Orexin Receptor Antagonists as Emerging Treatments for Psychiatric Disorders

Orexins comprise two neuropeptides produced by orexin neurons in the lateral hypothalamus and are released by extensive projections of these neurons throughout the central nervous system. Orexins bind and activate their associated G protein-coupled orexin type 1 receptors(OX1Rs) and OX2Rs and act on numerous physiological processes, such as sleep-wake regulation, feeding, reward,emotion, and motivation. Research on the development of orexin receptor antagonists has dramatically increased with the approval of suvorexant for the treatment of primary insomnia. In the present review, we discuss recent findings on the involvement of the orexin system in the pathophysiology of psychiatric disorders, including sleep disorders,depression, anxiety, and drug addiction. We discuss the actions of orexin receptor antagonists, including selective OX1R antagonists (SORA1s), selective OX2R antagonists(SORA2s), and dual OX1/2R antagonists (DORAs), in the treatment of these disorders based on both preclinical and clinical evidence. SORA2s and DORAs have more pronounced efficacy in the treatment of sleep disorders,whereas SORA1s may be promising for the treatment of anxiety and drug addiction. We also discuss potential challenges and opportunities for the application of orexin receptor antagonists to clinical interventions.     

N-acetylaspartylglutamate Inhibits Heroin Self-Administration and Heroin-Seeking Behaviors Induced by Cue or Priming in Rats

Activation of presynaptic group II metabotropic glutamate receptors(mGluR2/3) inhibits drug reward and drug-seeking behavior, but the role of N-acetylaspartylglutamate(NAAG), an agonist of endogenous mGluR2/3,in heroin reward and heroin-seeking behavior remained unclear. Here, we aimed to explore the effects of exogenous NAAG on heroin self-administration and heroinseeking behavior. First, rats were trained to self-administer heroin under a fixed ratio 1(FR1) schedule for 10 days,then received NAAG(50 or 100μg/10 μL in each nostril)in the absence or presence of LY341495(1 mg/kg, i.p.), an antagonist of mGluR2/3, on day 11 and the effects of NAAG on heroin self-administration under FR1 were recorded for 3 consecutive days. Motivation was assessed in heroin self-administration under a progressive ratio schedule on day 11 in another 5 groups with the same doses of NAAG. Additional rats were withdrawn for 14 days after 14 days of heroin self-administration, then received the same pharmacological pretreatment and were tested for heroin-seeking behaviors induced by heroin priming or cues. The results showed that intranasal administration of NAAG significantly decreased intravenous heroin selfadministration on day 12, but not on day 11. Pretreatment with LY341495 prior to testing on day 12 prevented the inhibitory effect of NAAG on heroin reinforcement. The break-point for reward motivation was significantly reduced by NAAG. Moreover, NAAG also significantly inhibited the heroin-seeking behaviors induced by heroinpriming or cues and these were restored by pretreatment with LY341495. These results demonstrated that NAAG,via activation of presynaptic mGluR2/3, attenuated the heroin reinforcement, heroin motivational value, and heroin-seeking behavior, suggesting that it may be used as an adjunct treatment for heroin addiction.     

Calcium-Impermeable NMDA Receptor: A Novel Target for Addiction

正Drug addiction results in long-term synaptic potentiation at excitatory synapses in the brain reward circuitry,especially in the ventral tegmental area(VTA)and nucleus accumbens(NAc),central parts of the mesolimbic dopamine system,and then progresses to other cortical regions[1,2].It has been proposed that a drug-induced increase in the     

Attenuated inhibition of medium spiny neurons participates in the pathogenesis of childhood depression

Accumulating evidence suggests that the nucleus accumbens, which is involved in mechanisms of reward and addiction, plays a role in the pathogenesis of depression and in the action of anti-depressants. In the current study, intraperitoneal injection of nomifensine, a dopamine reuptake inhibitor, decreased depression-like behaviors in the Wistar Kyoto rat model of depression in the sucrose-preference and forced swim tests. Nomifensine also reduced membrane excitability in medium spiny neurons in the core of the nucleus accumbens in the childhood Wistar Kyoto rats as evaluated by electrophysiological recording. In addition, the expression of dopamine D2-like receptor mRNA was downregulated in the nucleus accumbens, striatum and hippocampus of nomifensine-treated childhood Wistar Kyoto rats. These experimental ifndings indicate that impaired inhibition of medium spiny neurons, mediated by dopamine D2-like receptors, may be involved in the formation of depression-like behavior in childhood Wistar Kyoto rats, and that nomifensine can alleviate depressive behaviors by reducing medium spiny neuron membrane excitability.     

