To investigate the effect of dl-3n-butylphthalide (NBP) on the protection of cerebral tissue and possible mechanism on ischaemia-reperfusion injury, and to find out whether NBP therapy can extend the reperfusion window in an experimental stroke model in rats.

Seventy-two Sprague-Dawley rats were randomly divided into sham operation, ischaemia-reperfusion and ischaemia-reperfusion with NBP groups. Focal cerebral ischaemia was induced using the modified intraluminal thread method and maintained for 2, 3 or 4 h. The ischaemia-reperfusion group received reperfusion immediately after ischaemia-reperfusion. The NBP group received intraperitoneal injection of NBP immediately after ischaemia, followed by reperfusion. The sham operation group received only injection of physiological saline. The cerebral infarction volume and neurological deficit were analysed, and vascular endothelial growth factor (VEGF) expression in brain tissues was visualised by immunohistochemistry.

NBP treatment caused a significant decrease in both infarction volume and neurological deficit compared with the ischaemia-reperfusion group at corresponding time points in each (p < 0.05). In the NBP group, the infarction volume and neurological deficit did not change with different ischaemia times. The expression of VEGF was significantly decreased in the ischaemia-reperfusion group compared with the sham group (p < 0.01), while this change was partly prevented in the NBP group (p < 0.01). The expression of VEGF in brain tissue in both the NBP and ischaemia-reperfusion groups gradually decreased when the ischaemic period was prolonged.

NBP treatment has a protective effect against cerebral ischaemia; this possible mechanism maybe related to the VEGF expression and may extend the reperfusion window for subsequent salvage of cerebral ischaemia by reperfusion.

Glycine regulates glutamatergic neurotransmission, and several papers have reported the relationship between glycine and schizophrenia. The dysbindin-1 (DTNBP1: dystrobrevin-binding protein 1) gene is related to glutamatergic neurotransmission and has been found to be a strong candidate gene for schizophrenia. In this study, we clarified the relationship between dysbindin, glutamate, and glycine with in vivo microdialysis methods.

We measured extracellular glycine and glutamate levels in the striatum of sandy (sdy) mice using in vivo microdialysis methods. Sdy mice express no dysbindin protein owing to a deletion in the dysbindin-1 gene. In addition, we measured changes in those amino acids after methamphetamine (METH) administration.

The basal levels of extracellular glycine and glutamate in the striatum of sdy mice were elevated. These extracellular glutamate levels decreased gradually after METH administration and were not subsequently different from those of wild-type mice.

These results suggest that dysbindin might modulate glycine and glutamate release in vivo.

Selective serotonin reuptake inhibitors (SSRIs) have been widely used in the treatment of most anxiety disorders. In this study, to clarify the mechanism of the anxiolytic effect, we investigated the mechanism underlying the effect of the SSRI citalopram on rat contextual conditioned fear stress (CFS), an animal model of anxiety.

Rats individually received footshocks in a shock chamber. More than 1 day later, they were given citalopram and/or dl‐p‐chlorophenylalanine (PCPA), various subtype‐selective serotonin (5‐HT) receptor antagonists: the 5‐HT1A receptor antagonist WAY 100635, the 5‐HT2A receptor antagonist MDL 100907, the 5‐HT2C receptor antagonist SB 242084, the 5‐HT3 receptor antagonist tropisetron, the 5‐HT4 receptor antagonist GR 125487, the 5‐HT6 receptor antagonist SB 258585 or the 5‐HT7 receptor antagonist SB 269970. After drug administration, freezing behaviour, which was used as an index of anxiety, was analysed in the same shock chamber without shocks.

Citalopram dose dependently reduced conditioned freezing behaviour. The anxiolytic‐like effect of citalopram was prevented completely by pretreatment with the 5‐HT‐depleting agent PCPA, but not by the 5‐HT1A receptor antagonist WAY 100635. Furthermore, none of the subtype‐selective 5‐HT receptor antagonists significantly affected conditioned freezing or affected the anxiolytic‐like effect of citalopram.

The anxiolytic‐like effect of citalopram in contextual CFS model depends on 5‐HT availability. In addition, contextual CFS model is suggested to be completely different from conventional anxiety models in neural mechanism or manners of serotonergic involvement. However, further studies are needed to identify the pharmacological mechanisms responsible for the anxiolytic‐like effect of citalopram.

