Search

In this article, we deal with the nonlocal elliptic problems of the Kirchhoff type involving the Hardy potential and critical nonlinearity on a bounded domain in R 3 . Under an appropriate condition on the nonhomogeneous term and using variational methods, we obtain two distinct solutions. [ABSTRACT FROM AUTHOR]

The amygdala and raphe nuclei, which play crucial roles in mood regulation, are influenced by serotonergic neurotransmission. Alterations in this neurotransmission are associated with mood disorders. Therefore, using immunohistochemistry and quantitative methods this study was designed to evaluate potential alterations in the expression of serotoninergic markers in the amygdala and raphe nuclei of mice with oestrogen receptor β (ERβ) knock out which exhibit increased anxiety as evidenced by reduced locomotion and increased thigmotaxis. These alterations could either contribute to heightened anxiety or serve as a compensatory strategy for reducing it. The results show that in ERβ knock-out mice, 5-HT1B expression is significantly increased in the amygdala, while 5-HTT expression is significantly decreased in both the amygdala and raphe nuclei. Furthermore, ERβ deficiency does not affect TPH2. In conclusion, serotonin signalling is altered in the amygdala and raphe nuclei of ERβ knock-out females. It seems that an increase in 5-HTT levels has been associated with reduced anxiety, whereas a decrease in 5-HT1B receptors may encourage fear. However, further studies are required to determine the exact role of ERβ in anxiety-related behaviour., (© 2024 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

The environmental impact of the exploitation of geomaterials and their relatively high cost, coupled with the increasingly low financial capital in developing countries, are pushing road actors to turn to inexpensive local ecological materials. The present study is conducted on lateritic graveled soils of Bandjoun (LGSB) in the West Cameroon Region. The aim is to determine whether lateritic gravel soils, particularly those in Bandjoun, can be an ecological and economical alternative to rock aggregates in road construction, considering their geotechnical parameters and environmental impact. These soils were described in the field and were also subjected to complete geotechnical identification in the laboratory. The LGSB presents Californian bearing ratio indices ranging from 26% to 83.3%, a plasticity index of 10.11%, a fines content of 12.05%, an average methylene blue value of 4.25, a water content at the Proctor optimum of 27.6% and a dry density of 1.75 g/cm3. They are silty or clayey gravels and sands of subgroup A-2-7 according to the Highway Research Board classification; sandy and gravelly soils with fines of class B according to the classification of the Road Construction Guide; and silty gravels according to the classification of the Central Laboratory of Bridges and Highways. These soils can be used naturally in pavement layers, in particular in subgrade for all traffic classes and in subbase for low traffic. The tonnage of these soils has been estimated at 18,389 t. The global warming index shows that the use of these soils (18,389 t) in road construction can reduce 31,629–62,706 kg of carbon emissions. The use of lateritic soils in road construction is a very interesting alternative to reduce the environmental impacts associated with the manufacture of rock aggregates. So, lateritic soils should be used instead of rock aggregates for cleaner, more environmentally friendly road construction. The present work presented a specific evaluation of the geotechnical properties and ecological impact of lateritic graveled soils for road construction, as well as their potential for ecological and economic utilization. [ABSTRACT FROM AUTHOR]

In this paper, by using the mountain pass theorem and the concentration compactness principle, we prove the existence of a positive solution for a p -Kirchhoff-type problem with critical Sobolev exponent. [ABSTRACT FROM AUTHOR]

The first use of the Schiff base chelate N‐naphthalidene‐o‐aminophenol (naphH2) in Co/Ln chemistry has afforded a family of isostructural [CoIII2LnIII(OMe)2(naph)2(O2CMe)3(MeOH)2] (Ln=Tb, Dy and Er) complexes, revealing a rare {CoIII2Ln(μ3‐OMe)}8+ triangular core composed of two diamagnetic CoIII ions and a 4f‐ion with slightly distorted square antiprismatic geometry. Alternating current (ac) magnetic susceptibility studies revealed that {Co2Dy}, and its magnetic diluted analogue {Co2Dy0.05Y0.95}, behave as mononuclear single‐molecule magnets (SMMs) with similar energy barriers for the magnetization reversal, Ueff, of ~85‐90 K. SMM properties were also detected for {Co2Er}, with the compound exhibiting a Ueff of 18.7 K under an applied magnetic field of 800 Oe. To interpret the experimental magnetic results, ab initio CASSCF/RASSI‐SO and DFT calculations were performed as a means of exploring the single‐ion characteristics of LnIII ions and comprehend the role of the diamagnetic CoIII ions in the magnetization relaxation of the three heterometallic compounds. [ABSTRACT FROM AUTHOR]

