The International Journal of Neuropsychopharmacology最新文献

Background: Schizophrenia is a mental disorder caused by both environmental and genetic factors. Prenatal exposure to antipsychotics, an environmental factor for the fetal brain, induces apoptotic neurodegeneration and cognitive impairment of offspring similar to schizophrenia. The aim was to investigate molecular biological changes in the fetal hippocampus exposed to haloperidol (HAL) by RNA expression as a model of the disorder.

Methods: HAL (1 mg/kg/d) was administered to pregnant mice. Upregulated and downregulated gene expressions in the hippocampus of offspring were studied with RNA-sequencing and validated with the qPCR method, and micro-RNA (miR) regulating mRNA expressional changes was predicted by in silico analysis. An in vitro experiment was used to identify the miRNA using a dual-luciferase assay.

Results: There were significant gene expressional changes (1370 upregulated and 1260 downregulated genes) in the HAL group compared with the control group on RNA-sequencing analysis (P < .05 and q < 0.05). Of them, the increase of Nr3c1 mRNA expression was successfully validated, and in silico analysis predicted that microRNA-137-3p (miR-137-3p) possibly regulates that gene's expression. The expression of miR-137-3p in the hippocampus of offspring was significantly decreased in the first generation, but it increased in the second generation. In vitro experiments with Neuro2a cells showed that miR-137-3p inversely regulated Nr3c1 mRNA expression, which was upregulated in the HAL group.

Conclusions: These findings will be key for understanding the impact of the molecular biological effects of antipsychotics on the fetal brain.

Background: Male and female rats were exposed to repeated restraint to determine how changes in serotonin (5-hydroxytryptamine; 5-HT) 1A receptors associate with stress hypothalamic-pituitary-adrenal (HPA) axis habituation.

Methods: In response to 2-hour episodes of restraint, repeated daily for 5 consecutive days, males and females displayed reliable declines in HPA output, indicated by diminished adrenocorticotropin and corticosterone secretory responses. Using the 5-HT 1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) as a pharmacological challenge for inducing hypothermia and elevations in plasma corticosterone, males displayed sensitized hypothermal responses after repeated restraint, whereas corticosterone responses to 8-OH-DPAT were enhanced in both sexes following single or repeated exposure.

Results: Only males showed elevations in 5-HT 1A receptor G-protein coupling responses in the dorsal raphe after repeated restraint, whereas only females showed an increase in 5-HT 1A receptor responses in the hippocampus following single or repeated exposure. G-protein coupling responses within both regions correlated positively with 5-HT 1A receptor binding capacity. Thus, despite expressing similar capacities for stress HPA axis habituation, males and females emerged from repeated restraint to show region-specific changes in 5-HT 1A receptor function that may be explained, at least in part, by changes in receptor availability.

Conclusions: Based on the hypothermal and corticosteroid responses to 8-OH-DPAT, the present data suggest that stress habituation is met by an increase in the sensitivity of presynaptic 5-HT 1A receptors in males and by an increase in the sensitivity of a population of postsynaptic receptors in both sexes.

Background: Although clozapine is effective for treatment-resistant schizophrenia (TRS), the rate of clozapine prescription is still low. Whereas antipsychotic monotherapy is recommended in clinical practice guidelines, the rate of antipsychotic polypharmacy is still high. There is little evidence on whether a clozapine prescription influences changes in the rate of monotherapy and polypharmacy, including antipsychotics and other psychotropics. We therefore hypothesized that the rate of antipsychotic monotherapy in patients with TRS who were prescribed clozapine would be higher than that in patients with schizophrenia who were not prescribed clozapine.

Methods: We assessed 8306 patients with schizophrenia nationwide from 178 institutions in Japan from 2016 to 2019. We analyzed the psychotropic prescription data at discharge in patients diagnosed with TRS and with no description of TRS (ND-TRS) based on the diagnosis listed in the discharge summary.

Results: The rate of antipsychotic monotherapy in the TRS with clozapine group (91.3%) was significantly higher than that in the TRS without clozapine group (45.9%; P < 2.0 × 10-16) and the ND-TRS without clozapine group (54.7%; P < 2.0 × 10-16). The rate of antipsychotic monotherapy without any other concomitant psychotropics in the TRS with clozapine group (26.5%) was significantly higher than that in the TRS without clozapine group (12.6%; P = 1.1 × 10-6) and the ND-TRS without clozapine group (17.0%; P = 5.9 × 10-6).

Conclusions: Clozapine prescription could be associated with a high rate of antipsychotic monotherapy. Patients will benefit from the correct diagnosis of TRS and thus from proper clozapine prescription.

Background: The hypothalamic neuropeptide oxytocin (OXT) may exert anxiolytic and stress-reducing actions via modulatory effects on amygdala circuits. Animal models and initial findings in humans suggest that some of these effects are mediated by interactions with other neurotransmitter systems, in particular the serotonin (5-HT) system. Against this background, the present pharmacological resting-state functional magnetic resonance imaging study aimed to determine whether effects of OXT on stress-associated amygdala intrinsic networks are mediated by 5-HT.