Here, we examined the cingulum bundle, a long-range white matter tract mediating dorsal limbic connectivity, using diffusion tensor imaging (DTI) tractography, in children and adolescents with autism spectrum disorder (ASD) versus controls. We hypothesised that cingulum bundle microstructure would be altered in ASD, based on evidence implicating abnormal white matter connectivity in this disorder.

DTI data were acquired for 19 ASD participants (IQ ⩾ 70; 7–18 years; mean = 12.4 ± 3.1) and 16 age-matched controls (7–18 years; mean = 12.3 ± 3.6) on a 3 T magnetic resonance imaging system. Deterministic tractography was used to isolate the cingulum bundle. Left and right cingulum bundles were examined for differences in several DTI metrics in ASD children/adolescents versus controls, including: fractional anisotropy (FA), mean, axial, and radial diffusivity.

Significant age × group interaction effects were found for all DTI metrics (mean diffusivity: F1,28 = 9.5, p = 0.005, radial diffusivity: F1,28 = 7.8, p = 0.009, axial diffusivity: F1,28 = 5.2, p = 0.03, FA: F1,28 = 4.4, p = 0.04). Interaction effects were driven by increases in cingulum bundle diffusivity (mean, radial, and axial diffusivity), and decreased FA, in younger ASD participants within our sample versus controls.

Our results point to immature microstructural organisation of the cingulum bundle in ASD, particularly during the early years of life, with implications for limbic network synchronisation and complex socio-emotional performance.

The present study was aimed at evaluating the effects of the administration of β-carboline harmine on behaviour and citrate synthase activity in the brain of rats exposed to chronic mild stress (CMS) procedure.

To this aim, after 40 days of exposure to CMS procedure, rats were treated with harmine (15 mg/kg/day) for 7 days, then memory, anhedonia and citrate synthase activity were assessed.

Our findings demonstrated that stressed rats treated with saline increased the sucrose intake, and the stressed rats treated with harmine reversed this effect. Neither stress nor harmine treatment altered memory performance in rats. In addition, chronic stressful situations induced increase in citrate synthase activity in the prefrontal cortex, but not in the hippocampus and striatum. Treatment with harmine reversed the increase in citrate synthase activity in the prefrontal cortex.

These findings support the hypothesis that harmine could be involved in controlling the energy metabolism.

A large body of research that has investigated substance dependence and working memory (WM) resources, yet no prior study has used a comprehensive test battery to examine the impact of chronic drug dependence on WM as a multi‐component system.

This study examined the efficiency of several WM components in participants who were chronic drug dependents. In addition, the functioning of the four WM components was compared among dependents of various types of drugs.

In total, 128 chronic drug dependents participated in this study. Their average age was 38.48 years, and they were classified into four drug‐dependence groups. Chronic drug dependents were compared with a 36‐participant control group that had a mean age of 37.6 years. A WM test battery that comprised eight tests and that assessed each of four WM components was administered to each participant.

Compared with the control group, all four groups of drug dependents had significantly poorer test performance on all of the WM tasks. Among the four groups of drug users, the polydrug group had the poorest performance scores on each of the eight tasks, and the performance scores of the marijuana group were the least affected. Finally, the forward digit span task and the logical memory tasks were less sensitive than other tasks when differentiating between marijuana users and the normal participants.

The four components of WM are impaired among chronic drug dependents. These results have implications for the development of tools, classification methods and therapeutic strategies for drug dependents.

Typical and atypical antipsychotic drugs have been shown to have different clinical, biochemical and behavioural profiles. It is well described that impairment of metabolism, especially in the mitochondria, leads to oxidative stress and neuronal death and has been implicated in the pathogenesis of a number of diseases in the brain. In this context, we investigated the in vitro effect of antipsychotic drugs on energy metabolism parameters in the brain of rats.

Clozapine (0.1, 0.5 and 1.0 mg/ml), olanzapine (0.1, 0.5 and 1.0 mg/ml) and aripiprazole (0.05, 0.15 and 0.3 mg/ml) were suspended in buffer and added to the reaction medium containing rat tissue homogenates and the respiratory chain complexes, succinate dehydrogenase and creatine kinase (CK) activities were evaluated.

