Naoe Okamura

Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants

BACKGROUND Because researchers have reported that antidepressants increase the expression of brain-derived neurotrophic factor (BDNF) in the rat hippocampus, we investigated whether serum BDNF levels may be used as a putative biological marker for major depressive disorders (MDD). METHODS We measured serum BDNF in the following three groups: antidepressant-naive patients with MDD (n = 16), antidepressant-treated patients with MDD (n = 17), and normal control subjects (n = 50). Patients were evaluated using the Hamilton Rating Scale for Depression (HAM-D). Serum BDNF was assayed with the sandwich ELISA method. RESULTS We found that serum BDNF was significantly lower in the antidepressant-naive group (mean, 17.6 ng/mL; SD, 9.6) than in the treated (mean, 30.6 ng/mL; SD, 12.3; p =.001) or in the control group (mean, 27.7 ng/mL; SD, 11.4; p =.002). There was a significant negative correlation (r = -.350, z = -2.003, p =.045) between serum BDNF and HAM-D scores in all patients. In a preliminary examination, reduced BDNF values of three drug-naive patients recovered to basal levels after antidepressant treatment. CONCLUSIONS Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of MDD and that antidepressants may increase BDNF in depressed patients.

Neuropeptide S-Mediated Control of Fear Expression and Extinction: Role of Intercalated GABAergic Neurons in the Amygdala

A deficient extinction of memory is particularly important in the regime of fear, where it limits the beneficial outcomes of treatments of anxiety disorders. Fear extinction is thought to involve inhibitory influences of the prefrontal cortex on the amygdala, although the detailed synaptic mechanisms remain unknown. Here, we report that neuropeptide S (NPS), a recently discovered transmitter of ascending brainstem neurons, evokes anxiolytic effects and facilitates extinction of conditioned fear responses when administered into the amygdala in mice. An NPS receptor antagonist exerts functionally opposing responses, indicating that endogenous NPS is involved in anxiety behavior and extinction. Cellularly, NPS increases glutamatergic transmission to intercalated GABAergic neurons in the amygdala via presynaptic NPS receptors on connected principal neurons. These results identify mechanisms of NPS in the brain, a key role of intercalated neurons in the amygdala for fear extinction, and a potential pharmacological avenue for treating anxiety disorders.

Decreased levels of serum brain-derived neurotrophic factor in female patients with eating disorders

BACKGROUND Several lines of evidence suggest that brain-derived neurotrophic factor (BDNF) plays a role in the regulation of eating behavior. Because of its role in eating behavior, which is especially relevant to eating disorders, BDNF is an attractive candidate for investigation of potential biological markers of eating disorders such as bulimia nervosa (BN) and anorexia nervosa (AN). METHODS We enrolled 18 female patients with BN, 12 female patients with AN, and 21 age-matched female normal control subjects in this study. Eating-related psychopathology and depressive symptoms were evaluated using the Bulimic Investigatory Test, Edinburgh (BITE) and the Hamilton Depression Rating Scale (HDRS). Serum BDNF levels were measured by a sandwich enzyme-linked immunosorbent assay. RESULTS Serum levels of BDNF in the patients with AN or BN were significantly (p<.0001) decreased compared with those of normal control subjects, and serum BDNF levels in the patients with AN were significantly (p=.027) lower than those in patients with BN. A significant positive correlation (r=.378, p=.006) between serum BDNF levels and body mass index in all of the subjects was detected. Furthermore, there was a significant positive correlation (r=.435, p=.015) between the BITE symptom scale score and HDRS in these patients. CONCLUSIONS The present study suggests that BDNF may play a role in the pathophysiology of eating disorders.

Serum brain-derived neurotrophic factor (BDNF) levels in schizophrenia are indistinguishable from controls

Our previous study showed that serum brain-derived neurotrophic factor (BDNF) was significantly decreased in the antidepressant-naive patients with major depressive disorders. However, it was still unclear whether serum BDNF level was altered in drug-naive patients with schizophrenia. Using ELISA, we measured serum BDNF levels in antipsychotic-naive (n=15) and medicated (n=25) patients with schizophrenia, and in age- and sex-matched normal controls (n=40). There were no significant differences in serum BDNF levels among antipsychotic-naive (n=15) and medicated (n=25) patients and normal controls (n=40). Possible factors such as duration of illness, age of onset, Brief Psychiatric Rating Scale scores, and chlorpromazine equivalent dosages of antipsychotics did not reveal any significant correlations with BDNF levels. Our results do not support the view that serum BDNF levels are associated with schizophrenia.