Methods: We employed a randomized, placebo-controlled, double-blind parallel-group, pharmacological functional magnetic resonance imaging resting-state experiment with 4 treatment groups in n = 112 healthy male participants. Participants underwent a transient decrease in 5-HT signaling via acute tryptophan depletion (ATD) or a corresponding placebo-control protocol before the administration of intranasal OXT (24 IU) or placebo intranasal spray.

Results: OXT and 5-HT modulation exerted interactive effects on the coupling of the left amygdala with the ipsilateral hippocampus and adjacent midbrain. OXT increased intrinsic coupling in this pathway, whereas this effect of OXT was significantly attenuated during transiently decreased central serotonergic signaling induced via acute tryptophan depletion. In the absence of OXT or 5-HT modulation, this pathway showed a trend for an association with self-reported stress perception in everyday life. No interactive effects were observed for the right amygdala.

Conclusions: Together, the findings provide the first evidence, to our knowledge, that the effects of OXT on stress-associated amygdala-hippocampal-midbrain pathways are critically mediated by the 5-HT system in humans.

Background: Existing meta-analytic evidence on bipolar mania treatment has revealed that augmentation therapy (AUG) with antipsychotics and mood stabilizers is more effective than monotherapy. However, the speed of the onset of treatment effects and subsequent changes in risk/benefit are unclear.

Methods: We searched the Cochrane CENTRAL, MEDLINE, and EMBASE databases until January 2021. Our primary outcomes were response and tolerability. We set 3 time points: 1, 3, and 6 weeks after randomization.

Results: Seventeen studies compared AUG therapy and MS monotherapy (comparison 1), and 8 studies compared AUG therapy and antipsychotics monotherapy (comparison 2). In comparison 1, AUG therapy resulted in significantly more responses than monotherapy, with an odds ratio of 1.45 (95% confidence interval [CI]: 1.17 to 1.80) at 3 weeks and 1.59 (95% CI: 1.28 to 1.99) at 6 weeks. Significant improvement was observed in the first week with a standardized mean difference of -0.25 (95% CI: -0.38 to -0.12). In comparison 2, AUG therapy was significantly more effective than monotherapy, with an odds ratio of 1.73 (95% CI: 1.25 to 2.40) at 3 weeks and 1.74 (95% CI: 1.11 to 2.73) at 6 weeks. Significant improvement was observed in the first week with an standardized mean difference of -0.23 (95% CI: -0.39 to -0.07). Regarding tolerability, there was no significant difference between AUG therapy and monotherapy at 3 and 6 weeks in both comparisons.

Conclusions: Early AUG therapy should be considered, as it has shown efficacy from weeks 1 to 6, although attention to side effects is necessary for acute mania treatment.

Background: Anxiety is a negative emotion that contributes to craving and relapse during drug withdrawal. Sirtuins 1 (SIRT1) has been reported to be critical in both negative emotions and drug addiction. However, it remains incompletely elucidated whether SIRT1 is involved in morphine withdrawal-associated anxiety.

Methods: We established a mouse model of anxiety-like behaviors induced by morphine withdrawal and then detected neuronal activity with immunofluorescence and mitochondrial morphology with electron microscopy, mitochondrial DNA contents with quantitative real-time PCR, and mitochondrial function with the ATP content detection kit and the Mitochondrial Complex IV Activity Kit in the basolateral amygdala (BLA). The mitochondrial molecules were detected by western blot. Then we used virus-mediated downregulation and overexpression of SIRT1 in BLA to investigate the effect of SIRT1 on anxiety and mitochondrial function. Finally, we examined the effects of pharmacological inhibition of SIRT1 on anxiety and mitochondrial function.

Results: We found that BLA neuronal activity, mitochondrial function, and mtDNA content were significantly higher in morphine withdrawal mice. Furthermore, the expression levels of mitochondrial molecules increased in BLA cells. Virus-mediated downregulation of SIRT1 in BLA prevented anxiety-like behaviors in morphine withdrawal mice, whereas overexpression of SIRT1 in BLA facilitated anxiety-like behaviors in untreated mice through the SIRT1/ peroxisome proliferator activated receptor gamma coactivator 1-alpha pathway. Intra-BLA infusion of selective SIRT1 antagonist EX527 effectively ameliorated anxiety-like behaviors and mitochondrial dysfunction in mice with morphine withdrawal.

Conclusion: Our results implicate a causal role for SIRT1 in the regulation of anxiety through actions on mitochondrial biogenesis. Inhibitors targeting SIRT1 may have therapeutic potential for the treatment of opioid withdrawal-associated anxiety.