Special Topic on Mental Health and Addiction

<正>We are delighted to have been invited to edit this Special Topic on Mental Health and Addiction.Mental disorders like drug addiction,mood disorders,and schizophrenia affect a sizeable proportion of the human population,severely compromise the quality of life,and constitute a large global burden of disease.The evolution of molecular,cellular,and neurophysiological studies of rodents and the     

Abnormal brain activity in adolescents with Internet addiction who attempt suicide: an assessment using functional magnetic resonance imaging

Internet addiction is associated with an increased risk of suicidal behavior and can lead to brain dysfunction among adolescents.However,whether brain dysfunction occurs in adolescents with Internet addiction who attempt suicide remains unknown.This observational cross-sectional study enrolled 41 young Internet addicts,aged from 15 to 20 years,from the Department of Psychiatry,the First Affiliated Hospital of Chongqing Medical University,China from January to May 2018.The participants included 21 individuals who attempted suicide and 20 individuals with Internet addiction without a suicidal attempt history.Brain images in the resting state were obtained by a 3.0 T magnetic resonance imaging scanner.The results showed that activity in the gyrus frontalis inferior of the right pars triangularis and the right pars opercularis was significantly increased in the suicidal attempt group compared with the non-suicidal attempt group.In the resting state,the prefrontal lobe of adolescents who had attempted suicide because of Internet addiction exhibited functional abnormalities,which may provide a new basis for studying suicide pathogenesis in Internet addicts.The study was authorized by the Ethics Committee of Chongqing Medical University,China(approval No.2017 Scientific Research Ethics(2017-157))on December 11,2017.     

Evidence and explanation for the involvement of the nucleus accumbens in pain processing

Abstract The nucleus accumbens(NAc)is a subcortical brain structure known primarily for its roles in pleasure,reward,and addiction.Despite less focus on the NAc in pain research,it also plays a large role in the mediation of pain and is effective as a source of analgesia.Evidence for this involvement lies in the NAc's cortical connections,functions,pharmacology,and therapeutic targeting.The NAc projects to and receives information from notable pain structures,such as the prefrontal cortex,anterior cingulate cortex,periaqueductal gray,habenula,thalamus,etc.Additionally,the NAc and other pain-modulating structures share functions involving opioid regulation and motivational and emotional processing,which each work beyond simply the rewarding experience of pain offset.Pharmacologically speaking,the NAc responds heavily to painful stimuli,due to its high density ofμopioid receptors and the activation of several different neurotransmitter systems in the NAc,such as opioids,dopamine,calcitonin gene-related peptide,γ-aminobutyric acid,glutamate,and substance P,each of which have been shown to elicit analgesic effects.In both preclinical and clinical models,deep brain stimulation of the NAc has elicited successful analgesia.The multi-functional NAc is important in motivational behavior,and the motivation for avoiding pain is just as important to survival as the motivation for seeking pleasure.It is possible,then,that the NAc must be involved in both pleasure and pain in order to help determine the motivational salience of positive and negative events.     

Advances in genetic studies of substance abuse in China

Summary:The importance of genetic factors in substance addiction has long been established. The rationale for this work is that understanding of the function of addiction genes and delineation of the k...     

Dopamine as a growth differentiation factor in the mammalian brain

The catecholamine, dopamine, plays an important role in the central nervous system of mammals, including executive functions, motor control, motivation, arousal, reinforcement, and reward. Dysfunctions of the dopaminergic system lead to diseases of the brains, such as Parkinson's disease, Tourette's syndrome, and schizophrenia. In addition to its fundamental role as a neurotransmitter, there is evidence for a role as a growth differentiation factor during development. Recent studies suggest that dopamine regulates the development of γ-aminobutyric acidergic interneurons of the cerebral cortex. Moreover, in adult brains, dopamine increases the production of new neurons in the hippocampus, suggesting the promoting effect of dopamine on proliferation and differentiation of neural stem cells and progenitor cells in the adult brains. In this mini-review, I center my attention on dopaminergic functions in the cortical interneurons during development and further discuss cell therapy against neurodegenerative diseases.     

