there is little evidence indicating that TAAR1 could play a role in behavioral effects of ethanol. METHODS: By using the animal model of behavioral sensitization induced by ethanol in mice, the present study was performed to investigate whether the activation of TAAR1 would affect the behavioral plasticity of ethanol. RESULTS: Repeated administration with ethanol induced a significant increased locomotion in WT mice with females showing higher level of sensitization to ethanol than male mice. The TAAR1 agonist RO5263397 significantly decreased the expression of ethanol-induced behavioral sensitization both in male and female WT mice (0.1 and 0.32 mg/kg). Repeated RO5263397 exposure also prevented the development of behavioral sensitization to ethanol both in male and female WT mice. Moreover, while TAAR1-KO mice developed normal levels of ethanol-induced behavioral sensitization, RO5263397 did not affect this behavior in TAAR1-KO mice. CONCLUSIONS: These results indicated that the TAAR1 agonist RO5263397 negatively regulated the expression and development of ethanol-elicited behavioral sensitization in WT but not in TAAR1-KO mice. The present study suggests that TAAR1 is probably involved in certain addiction-like effects of alcohol and could be a useful drug target for the development of new medications to treat alcohol dependence.

TAAR1 agonists attenuate extended-access cocaine self-administration and yohimbine-induced reinstatement of cocaine-seeking.

BACKGROUND AND PURPOSE: The trace amine-associated receptor 1 (TAAR1) negatively modulates dopamine transmission. Our previous studies demonstrated that TAAR1 agonists attenuated cue- and drug-induced cocaine-seeking and increased the elasticity of the cocaine demand curve, in the short-access cocaine self-administration model. Compulsive use of cocaine, which is an essential criterion of cocaine use disorder, can be induced by extended access to cocaine self-administration. EXPERIMENTAL APPROACH: To characterize the role of TAAR1 in compulsive cocaine use, we evaluated the effects of activation of TAAR1 on cocaine intake, cocaine binge and cue-induced cocaine-seeking using the extended-access cocaine self-administration model in adult male Sprague-Dawley rats. We also investigated the role of TAAR1 in stress-triggered cocaine relapse by using the α2 -adrenoceptor antagonist yohimbine-induced reinstatement of cocaine-seeking. KEY RESULTS: The selective TAAR1 partial agonist RO5263397 attenuated cocaine intake and did not develop tolerance during the 10-day extended-access cocaine self-administration. RO5263397 reduced a 12-h binge intake of cocaine after forced abstinence. RO5263397 also decreased cue-induced cocaine-seeking after prolonged abstinence from extended-access cocaine self-administration. Furthermore, RO5263397 and the selective TAAR1 full agonist RO5166017 reduced yohimbine-induced reinstatement of cocaine-seeking behaviour. CONCLUSION AND IMPLICATIONS: Activation of TAAR1 attenuated extended-access cocaine self-administration and stress-induced cocaine reinstatement. These results suggest that TAAR1 agonists are promising pharmacological interventions to treat cocaine use disorder and relapse.

Rapid and Prolonged Antidepressant-like Effect of Crocin Is Associated with GHSR-Mediated Hippocampal Plasticity-related Proteins in Mice Exposed to Prenatal Stress.

Prenatal stress (PNS) has a prolonged and adverse effect on offspring, leading to a significantly increased vulnerability to developing depression in their later life. Traditional therapies have delayed onset and limited efficacy; thus, it remains an urgent need to find novel medications with fast-onset and high-efficacy potentials. Crocin, with its structure clearly examined, has shown antidepressant-like effects. However, few studies extensively investigated its effect especially in mice exposed to PNS. Using an established PNS model, we tested whether crocin could have a rapid and persistent antidepressant-like effect in PNS mice. Growth hormone secretagogue receptor (GHSR) and phosphoinositide 3-kinase (PI3K) inhibitors were used to test their effects in antidepressant-like effect of crocin. Hippocampal GHSR-PI3K signaling was examined both in PNS mice treated with a single dose of crocin and in combination of GHSR inhibitor. PNS mice showed depression-like behaviors at juvenile and adulthood, and crocin induced an instant and persistent antidepressant-like response in PNS mice in a dose-dependent manner. Moreover, crocin increased the expression of hippocampal synaptic plasticity-associated proteins through the restoration of GHSR-PI3K signaling. Inhibitions of both GHSR and PI3K abolished the effect of crocin in alleviating depressive-like behaviors. More importantly, GHSR inhibitor JMV2959 blocked the enhanced expression of hippocampal plasticity-related proteins induced by crocin. The present study demonstrated that crocin induced a fast-onset and prolonged antidepressant effect in PNS mice and suggested that GHSR-PI3K signaling may play a key role in crocin's effect at least partially by a restoration of hippocampal synaptic plasticity-associated proteins.

TAAR1 and Psychostimulant Addiction.