We aimed to determine the level of miRNAs 16 and 135a in lifelong premature ejaculation (LPE) patients versus controls. Moreover, we evaluated the potential interplay between the studied miRNAs and fluoxetine in these patients after utilizing fluoxetine daily for 3 months. The study involved 60 consecutive LPE patients and 20 healthy age matched individuals as controls. The median miRNA16 was significantly higher in the controls (1.02) compared to the patients (0.31) (p < 0.001). Moreover, the median miRNA‐135a was significantly higher in the controls compared to the patients 1.02 and 0.35, p < 0.001, respectively. In addition, the median pre‐treatment miRNA16 in the responders was 0.29 that significantly increased to 0.66 (p < 0.001). The median pre‐treatment miRNA‐135a in the responders was 0.27 that significantly increased to 0.65 (p < 0.001). Furthermore, considering EXP(β) for the odds ratio evaluation, with a 95% degree of confidence, a 1 fold increase in pre‐treatment miRNA 135a fold change decreases the odds for being responsive to SSRI by 0.028. Meanwhile, there was non‐significant association between fluoxetine responsiveness and age, pre‐treatment miRNA 16, pre‐treatment PEDT and pre‐treatment IELT. The current study had shown that a lower pre‐treatment miRNA 135a was significantly associated with response to fluoxetine. [ABSTRACT FROM AUTHOR]

Cognitive affective biases describe the tendency to process negative information or positive information over the other. These biases can be modulated by changing extracellular serotonin (5‐HT) levels in the brain, for example, by pharmacologically blocking and downregulating the 5‐HT transporter (5‐HTT), which remediates negative affective bias. This suggests that higher levels of 5‐HTT are linked to a priority of negative information over positive, but this link remains to be tested in vivo in healthy individuals. We, therefore, evaluated the association between 5‐HTT levels, as measured with [11C]DASB positron emission tomography (PET), and affective biases, hypothesising that higher 5‐HTT levels are associated with a more negative bias. We included 98 healthy individuals with measures of [11C]DASB binding potential (BPND) and affective biases using The Emotional Faces Identification Task by subtracting the per cent hit rate for happy from that of sad faces (EFITAB). We evaluated the association between [11C]DASB BPND and EFITAB in a linear latent variable model, with the latent variable (5‐HTTLV) modelled from [11C]DASB BPND in the fronto‐striatal and fronto‐limbic networks implicated in affective cognition. We observed an inverse association between 5‐HTTLV and EFITAB (β = −8% EFITAB per unit 5‐HTTLV, CI = −14% to −3%, p =.002). These findings show that higher 5‐HTT levels are linked to a more negative bias in healthy individuals. High 5‐HTT supposedly leads to high clearance of 5‐HT, and thus, a negative bias could result from low extracellular 5‐HT. Future studies must reveal if a similar inverse association exists in individuals with affective disorders. [ABSTRACT FROM AUTHOR]

Topography and bathymetry are principally supported by some combination of crustal and sub‐crustal density variations. However, dynamic topography is generated by vertical deflection of the Earth's surface as a result of mantle convection. Isolating and quantifying observable dynamic topography yields valuable information about mantle processes. Here, we investigate global dynamic topography by calculating residual depth anomalies throughout the oceanic realm and residual topographic anomalies across the continents. We correct for sedimentary and crustal loading by exploiting a variety of seismologic datasets that include seismic reflection profiles, wide‐angle/refraction surveys, and receiver functions. In this way, an extensively revised and augmented global compilation of 10,874 oceanic residual depth measurements and 3,777 continental residual topographic measurements is constructed. In the oceanic realm, the methodology has been revised to improve accuracy and resolution. First, quartz/clay content of the sedimentary column is adjusted to remove minor skewness of residual depth anomalies as a function of plate age. Secondly, variation of bulk density as a function of crustal thickness is taken into account. Our global compilation is used to generate spherical harmonic representations of observable dynamic topography out to degree 40 (i.e., ∼1,000 km). Resultant spectra demonstrate that dynamic topographic power varies linearly with inverse wavenumber. The spectral slope directly reflects the way by which dynamic topography is generated by Stokes' flow. Our global results are consistent with independent and diverse geologic markers of uplift and subsidence together with Neogene‐Quaternary intraplate basalt magmatism. Plain Language Summary: The Earth's surface consists of interlocking tectonic plates that move with respect to each other at rates which we can now observe using the global positioning system. The story of how plate tectonics was discovered in the late 1960s is a very exciting one but the emphasis on horizontal movement of plates has tended to deflect attention away from a significant and related topic. Plate motion must be caused by slow stirring of the Earth's interior and this stirring should also generate lazy up‐and‐down displacement of the surface we live on. Unfortunately, these vertical movements are probably very slow and so hard to directly measure. In this study, we build upon previous attempts to measure vertical movements across the globe that we think can be attributed to slow stirring of the interior. Our analysis of depth measurements from the oceans and of anomalous topography onshore has enabled us to pinpoint the surface effects of stirring, which appear to occur on a whole host of length scales from hundreds of kilometers to tens of thousands of kilometers. Key Points: 7,601 seismic profiles yield residual depth measurements throughout the oceanic realmSpherical harmonic representations of dynamic topography are generated from combined oceanic and continental measurementsResultant power spectra are consistent with Stokes' flow of convecting mantle [ABSTRACT FROM AUTHOR]