Disruption of dopamine D1 receptor phosphorylation at serine 421 attenuates cocaine-induced behaviors in mice

Dopamine D1 receptors（D1Rs） play a key role in cocaine addiction, and multiple protein kinases such as GRKs, PKA, and PKC are involved in their phosphorylation. Recently, we reported that protein kinase D1 phosphorylates the D1 R at S421 and promotes its membrane localization. Moreover, this phosphorylation of S421 is required for cocaineinduced behaviors in rats. In the present study, we generated transgenic mice over-expressing S421A-D1 R in the forebrain. These transgenic mice showed reduced phospho-D1R（S421） and its membrane localization, and reduced downstream ERK1/2 activation in the striatum. Importantly, acute and chronic cocaine-induced locomotor hyperactivity and conditioned place preference were significantly attenuated in these mice. These findings provide in vivo evidence for the critical role of S421 phosphorylation of the D1 R in its membrane localization and in cocaine-induced behaviors. Thus, S421 on the D1 R represents a potential pharmacotherapeutic target for cocaine addiction and other drug-abuse disorders.     

Decreased frontal lobe function in people with Internet addiction disorder

In our previous studies, we showed that frontal lobe and brainstem functions were abnormal in online game addicts. In this study, 14 students with Internet addiction disorder and 14 matched healthy controls underwent proton-magnetic resonance spectroscopy to measure cerebral function. Results demonstrated that the ratio of N-acetylaspartate to creatine decreased, but the ratio of cho- line-containing compounds to creatine increased in the bilateral frontal lobe white matter in people with Internet addiction disorder. However, these ratios were mostly unaltered in the brainstem, suggesting that frontal lobe function decreases in people with Internet addiction disorder.     

Extracellular Signal-Regulated Kinase in Nucleus Accumbens Mediates Propofol Self-Administration in Rats

Clinical and animal studies have indicated that propofol has potential for abuse,but the specific neurobiological mechanism underlying propofol reward is not fully understood.The purpose of this study was to investigate the role of extracellular signal-regulated kinase(ERK) signal transduction pathways in the nucleus accumbens(NAc) in propofol self-administration.We tested the expression of p-ERK in the NAc following the maintenance of propofol self-administration in rats.We also assessed the effect of administration of SCH23390,an antagonist of the D1 dopamine receptor,on the expression of p-ERK in the NAc in propofol self-administering rats,and examined the effects of intra-NAc injection of U0126,an MEK inhibitor,on propofol reinforcement in rats.The results showed that the expression of p-ERK in the NAc increased significantly in rats maintained on propofol,and pre-treatment with SCH23390 inhibited the propofol selfadministration and diminished the expression of p-ERK in the NAc.Moreover,intra-NAc injection of U0126(4 μg/side) attenuated the propofol self-administration.The data suggest that ERK signal transduction pathways coupled with D1 dopamine receptors in the NAc may be involved in the maintenance of propofol self-administration and its rewarding effects.     

Prenatal programing of motivated behaviors:can innate immunity prime behavior?

Prenatal programming during pregnancy sets physiological outcomes in the offspring by integrating external or internal stimuli.Accordingly,pregnancy is an important stage of physiological adaptations to the environment where the fetus becomes exposed and adapted to the maternal milieu.Maternal exposure to high-energy dense diets can affect motivated behavior in the offs p ring leading to addiction and impaired sociability.A high-energy dense exposure also increases the pro-inflammatory cytokines profile in plasma and brain and favors microglia activation in the offspring.While still under investigation,prenatal exposure to high-energy dense diets promotes structural abnormalities in selective brain regions regulating motivation and social behavior in the offspring.The current review addresses the role of energy-dense foods programming central and peripheral inflammatory profiles during embryonic development and its effect on motivated behavior in the offspring.We provide preclinical and clinical evidence that supports the contribution of prenatal programming in shaping immune profiles that favor structural and brain circuit disruption leading to aberrant motivated behaviors after birth.We hope this minireview encourages future research on novel insights into the mechanisms underlying maternal programming of motivated behavior by central immune networks.     

