Abstract Background Schizophrenia is a chronic psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive dysfunction. In particular, neurocognitive and social cognitive deficits have negative consequences on functional capacity or community functioning, and then a significant reduced the quality of life. Nonetheless, antipsychotics are limited as they provide only minimal ameliorating efficacy on cognitive performance. Clozapine (CLZ), an atypical antipsychotic, has remarkable effectiveness for treatment-resistant schizophrenia, as a result patients were provided. However, the effects of CLZ on neurocognitive and social cognitive functions and its molecular mechanisms remain unclear. Objective This study aims to investigate the effects of CLZ on neurocognitive and social cognitive behaviors in phencyclidine (PCP) administered mouse repeastedly, as a schizophrenia-like mouse model, or subsequently mouse treated with CLZ. In addition, we determined whether changes in neurotransmitters associated with these behaviors. Methods PCP (10 mg/kg, s.c.) or saline (10 mL/kg, s.c.) was injected once a day for 14 consecutive days to the 6-week-old male ICR strain mice. CLZ (10 mg/kg or 30 mg/kg, p.o.) or vehicle (10 mL/kg, p.o.) was treated once a day for 7 consecutive days from the next day of the final PCP or saline administration. Twenty-four hours after the last administration, the novel object recognition test and the 3-chamber social behavior test were performed sequentially. For the measurement of the contents of monoamines and their metabolites, the prefrontal cortex (PFC), nucleus accumbens (NAc), striatum (STR), hippocampus (HIP), and amygdala (AMY) were collected 24 hours after the last administration and quantified by using high-performance liquid chromatography. Results The mice administered PCP exhibited impairment in the object recognition. These neurocognitive impairments deficits were ameliorated by administration of CLZ (10 mg/kg and 30 mg/kg) repeatedly. In the 3-chamber social behavior test, PCP-administered mice exhibited sociability, as similar to the saline- administered control mice, but social novelty was impaired. The impairment of social novelty was by the administration of CLZ (10mg/kg) repeatedly. The levels of monoamines and their metabolites in the brains of PCP-treated mice did not show any significant changes across all regions. In PCP-administered mice, administration of CLZ (10 mg/kg) resulted in an increase in noradrenaline content in the NAc and a decrease in serotonin and its metabolite levels in the HIP. Furthermore, CLZ (30 mg/kg) administration induced the enhanced dopamine metabolism in the PFC and reduced dopamine metabolism in the NAc. Discussion And Conclusion PCP administration induced the impaired neurocognitive and social cognitive function. These behavioral impairments were attenuated by the subsequent administration of CLZ repeatedly. It is suggested that the brain region-specific monoaminergic systems is associated as attenuating mechanism of CLZ on cognitive impairments. Given the varying responses based on CLZ dosage and brain regions, further investigations are needed to elucidate the relationship between changes in monoamines in each brain region and cognitive impairments.
Leptin plays an important role in the pathogenesis of obesity and diabetes, yet the regulatory mechanisms of this hormone have not been fully elucidated. In this study, we aimed to clarify the roles of insulin and glucose in leptin secretion and mRNA production using inhibitors of insulin signal transduction in adipocytes cultured under glucose-free or normal conditions.Differentiated 3T3-L1 adipocytes were stimulated with insulin in combination with inhibitors for phosphoinositide 3-kinase (PI3K), Akt, and phosphodiesterase 3B (PDE3B), as well as epinephrine and a cyclic AMP (cAMP) analog under glucose-free or normal conditions. After 8 h of stimulation, leptin protein levels in the media and leptin mRNA expression levels in the adipocytes were measured.Insulin significantly increased the secretion and mRNA levels of leptin under the depletion of glucose. Glucose augmented basal leptin secretion without insulin, while glucose nullified insulin-induced leptin mRNA upregulation. The PI3K inhibitor BEZ-235, the Akt inhibitor MK-2206, and the PDE3B inhibitor cilostazol attenuated the insulin stimulation of leptin secretion, but did not suppress the insulin-induced leptin mRNA upregulation with glucose depletion. In contrast to the glucose-free condition, insulin failed to upregulate leptin mRNA in the presence of glucose. The cAMP analog dibutyryl cAMP and epinephrine decreased both leptin secretion and mRNA regardless of glucose supplementation.Insulin alone stimulates leptin secretion and elevates leptin mRNA levels via cAMP under the lack of glucose metabolism, while glucose is a significant and ambivalent effector on the insulin effects of leptin.