Our results showed that olanzapine and aripriprazole increased the activities of respiratory chain complexes. On the other hand, complex IV activity was inhibited by clozapine, olanzapine and aripriprazole. CK activity was increased by clozapine at 0.5 and 1.0 mg/ml in prefrontal cortex, cerebellum, striatum, hippocampus and posterior cortex of rats. Moreover, olanzapine and aripiprazole did not affect CK activity.

In this context, if the hypothesis that metabolism impairment is involved in the pathophysiology of neuropsychiatric disorders is correct and these results also occur in vivo, we suggest that olanzapine may reverse a possible diminution of metabolism.

Altered cardiac autonomic function has been proposed in schizophrenia, but the results are mixed. Therefore, analyses with larger sample sizes and better methodology are needed.

To examine whether acute schizophrenia is associated with cardiac autonomic dysfunction, 314 unmedicated patients with acute schizophrenia and 409 healthy volunteers, aged 18–65 years, were recruited for a case–control analysis. The severity of schizophrenia symptoms was assessed with the Positive and Negative Syndrome Scale. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters during the supine–standing–supine test. Frequency-domain indices of HRV were obtained.

Unmedicated patients with acute schizophrenia consistently exhibited reduced mean RR interval and HRV levels in a supine rest and standing position compared with healthy volunteers. The severity of psychopathology, in particular positive symptoms, was negatively correlated with cardiac vagal control.

These data suggest that acute schizophrenia is accompanied by cardiac autonomic dysregulation. In view of the higher risk for cardiac complications in these patients, one might also consider the antipsychotic treatment in favour of improving cardiac autonomic modulation. Further studies using larger patient groups and controlled therapeutics may better understand the influence of antipsychotic treatment on cardiac autonomic regulation in schizophrenia.

There has been increasing evidence that the γ-aminobutyric acid (GABA)ergic system is involved in the neurobiology of anxiety. The present study aimed to investigate the role of GABAergic systems in the modulation of anxiety in the medial prefrontal cortex (mPFC) of rats using the elevated plus maze test.

Rats were anaesthetised with a mixture of ketamine and xylazine, and then special cannulae were inserted stereotaxically into the mPFC. After 5–7 days of recovery, the effects of intra-mPFC administration of GABAergic agents were studied.

Bilateral injection of the GABAA receptor agonist muscimol (0.25, 0.5 and 1 μg/rat) produces an anxiolytic-like effect, shown by significant increases in the percentage of open-arm time (%OAT) and percentage of open-arm entries (%OAE). Intra-mPFC administration of the GABAA receptor antagonist bicuculline (0.25, 0.5 and 1 μg/rat) produces significant anxiogenic-like behaviour. However, intra-mPFC injection of the GABAB receptor agonist baclofen (0.05, 0.1 and 0.2 μg/rat) and the GABAB receptor antagonist CGP35348 (5, 10 and 15 μg/rat) did not alter %OAT and %OAE significantly.

The results of the present study demonstrate that the GABAergic system of the mPFC modulates anxiety-related behaviours of rats through GABAA receptors.

Paliperidone palmitate long‐acting injection (PP‐LAI) has recently been approved for treatment of chronic schizophrenia. Its cost‐effectiveness has not been established. The objective was to compare direct costs and outcomes between PP‐LAI and olanzapine pamoate (OLZ‐LAI) in treating chronic schizophrenia in Norway from the perspective of the government payer.

We used a decision analytic model over a 1‐year time horizon. Clinical inputs were derived from the literature and an expert panel; costs were taken from standard lists, adjusted to 2010 Norwegian kroner (NOK). Discounting was not done. Main outcomes included average cost per patient treated, hospitalisations, emergency room (ER) visits and quality‐adjusted life years (QALYs). The pharmacoeconomic outcome was the incremental cost per QALY. Robustness was examined using one‐way sensitivity analyses on critical variables and a 5000‐iteration probabilistic Monte Carlo sensitivity analysis with all variables included.

PP‐LAI generated 0.845 QALY at a cost of 151 336 NOK of which 23% was due to drugs; 25% of patients were hospitalised and another 12% required ER visits. OLZ‐LAI cost 174 351 NOK (21% due to drugs); patient outcomes included 0.844 QALY, 27% hospitalisations and 14% ER visits. PP‐LAI dominated OLZ‐LAI in the base case. The analysis was reasonably robust against variations in drug cost but sensitive to small changes in adherence and hospitalisation rates. Overall, PP‐LAI was dominant over OLZ‐LAI in 54.5% of simulations. Replacing OLZ‐LAI with PP‐LAI would be cost saving for the Norwegian healthcare system.