Tropisetron improves deficits in auditory P50 suppression in schizophrenia

Physiological deficits in inhibition of the P50 auditory evoked potential in schizophrenia have been related to diminished expression of alpha7 nicotinic acetylcholine receptors. Diminished P50 inhibition is correlated with neuropsychological deficits in attention, one of the principal neurocognitive disturbances in schizophrenia. Nicotine administration improves P50 inhibition, presumably by achieving additional activation of these diminished receptors, but its toxicity and marked tachyphylaxis make it an ineffective therapeutic. Nicotine also has weak positive effects on several neurocognitive deficits in schizophrenia, which raises the possibility that the alpha7 nicotinic receptor is a clinically relevant therapeutic target that should be addressed by less toxic agents. Tropisetron, a drug already approved for clinical use outside the United States as an anti-emetic, is a partial agonist at alpha7 nicotinic receptors and an antagonist at 5-HT(3) receptors. As an initial proof-of-principle study, we determined that a single administration of tropisetron significantly improves P50 inhibition in schizophrenia. These data are consistent with biological activity at a pathophysiological mechanism in schizophrenia and support further trials of this drug as a possible therapeutic for neurocognitive deficits in schizophrenia.

Effect of antioxidant N-acetyl-l-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine

Several lines of evidence suggest that oxidative stress may play a role in the behavioral changes and neurotoxicity in rats after administration of methamphetamine (MAP). N-acetyl-L-cysteine (NAC) is a precursor of glutathione, and it also exerts as an antioxidant. In this study, we investigated the effects of NAC on the behavioral changes (hyperlocomotion and development of sensitization) and neurotoxicity in male Wistar rats after administration of MAP. Pretreatment with NAC (30, 100 or 300 mg/kg, i.p.) attenuated significantly hyperlocomotion in rats induced by a single administration of MAP (2 mg/kg, i.p.), in a dose-dependent manner. Furthermore, pretreatment with NAC (100 mg/kg, i.p., 15 min before MAP injection, once daily for 5 consecutive days) blocked significantly the development of behavioral sensitization in rats after repeated administration of MAP (2 mg/kg, once daily for 5 consecutive days), whereas the behaviors in rats after repeated administration of NAC plus saline groups were not different from those of control (vehicle plus saline) groups. One week after administration of MAP (7.5 mg/kg x 4, 2-h intervals), levels of dopamine (DA) in rat striatum were significantly decreased as compared with control groups. Pretreatment with NAC (1, 3, 10 or 30 mg/kg, i.p., 30 min before each MAP injection) attenuated significantly the MAP-induced reduction of DA in rat striatum, in a dose-dependent manner. These results suggest that NAC could prevent the behavioral changes (acute hyperlocomotion and development of behavioral sensitization) in rats and neurotoxicity in rat striatum after administration of MAP, and that NAC would be a useful drug for treatment of several symptoms associated with MAP abuse.

Synthesis and Pharmacological in Vitro and in Vivo Profile of 3-Oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic Acid 4-Fluoro-benzylamide (SHA 68), a Selective Antagonist of the Neuropeptide S Receptor

Neuropeptide S (NPS) has been shown to modulate arousal, sleep wakefulness, anxiety-like behavior, and feeding after central administration of the peptide agonist to mice or rats. We report here the chemical synthesis and pharmacological characterization of SHA 66 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid benzylamide) and SHA 68 (3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide), two closely related bicyclic piperazines with antagonistic properties at the NPS receptor (NPSR). The compounds block NPS-induced Ca2+ mobilization, and SHA 68 shows displaceable binding to NPSR in the nanomolar range. The antagonistic activity of SHA 68 seems to be specific because it does not affect signaling at 14 unrelated G protein-coupled receptors. Analysis of pharmacokinetic parameters of SHA 68 demonstrates that the compound reaches pharmacologically relevant levels in plasma and brain after i.p. administration. Furthermore, peripheral administration of SHA 68 in mice (50 mg/kg i.p.) is able to antagonize NPS-induced horizontal and vertical activity as well as stereotypic behavior. Therefore, SHA 68 could be a useful tool to characterize physiological functions and pharmacological parameters of the NPS system in vitro and in vivo.