Abstract Objective To assess the effects of hypnotics on prefrontal cortex activity in healthy subjects using near‐infrared spectroscopy (NIRS) in a double‐blind, placebo‐controlled crossover trial. Methods Eighteen healthy males received acute doses of ramelteon (8 mg), triazolam (0.125 mg), or placebo in a predetermined randomization schedule, with a washout period of more than 1 week. All subjects performed a verbal fluency task during NIRS assessments at baseline and at 1 and 4 hr post‐dose. The number of words correctly generated during the task (behavioral performance) and scores on the Stanford Sleepiness Scale (SSS) were also recorded at each test time. Results Compared with the placebo, triazolam (0.125 mg) significantly decreased oxyhemoglobin (oxy‐Hb) concentration change in NIRS during the posttask period and significantly increased behavioral performance, whereas triazolam (0.125 mg) and ramelteon (8 mg) significantly increased SSS scores. Conclusions The differential effects of two types of hypnotics on oxy‐Hb change measured by NIRS were observed in acute dosing, suggesting that when assessing brain activity of patients with psychiatric disorders, researchers should consider how certain types of hypnotics can influence brain function. This would also provide useful information to clinicians when prescribing hypnotics suitable for their patients' conditions.
Place conditioning paradigms are widely used for determining the motivational properties of drugs. Phencyclidine (PCP) has been a common drug of abuse during the past two decades and has a rewarding effect in animals. However, PCP produces place aversion in the conditioned place preference (CPP) task in animals. Here, we report the possible neuronal mechanisms of PCP-induced place aversion and preference in the CPP task in rodents. In naive rats and mice, PCP dose-dependently produced place aversion and PCP had a significant effect at the doses of 4 and 8 mg/kg in rats and mice, respectively. The aversive effect of PCP (4 mg/kg) in rats was significantly attenuated by ritanserin (3 and 10 mg/kg), a serotonin 15-HT2) receptor antagonist whereas the lesion of serotonergic (5-HTergic) neurons by 5,7-dihydroxytryptamine (100 micrograms i.c.v.) and alpha-methyl-rho-tyrosine (AMPT; 100 mg/kg), a tyrosine hydroxylase inhibitor, did not affect the aversive effect of PCP. In rats pretreated with PCP (10 mg/kg/day) for 14 days, tolerance was developed to PCP (4 mg/kg)-induced place aversion. In rats and mice pretreated with PCP (10 mg/kg/day) for 28 days, however, PCP dose-dependently produced place preference but not aversion. The preferred effect of PCP (8 mg/kg) in mice preteated with PCP (10 mg/kg/day for 28 days) was significantly attenuated by AMPT (100 mg/kg) and 6-hydroxydopamine (100 micrograms i.c.v.) a dopaminergic (DAergic) neurotoxin, but not by DSP-4 (30 mg/kg), a noradrenergic neurotoxin and ritanserin. In mice pretreated with methamphetamine (1 mg/kg/day) for 14 days, PCP (8 mg/kg) produced place preference. These findings suggest that 5-HTergic and DAergic systems are involved in the PCP-induced place aversion and preference, respectively, and some changes in the neuronal systems including DAergic systems, induced by repeated PCP treatment play a critical role in the addiction of PCP.
Neprilysin is a rate–limiting peptidase participating in Aβ degradation in the brain, and disruption of neprilysin gene causes elevation of endogenous Aβ levels in mouse brain. Down–regulation of neprilysin in the hippocampus and cerebral cortex with aging and at an early stage of AD development, suggests a close association of neprilysin with AD etiology and pathogenesis. In the present study, to clarify a possible connection between a reduction in neprilysin activity and impairment of synaptic and cognitive functions, we crossbred APP transgenic mice (APP23) with neprilysin–deficient mice, and analyzed the mice for brain Aβ accumulation, hippocampal synaptic plasticity using an in vivo recording technique, and cognitive function using a battery of learning and memory behavior tests, such as Y–maze, novel–object recognition, Morris water maze, and cued and contextual fear conditioning tests at the age of 13–16 weeks. Western blot analysis revealed that the major (more than 90% of total Aβ) form of Aβ observed in the transgenic mouse brains was oligomers, the level of which was elevated nearly 3 times by neprilysin deficiency. Although neither amyloid plaque formation nor neuron loss was detected in the brain of the mice at this age, we confirmed that a density of oligomeric Aβ was elevated at presynaptic areas using an immunoelectron microscopic technique with anti–oligomeric Aβ antibody. Next, the long–term potentiation (LTP) recorded in the dentate gyrus and in the CA1 area of the hippocampus was significantly suppressed in the crossbred mice, compared with APP transgenic mice. The LTP in the dentate gyrus was more strongly suppressed than that in the CA1 area of the hippocampus, reflecting an increase in quantity of Aβ oligomers. Finally, the crossbred mice displayed obvious cognitive abnormalities consistently in different learning and memory paradigms. These results indicate that a reduction in neprilysin activity causes synaptic and cognitive impairment through a local increase of oligomeric Aβ in the synaptic sites of the brain before the onset of amyloid plaque formation. Thus, reduced neprilysin activity appears to be a causative event that is at least partly responsible for the memory–associated symptoms of AD.