PP‐LAI was cost‐effective compared with OLZ‐LAI in treating patients with chronic schizophrenia in Norway but sensitive to changes in adherence and hospitalisation rates.

We investigated the relationship of oestrogen receptor (ER) status to the severity of depressive symptoms and quality of life (QOL) impairment in breast cancer patients.

Seventy-seven breast cancer patients with comorbid depression were evaluated with the Hamilton Depression Rating Scale (HAMD), the Clinical Global Impression-Severity of Illness (CGI-S) for depression, and the Functional Assessment of Cancer Therapy-Breast (FACT-B). ER status was determined using immunohistochemical analysis.

The ER-positive group (n = 31) showed significantly higher scores compared with the ER-negative group (n = 46) on HAMD total (p = 0.04) and somatic anxiety factor (p = 0.004) scores as well as CGI-S score (p = 0.03). As for QOL measured with the FACT-B, a significantly higher score was found on the Functional Well-Being (FWB) subscale in the ER-positive group (p = 0.001). The relationships were further analysed using generalised linear models (GLM), after controlling for the influence of the current anti-oestrogen treatment. The analysis revealed that ER status was still significantly related to the FWB subscale score of the FACT-B (p = 0.04). However, the HAMD and CGI-S scores were no longer significantly related to ER status after the influence of anti-oestrogen treatment was controlled for.

These results suggest that ER status, which is a well-known biological prognostic factor in breast cancer, may be related to the severity of certain aspects of depressive symptoms or QOL impairment, implying a role of the ER in affective and behavioural regulation. However, anti-oestrogen treatments significantly influence these relationships.

Neuropathic pain is a chronic and disabling syndrome with complex pathogenesis. It has been suggested that the function of glutamate transporters (GLTs) has a major role in the development of neuropathic pain. This study was performed to evaluate various doses of ceftriaxone, a beta-lactam antibiotic, on the symptoms in the rat chronic constriction injury (CCI) model of neuropathic pain. This drug has been recently introduced as a selective up-regulator and activator of GLT1.

Neuropathy was induced in adult male Wistar rats and animals were treated intraperitoneally with 100–400 mg/kg of ceftriaxone for seven consecutive days immediately after surgery. Gabapentin (100 mg/kg, i.p.) was used as a reference drug. von Frey filaments, acetone drop and radiant heat methods were used to assess mechanical allodynia, thermal allodynia and thermal hyperalgesia, respectively.

Ceftriaxone in the repeated doses for 7 days showed significant antiallodynic and antihyperalgesic effects especially at a dose of 200 mg/kg twice a day.

The results suggest that ceftriaxone as a modulator of glutamate uptake could provide beneficial effects in the treatment of chronic neuropathic pain, especially allodynia that is less sensitive to the most available drugs.

Even though cognitive deficits are well recognised in schizophrenia and depression, direct comparisons between the disorders are scarce in literature. This study aims to assess specificity and degree of cognitive deficits in inpatients with acute schizophrenia and unipolar major depression.

A neuropsychological test battery was administered to 76 schizophrenic patients, 102 patients with unipolar major depression and 85 healthy controls (HCs), assessing verbal learning [Rey Auditory Verbal Learning Test (RAVLT)], processing speed (Trail Making Test), verbal fluency and visual memory (Wechsler Memory Scale-Revised test).

Both patient groups were significantly impaired compared with HCs with regard to all test outcomes. The schizophrenia group (SG) performed significantly worse in the Wechsler Memory Scale and verbal fluency than the depression group (DG). The DG reached significantly lower scores than the SG in the RAVLT delayed recall subtest. No significant group difference between SG and DG was found for the Trail Making Test and the RAVLT direct recall trails.

Our results indicate that cognitive impairment is present in both disorders. Schizophrenic patients performed worse than patients with unipolar depression in only two of the administered tests. Differences in cognitive performance between the groups are not as general as often assumed. Therefore, during the acute phase of illness, a diagnostic classification on the grounds of the patients’ neurocognitive performance has to be done with caution.