Gender-specific association of a functional coding polymorphism in the Neuropeptide S receptor gene with panic disorder but not with schizophrenia or attention-deficit/hyperactivity disorder

Panic disorder is a common anxiety disorder characterized by sudden and recurrent panic attacks. Previous studies have indicated significant genetic contributions and a susceptibility locus for panic disorder has been mapped to human chromosome 7p 15. The receptor for Neuropeptide S (NPS) is located in the same genomic region while NPS is known to produce arousal and anxiolytic-like effects in rodents. Here we report that a coding polymorphism in the Neuropeptide S receptor (NPSR) is associated with panic disorder in male patients of Japanese ancestry. The polymorphism (Asn(107)Ile) results in a gain-of-function of the receptor protein by increasing the agonist sensitivity about tenfold. The allele representing the less active isoform (NPSR Asn(107)) was found under-represented in male panic disorder patients, indicating a potential protective function of the protein. Two unrelated groups of patients diagnosed with schizophrenia or attention-deficit/hyperactivity disorder (ADHD) showed no association of particular NPSR alleles with the disorders. These results provide evidence for a gender-specific effect of NPSR in the pathogenesis of panic disorder.

Neuropeptide S enhances memory during the consolidation phase and interacts with noradrenergic systems in the brain.

Neuropeptide S (NPS) has been shown to promote arousal and anxiolytic-like effects, as well as facilitation of fear extinction. In rodents, NPS receptors (NPSR) are prominently expressed in brain structures involved in learning and memory. Here, we investigate whether exogenous or endogenous NPS signaling can modulate acquisition, consolidation, or recall of emotional, spatial, and contextual memory traces, using two common behavioral paradigms, inhibitory avoidance (IA) and novel object recognition. In the IA paradigm, immediate and delayed post-training central NPS administration dose dependently enhanced memory retention in mice, indicating that NPS may act during the consolidation phase to enhance long-term memory. In contrast, pre-training or pre-test NPS injections were ineffective, suggesting that NPS had no effect on IA memory acquisition or recall. Peripheral administration of a synthetic NPSR antagonist attenuated NPS-induced IA memory enhancement, showing pharmacological specificity. NPS also enhanced hippocampal-dependent non-aversive memory in the novel object recognition task. In contrast, NPSR knockout mice displayed deficits in IA memory, novel object recognition, and novel place or context recognition, suggesting that activity of the endogenous NPS system is required for memory formation. Blockade of adrenergic signaling by propranolol attenuated NPS-induced memory enhancement in the IA task, indicating involvement of central noradrenergic systems. These results provide evidence for a facilitatory role of NPS in long-term memory, independent of memory content, possibly by acting as a salience signal or as an arousal-promoting factor.

Behavioral phenotyping of Neuropeptide S receptor knockout mice

Central administration of neuropeptide S (NPS) in rodents induces arousal and prolonged wakefulness as well as anxiolytic-like effects. NPS has also been implicated in modulation of cognitive functions and energy homeostasis. Here we present a comprehensive phenotypical analysis of mice carrying a targeted mutation in the NPS receptor (NPSR) gene. NPSR knockout mice were found to exhibit reduced exploratory activity when challenged with a novel environment, which might indicate attenuated arousal. We also observed attenuated late peak wheel running activity in NPSR knockout mice, representing reduced activity during the subjective evening. These mice also displayed increased anxiety-like behaviors when compared to their wildtype littermates, although analysis of anxiety behaviors was limited by genetic background influences. Unexpectedly, NPSR knockout mice showed enhanced motor performance skills. No phenotypical differences were detected in the forced-swim test, startle habituation and pre-pulse inhibition paradigms. Together, these data indicate that the endogenous NPS system might be involved in setting or maintaining behavioral arousal thresholds and that the NPS system might have other yet undiscovered physiological functions.