In this paper, we prove the existence of two positive solutions for a critical elliptic problem with nonlocal term and Sobolev exponent in dimension four. [ABSTRACT FROM AUTHOR]

The aim of the paper was to synthesize Mn/Ca entities that are structurally similar to the reported oxygen‐evolving complex (OEC) of photosystem II (PSII). Here we have ventured Schiff base combinations of racemic (±)‐3‐Aminopropane‐1,2‐diol and Salicyladehyde (H3L1)/o‐Vanillin (H3L2) with varied ratios of ligand : CaIIsalt : MnIIIsalt. Interestingly, H3L2 : CaCl2 : MnCl2 (2 : 1 : 1) afforded [{MnIII2CaII2(HL2)2Cl2(μ3‐OH)2(H2O)6}Cl2 ⋅ 2H2O] (3) whereas H3L1 : CaCl2 : Mn(acetate)2 (2 : 1 : 1) and H3L1 : CaCl2 : MnCl2 (2 : 1 : 2), generated [{MnIV(HL1)2}2 ⋅ 6H2O](1) and [{MnIII3MnII(HL1)3(μ2‐Cl)3(μ3‐O)} ⋅ 2CH3OH ⋅ 2H2O] (2) respectively. More importantly, we have been able to get a structure which offers partial similarity to reported structure of the OEC. Variable temperature magnetic susceptibility measurements have been performed in the 1.8–30 K region for all the compounds. Overall, these studies provide a critical understanding for the rational design and construction of synthetic OEC. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was evaluation of the association between severity of pain and expression of total or ubiquitinated serotonin transporter (SERT) protein in patients with burning mouth syndrome and atypical odontalgia (BMS/AO), who were treated by duloxetine. Methods: Patients with BMS/AO were assessed for severity of pain using the visual analog scale (VAS), and expression of total and ubiquitinated SERT protein in platelets before (baseline) and 12 weeks after duloxetine‐treatment. Results: The expression of total and ubiquitinated SERT protein at baseline in all patients (n = 33) were higher and lower, respectively, compared to those in healthy controls. 12 weeks after duloxetine‐treatment, there was no difference in the total SERT protein levels between patients (n = 21) and healthy controls. In the 16 patients who could be measured, mean VAS scores and total SERT protein levels were significantly decreased after the treatment, compared to those at baseline. There was tendency for a positive correlation between total SERT protein levels and VAS scores in these patients. Conclusions: Our findings indicate that duloxetine relieves pain in association with downregulation of platelet SERT expression in patients with BMS/AO. [ABSTRACT FROM AUTHOR]

Automatic guided vehicles (AGVs) have been successfully applied to cargo terminals to reduce operating costs and improve productivity. However, the focus was on container terminal operations. Ports with roll-on/roll-off (RORO) terminals still heavily depend on human resources for the loading/unloading processes. Work operations are affected by human errors and safety issues. In particular, terminals where vehicles cannot be stacked pressure workers to handle cargo more rapidly, which induces more errors. In this study, we propose automating RORO terminal operations by using AGVs. We assessed the impact of AGVs on the productivity, cost efficiency, and environment. A series of simulation models was developed on the basis of the current loading system at an actual port to test the impact of AGVs. Then, we developed a cost model to analyze the economic benefit of AGVs compared with the current loading system. The environmental benefits were also analyzed. Results revealed that a system using 29 AGVs matched the productivity of the current loading system, and using more AGVs increased the productivity. For a given productivity level, the total operating cost of the AGV system was three times less than that of the current system over a 15-year period. The AGV system also showed great potential for improving the environmental friendliness of terminal operations. This is the first study to propose automating RORO terminal operations to improve productivity and sustainability through AGV technology rather than human factors. AGVs are expected to become a good option in the future to address labor shortages and the "untact" era. [ABSTRACT FROM AUTHOR]