Preclinical models of human mood disorders commonly focus on the study of negative affectivity, without comparably stressing the role of positive affects and their ability to promote resilient coping styles. We evaluated the role of background constitutional affect of rats by studying the separation and reunion responses of infants from low and high positive affect genetic lines (i.e., differentially selected for High and Low 50 kHz ultrasonic vocalisations (USVs).

Infants from Low and High 50 kHz USV breeding lines were isolated from mothers and exposed to either social (familiar or unfamiliar bedding) or neutral (clean bedding) odour cues between two short isolation periods, and tested in homeothermic and hypothermic ambient temperatures. Negative affect was estimated by monitoring separation distress calls (35–45 kHz USVs).

Low Line pups called at higher rates than High Line, and their rates were stable regardless of odour cue. In contrast, High Line pups increased vocalisations during the second compared with the first isolation periods and during exposure to both familiar and unfamiliar odour cues, but not to neutral odour. Furthermore, the greatest increase in USV emission was seen in the second isolation period following exposure to the unfamiliar odour. However, both lines showed comparable elevated distress USVs to the thermal stressor.

High Line animals, selected for a positive affective phenotype (50 kHz USVs), exhibited reduced separation anxiety responses in infancy, making this a promising animal model for the role of constitutional affective states in emotional responsivity and potential resilience against emotional disorders.

Comorbid personality pathologies may affect the outcome of patients with major depression (MD). The dopamine transporter gene DAT1 (SLC6A3) has been suggested to play a role in both depression and specific personality traits. The aim of this study was to assess five polymorphisms of the DAT1 gene (rs2550948, rs2975226, rs6347, rs27072, and 3′-VNTR) to determine whether this gene influences personality traits in patients with MD or its subgroups.

The DAT1 polymorphisms were analysed in 463 unrelated Han Chinese MD patients. The personality traits, novelty seeking (NS), and harm avoidance (HA), were examined using the Tridimensional Personality Questionnaire. The patients were also divided into four clinical subgroups on the basis of differences in their sex (male or female) and age at disease onset (early or late).

There was no association between the DAT1 gene and either NS or HA in the total MD sample or in the sex-based subgroups. However, early-onset MD patients with the G/G genotype of rs2550948 and the T/T genotype of rs2975226 had lower NS scores than did patients with the other genotypes (pcorrected = 0.05 for rs2550948 and pcorrected = 0.005 for rs2975226).

Our study suggests that DAT1 promoter variants possibly influence specific personality traits in the early-onset subgroup of depressed patients in the Han Chinese population. Further prospective cohort studies are required to verify our preliminary finding and to confirm the effects of personality susceptibility on long-term disease outcomes.

Bacterial meningitis is an infection of the central nervous system characterised by strong inflammatory response. The brain is highly dependent on ATP, and the cell energy is obtained through oxidative phosphorylation, a process which requires the action of various respiratory enzyme complexes and creatine kinase (CK) as an effective buffering system of cellular ATP levels in tissues that consume high energy.

Evaluate the activities of mitochondrial respiratory chain complexes I, II, III, IV and CK activity in hippocampus and cortex of the Wistar rat submitted to meningitis by Klebsiella pneumoniae.

Adult Wistar rats received either 10 µl of sterile saline as a placebo or an equivalent volume of K. pneumoniae suspension. The animals were killed in different times at 6, 12, 24 and 48 h after meningitis induction. Another group was treated with antibiotic, starting at 16 h and continuing daily until their decapitation at 24 and 48 h after induction.

In the hippocampus, the meningitis group without antibiotic treatment, the complex I was increased at 24 and 48 h, complex II was increased at 48 h, complex III was inhibited at 6, 12, 24 and 48 h and in complex IV all groups with or without antibiotic treatment were inhibited after meningitis induction, in the cortex there was no alteration.

Although descriptive, our results show that antibiotic prevented in part the changes of the mitochondrial respiratory chain. The meningitis model could be a good research tool to study the biological mechanisms involved in the pathophysiology of the K. pneumoniae meningitis.

To investigate gender differences in psychiatric comorbidity patients diagnosed with attention-deficit hyperactivity disorder (ADHD) as adults.