吗啡对糖奖赏剥夺所致大鼠挫折反应的抑制作用

In this study,a T-maze-based frustration model in rats was established using sucrose-reward de-privation.The results revealed that rats maintained a 75% preference for the sucrose-reward arm in the reward phase.During the sucrose-deprivation frustration phase,both the preference for the sucrose-deprivation arm (62.5%) and time spent waiting in the sucrose-deprivation arm decreased.Acute injection of morphine increased the preference in a dose-dependent fashion,and prolonged the waiting duration in the sucrose-deprivation arm.These findings indicate that morphine specifically inhibited the frustration response induced by sucrose reward deprivation.To further elucidate the pharmacological mechanisms involved,the opioid receptor antagonist naloxone was given to model rats prior to the injection of morphine.The results revealed that naloxone administration markedly attenuated the anti-frustration-like effects of 3 mg/kg morphine treatment.These findings suggest that morphine attenuates the frustration-like response to reward deprivation in rats through the opioid receptor.     

The Annual Meeting of American Academy of Addiction Psychiatry 2017

<正>Time:December 7-10,2017Venue:San Diego,California,USA Website:www.aaap.org/annual-meeting The Annual Meeting of American Academy of Addiction Psychiatry 2017 will be held on December 7-10,2017 in San Diego,California,USA.The Annual Meeting and Scientific Symposium provide the latest scientific developments in addiction psychiatry     

The Annual Meeting of American Academy of Addiction Psychiatry 2017

<正>Time:December 7-10,2017Venue:San Diego,California,USA Website:www.aaap.org/annual-meeting The Annual Meeting of American Academy of Addiction Psychiatry 2017 will be held on December 7-10,2017 in San Diego,California,USA.The Annual Meeting and Scientific Symposium provide the latest scientific developments in addiction psychiatry     

Deriving striatal projection neurons from human pluripotent stem cells with Activin A

<正>The striatum is the main input structure of the basal ganglia and is involved in voluntary motor control,habit learning and reward processing.Medium spiny neurons(MSNs)comprise80%and 95%of striatal neurons in primates and rodents,respectively,while the remaining population is made up of     

Dopamine regulation of striatal inhibitory transmission and plasticity: dopamine,low or high?

正Basal ganglia are known for their involvement in motor control.This function is accomplished via the modulatory actions of different signalling molecules;one of these is dopamine(DA),which,besides regulating cognition and reward mechanisms,participates in the organization of motor programmes by filtering and selecting     

The Annual Meeting of American Academy of Addiction Psychiatry 2017

<正>Time:December 7-10,2017Venue:San Diego,California,USAWebsite:www.aaap.org/annual-meeting Abstract deadline:June 1,2017The Annual Meeting of American Academy of Addiction Psychiatry 2017 will be held on December 7-10,2017 in San Diego,California,USA.The Annual Meeting and Scientific Symposium provide the latest scientific developments in addiction psychiatry     

Dietary habits,lifestyle factors and neurodegenerative diseases

Worldwide stroke is increasing in parallel with modernization, changes in lifestyle, and the growing elderly population. Our review is focused on the link between diet, as part of ‘modern lifestyle', and health in the context of genetic predisposition of individuals to ‘unhealthy' metabolic pathway activity. It is concluded that lifestyle including high sugar diets, alcohol and tobacco addiction or high fat diets as well as ageing, brain injury, oxidative stress and neuroinflammation, negatively influence the onset, severity and duration of neurodegenerative diseases. Fortunately, there are several healthy dietary components such as polyunsaturated fatty acids and the anti-oxidants curcumin, resveratrol, blueberry polyphenols, sulphoraphane, salvionic acid as well as caloric restriction and physical activity, which may counteract ageing and associated neurodegenerative diseases via increased autophagy or increased neurogenesis in the adult brain.