Background: Fragile X syndrome (FXS) is a genetic condition that causes a range of developmental problems, including intellectual disability, aggressive behavior, anxiety, abnormal sensory processing, and cognitive impairment. Despite intensive preclinical research in Fmr1-targeted transgenic mice, an effective treatment for FXS has yet to be developed. We previously demonstrated that ASP5736, a 5-Hydroxytryptamine (serotonin) receptor 5A receptor antagonist, ameliorated scopolamine-induced working memory deficits in mice, reference memory impairment in aged rats, and methamphetamine-induced positive symptoms and phencyclidine-induced cognitive impairment in animal models of schizophrenia. We hypothesized that ASP5736 may be effective for ameliorating similar behavior deficits in male Fmr1-targeted transgenic rats as a preclinical model of FXS.

Methods: We evaluated the effect of acute oral administration of ASP5736 on the abnormal behavior of hyperactivity (0.01, 0.1 mg/kg), prepulse inhibition (0.01, 0.03, 0.1 mg/kg), and the novel object recognition task (0.1 mg/kg) in Frmr1-knockout (KO) rats.

Results: Fmr1-KO rats showed body weight gain, hyperactivity, abnormal sensory motor gating, and cognitive impairment. ASP5736 (0.1 mg/kg) reversed the hyperactivity and ameliorated the sensory motor gating deficits (0.03-0.1 mg/kg). ASP5736 (0.01 mg/kg) also improved cognitive impairment.

Conclusions: ASP5736 is a potential drug candidate for FXS. Further studies are needed to confirm its clinical efficacy.

Background: Hyperconsolidation of aversive associations and poor extinction learning have been hypothesized to be crucial in the acquisition of pathological fear. Previous animal and human research points to the potential role of the catecholaminergic system, particularly noradrenaline and dopamine, in acquiring emotional memories. Here, we investigated in a between-participants design with 3 groups whether the noradrenergic alpha-2 adrenoreceptor antagonist yohimbine and the dopaminergic D2-receptor antagonist sulpiride modulate long-term fear conditioning and extinction in humans.

Methods: Fifty-five healthy male students were recruited. The final sample consisted of n = 51 participants who were explicitly aware of the contingencies between conditioned stimuli (CS) and unconditioned stimuli after fear acquisition. The participants were then randomly assigned to 1 of the 3 groups and received either yohimbine (10 mg, n = 17), sulpiride (200 mg, n = 16), or placebo (n = 18) between fear acquisition and extinction. Recall of conditioned (non-extinguished CS+ vs CS-) and extinguished fear (extinguished CS+ vs CS-) was assessed 1 day later, and a 64-channel electroencephalogram was recorded.

Results: The yohimbine group showed increased salivary alpha-amylase activity, confirming a successful manipulation of central noradrenergic release. Elevated fear-conditioned bradycardia and larger differential amplitudes of the N170 and late positive potential components in the event-related brain potential indicated that yohimbine treatment (compared with a placebo and sulpiride) enhanced fear recall during day 2.

Conclusions: These results suggest that yohimbine potentiates cardiac and central electrophysiological signatures of fear memory consolidation. They thereby elucidate the key role of noradrenaline in strengthening the consolidation of conditioned fear associations, which may be a key mechanism in the etiology of fear-related disorders.

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity is implicated as a moderator of the progression of multiple diseases and disorders in medicine and is actively subject to investigation as a therapeutic target. Here we summarize the mechanisms of the enzyme and detail the novel agents under investigation. Such agents modulate peripheral cortisol and cortisone levels in hypertension, type 2 diabetes, metabolic disorders, and Alzheimer's disease models, but there is mixed evidence for transduction into symptom management. There is inchoate evidence that 11β-HSD1 modulators may be useful pharmacotherapies for clinical improvement in psychiatry and neurology; however, more research is required.

Background: Auditory verbal hallucinations (AVH) commonly occur in the context of borderline personality disorder (BPD) yet remain poorly understood. AVH are often perceived by patients with BPD as originating from inside the head and hence viewed clinically as "pseudohallucinations," but they nevertheless have a detrimental impact on well-being.

Methods: The current study characterized perceptual, subjective, and neural expressions of AVH by using an auditory detection task, experience sampling and questionnaires, and functional neuroimaging, respectively.

Results: Perceptually, reported AVH correlated with a bias for reporting the presence of a voice in white noise. Subjectively, questionnaire measures indicated that AVH were significantly distressing and persecutory. In addition, AVH intensity, but not perceived origin (i.e., inside vs outside the head), was associated with greater concurrent anxiety. Neurally, fMRI of BPD participants demonstrated that, relative to imagining or listening to voices, periods of reported AVH induced greater blood oxygenation level-dependent activity in anterior cingulate and bilateral temporal cortices (regional substrates for language processing). AVH symptom severity was associated with weaker functional connectivity between anterior cingulate and bilateral insular cortices.

Conclusion: In summary, our results indicate that AVH in participants with BPD are (1) underpinned by aberrant perceptual-cognitive mechanisms for signal detection, (2) experienced subjectively as persecutory and distressing, and (3) associated with distinct patterns of neural activity that inform proximal mechanistic understanding. Our findings are like analogous observations in patients with schizophrenia and validate the clinical significance of the AVH experience in BPD, often dismissed as "pseudohallucinations." These highlight a need to reconsider this experience as a treatment priority.