Trace amine-associated receptor 1 is one of the best-characterized receptors of trace amines. Growing evidence shows that TAAR1 negatively regulates the monoaminergic activity, including dopamine transmission in the mesocorticolimbic system. Neurochemical assays demonstrated that selective TAAR1 full and partial agonists were effective to prevent psychostimulants-induced dopamine transmission in vitro and in vivo. In the last decade, many preclinical models of psychostimulant addiction such as drug-induced behavioral sensitization, drug-induced conditioned place preference, drug self-administration, drug discrimination, and relapse models were used to assess the effects of TAAR1 agonists on psychostimulants' behavioral effects. In general, activation of TAAR1 attenuated while knockout of TAAR1 potentiated psychostimulant abuse-related behaviors. Here, we review the advances in TAAR1 and its agonists in modulating psychostimulant addiction. We discuss the similarities and differences between the neurochemical and behavioral effects of TAAR1 full and partial agonists. We also discuss several concerns including the abuse liability, sleep reduction, and species-dependent effects that might affect the successful translation of TAAR1 agonists from preclinical studies to clinical application. In conclusion, although further investigations are in need to address certain concerns and the underlying neural mechanisms, TAAR1 agonists appear to be a promising pharmacotherapy to treat psychostimulant addiction and prevent relapse.

Toll-Like Receptor 4 Signaling and Drug Addiction.

The emphasis of neuronal alterations and adaptations have long been the main focus of the studies of the mechanistic underpinnings of drug addiction. Recent studies have begun to appreciate the role of innate immune system, especially toll-like receptor 4 (TLR4) signaling in drug reward-associated behaviors and physiology. Drugs like opioids, alcohol and psychostimulants activate TLR4 signaling and subsequently induce proinflammatory responses, which in turn contributes to the development of drug addiction. Inhibition of TLR4 or its downstream effectors attenuated the reinforcing effects of opioids, alcohol and psychostimulants, and this effect is also involved in the withdrawal and relapse-like behaviors of different drug classes. However, conflicting results also argue that TLR4-related immune response may play a minimal part in drug addiction. This review discussed the preclinical evidence that whether TLR4 signaling is involved in multiple drug classes action and the possible mechanisms underlying this effect. Moreover, clinical studies which examined the potential efficacy of immune-base pharmacotherapies in treating drug addiction are also discussed.

The Claustrum-Prefrontal Cortex Pathway Regulates Impulsive-Like Behavior.

The claustrum connects with a broad range of cortical areas including the prefrontal cortex (PFC). However, the function of the claustrum (CLA) and its neural projections remains largely unknown. Here, we elucidated the role of the neural projections from the CLA to the PFC in regulating impulsivity in male rats. We first identified the CLA-PFC pathway by retrograde tracer and virus expression. By using immunofluorescent staining of the c-Fos-positive neurons, we showed that chemogenetic activation and inhibition of the CLA-PFC pathway reduced and increased overall activity of the PFC, respectively. In the 5-choice serial reaction time task (5-CSRTT), we found that chemogenetic activation and inhibition of the CLA-PFC pathway increased and reduced the impulsive-like behavior (i.e., premature responses), respectively. Furthermore, chemogenetic inhibition of the CLA-PFC pathway prevented methamphetamine-induced impulsivity, without affecting methamphetamine-induced hyperactivity. In contrast to the role of CLA-PFC pathway in selectively regulating impulsivity, activation of the claustrum disrupted attention in the 5-CSRTT. These results indicate that the CLA-PFC pathway is essential for impulsivity. This study may shed light on the understanding of impulsivity-related disorders such as drug addiction.SIGNIFICANCE STATEMENT The claustrum is one of the most mysterious brain regions. Although extensive anatomical studies demonstrated that the claustrum connects with many cortical areas, the function of the neural projections between the claustrum and cortical areas remain largely unknown. Here, we showed that the neural projections from the claustrum to the prefrontal cortex regulates impulsivity by using the designer drugs (DREADDs)-based chemogenetic tools. Interestingly, the claustrum-prefrontal cortex pathway also regulates methamphetamine-induced impulsivity, suggesting a critical role of this neural pathway in regulating impulsivity-related disorders such as drug addiction. Our results provided preclinical evidence that the claustrum-prefrontal cortex regulates impulsivity. The claustrum-prefrontal cortex pathway may be a novel target for the treatment of impulsivity-related brain disorders.

Nanosheet-like Lithium Borohydride Hydrate with 10 wt % Hydrogen Release at 70 °C as a Chemical Hydrogen Storage Candidate.

A nanosheet-like lithium borohydride hydrate (LiBH4·H2O) measuring 20-30 nm in thickness is successfully synthesized for the first time by a facile, scalable freeze-drying strategy. The prepared LiBH4·H2O nanosheets start releasing hydrogen below 50 °C and release an amount up to approximately 10 wt % at 70 °C because of the strong affinity of H+ in the H2O ligand and H- in the BH4 group. The reported dehydrogenation properties here are superior to those of all known complex hydrides, indicating applicability as an advanced chemical hydrogen storage medium.