Interviews about current ADHD symptoms and psychiatric comorbidity on axis I and II (Structured Clinical Interview for DSM-IV axis I and axis II) were conducted in a clinical cohort of 168 patients (78 women, 90 men). Independent information on childhood and current symptoms was collected from parents, partners and patient files.

The lifetime prevalence of psychiatric comorbidity on axis I reached 92%, and current comorbidity, including autism spectrum disorders and Tourette's syndrome, was 47%. Women had a higher lifetime prevalence of mood and eating disorders compared with men, where substance-use disorders were more frequent. Ten per cent of patients fulfilled diagnostic criteria for a personality disorder. When excluding the general diagnostic criteria, 46% of the patients endorsed the specific criteria for at least one personality disorder. Gender differences were identified with predominance of histrionic personality traits in women and conduct disorder in men.

Patients diagnosed with ADHD as adults display an extremely high lifetime axis I comorbidity with a gender-specific pattern similar to the general population. No gender differences were identified with regard to personality disorders; however, an increased prevalence of deviant personality traits was confirmed. This study stresses the importance of evaluating comorbidity among patients diagnosed with ADHD as adults to secure optimal treatment.

Cardiac autonomic dysregulation has been reported in major depressive disorder (MDD), but scarce studies investigated that in fully remitted MDD.

To examine cardiac autonomic function in remitted MDD, 470 unmedicated individuals with a diagnosis of MDD earlier in life and 462 healthy volunteers, aged 18–65 years, were recruited for a case–control analysis. Cardiac autonomic function was evaluated by measuring heart rate variability (HRV) parameters. Frequency-domain indices of HRV were obtained. The obtained results were evaluated in association with personality traits assessed by the Tridimensional Personality Questionnaire.

In patients with remitted MDD, no differences in RR intervals and all frequency-domain indices of HRV could be detected as compared with controls. Stratified analyses by the presence of a history of suicide ideation (the SI+ vs. the SI-subgroup) revealed decreased cardiac vagal control in the SI+ subgroup. The correlation analysis revealed an inverse relation between HRV levels and the harm avoidance score (which has been suggested to be associated with serotonergic activity), mainly attributable to the robust association in the SI+ subgroup.

Our study shows that cardiac autonomic dysregulation is not shown in remitted MDD patients as a whole but is limited to the subgroup of remitted MDD patients with a history of suicidal ideation. In view of the higher risk for cardiac complications in these vulnerable individuals, one might consider the treatment to restore their autonomic function.

The aim of this study is to investigate whether there were any associations between the T102C and 1438 A/G polymorphisms of the 5-HT2A receptor gene and schizophrenia. We conducted a case–control study of the T102C and 1438 A/G polymorphisms in Turkish patients.

We compared genotypes and allele frequencies of T102C and 1438 A/G polymorphisms of 5-HT2A receptor gene in 102 patients with schizophrenia diagnosed, according to DSM-IV, and 107 healthy controls. Genotyping was performed by real-time polymerase chain reaction.

We found no significant association between schizophrenia and genotypic or allele frequencies of HTR2A gene 102T/C (rs6313) and 1438 A/G (6311) polymorphisms. However, comparison of HTR2A gene 102 T/C and 1438 A/G polymorphisms in terms of genotypic and allele frequencies between the two patient groups, with or without a family history of schizophrenia, shows that T- and A-allele frequencies were significantly higher (p < 0.05) in the case group that has a history of schizophrenia in their family.

In conclusion, our results do not support the hypothesis that the T102C and 1438 A/G polymorphisms in the 5-HT2A receptor gene are associated with schizophrenia, but further studies in a larger sample are needed.

The impact of depression and anxiety on heart rate variability (HRV) is not clear in adolescents. We hypothesised that HRV investigation in adolescents may early prevent the mental diseases occurrence.

Three hundred and thirty‐three seventh grade students participated in this study programme. HRV instrumental analysis and spectral with scale of depression were measured respectively.

It showed that among the participants, the depression score of female was higher than male. The population with lower depression score present with lower high frequency and higher low frequency/high frequency ratio but not statistically significant. Oppositely, participants with higher depression score were increased with heart rate and present with lower standard deviation of heart rate. However, it is also not statistically significant.

This study supported the positive relation between HRV and depression, especially in the female gender. Therefore, HRV in depression may be beneficial in the detection and prevention of mental disorder development, even suicide behaviour in teenagers.