Neuronal networks cause changes in behaviorally important information processing through the vesicular release of neurotransmitters governed by the rate and timing of action potentials (APs). Herein, we provide evidence that dopamine (DA), nonquantally released from the cytoplasm, may exert similar effects in vivo. In mouse slice preparations, (+/−)‐3,4‐methylenedioxy‐methamphetamine (MDMA, or ecstasy) and β‐phenylethylamine (β‐PEA)‐induced DA release in the striatum and nucleus accumbens (NAc), two regions of the brain involved in reward‐driven and social behavior and inhibited the axonal stimulation‐induced release of tritiated acetylcholine ([3H]ACh) in the striatum. The DA transporter (DAT) inhibitor (GBR‐12909) prevented MDMA and β‐PEA from causing DA release. GBR‐12909 could also restore some of the stimulated acetylcholine release reduced by MDMA or β‐PEA in the striatum confirming the fundamental role of DAT. In addition, hypothermia could prevent the β‐PEA‐induced release in the striatum and in the NAc. Sulpiride, a D2 receptor antagonist, also prevented the inhibitory effects of MDMA or β‐PEA on stimulated ACh release, suggesting they act indirectly via binding of DA. Reflecting the neurochemical interactions in brain slices at higher system level, MDMA altered the social behavior of rats by preferentially enhancing passive social behavior. Similar to the in vitro effects, GBR‐12909 treatment reversed specific elements of the MDMA‐induced changes in behavior, such as passive social behavior, while left others including social play unchanged. The changes in behavior by the high level of extracellular DA–– a significant amount originating from cytoplasmic release––suggest that in addition to digital computation through synapses, the brain also uses analog communication, such as DA signaling, to mediate some elements of complex behaviors, but in a much longer time scale. [ABSTRACT FROM AUTHOR]

Background: Altered monoamine (i.e., serotonin, dopamine, and norepinephrine) activity following episodes of alcohol abuse plays key roles not only in the motivation to ingest ethanol, but also physiological dysfunction related to its misuse. Although monoamine activity is essential for physiological processes that require coordinated communication across the gut–brain axis (GBA), relatively little is known about how alcohol misuse may affect monoamine levels across the GBA. Therefore, we evaluated monoamine activity across the mouse gut and brain following episodes of binge‐patterned ethanol drinking. Methods: Monoamine and select metabolite neurochemical concentrations were analyzed by ultra‐high‐performance liquid chromatography in gut and brain regions of female and male C57BL/6J mice following "Drinking in the Dark" (DID), a binge‐patterned ethanol ingestion paradigm. Results: First, we found that alcohol access had an overall small effect on gut monoamine‐related neurochemical concentrations, primarily influencing dopamine activity. Second, neurochemical patterns between the small intestine and the striatum were correlated, adding to recent evidence of modulatory activity between these areas. Third, although alcohol access robustly influenced activity in brain areas in the mesolimbic dopamine system, binge exposure also influenced monoaminergic activity in the hypothalamic region. Finally, sex differences were observed in the concentrations of neurochemicals within the gut, which was particularly pronounced in the small intestine. Conclusion: Together, these data provide insights into the influence of alcohol abuse and biological sex on monoamine‐related neurochemical changes across the GBA, which could have important implications for GBA function and dysfunction. [ABSTRACT FROM AUTHOR]

Objective: Sex steroid hormones potently shape brain functions, including those critical to maintain mental health such as serotonin signaling. Use of oral contraceptives (OCs) profoundly changes endogenous sex steroid hormone levels and dynamics. Recent register‐based studies show that starting an OC is associated with increased risk of developing depression. Here, we investigate whether use of OCs in healthy women is associated with a marker of the serotonin system in terms of serotonin 4 receptor (5‐HT4R) brain imaging. Methods: [11C]SB207145‐PET imaging data on 53 healthy women, of whom 16 used OCs, were available from the Cimbi database. We evaluated global effects of OC use on 5‐HT4R binding in a latent variable model based on 5‐HT4R binding across cortical and subcortical regions. Results: We demonstrate that OC users have 9–12% lower global brain 5‐HT4R binding potential compared to non‐users. Univariate region‐based analyses (pallidostriatum, caudate, hippocampus, amygdala, anterior cingulate cortex, and neocortex) supported the global effect of OC use with the largest difference present in the hippocampus (−12.8% (95% CI [−21.0; −3.9], Pcorrected = 0.03). Conclusion: We show that women who use OCs have markedly lower brain 5‐HT4R binding relative to non‐users, which constitutes a plausible molecular link between OC use and increased risk of depressive episodes. We propose that this reflects a reduced 5‐HT4R gene expression, possibly related to a blunted ovarian hormone state among OC users. [ABSTRACT FROM AUTHOR]

In classical rodent anxiety models, females usually display lower anxiety than males, whereas anxiety disorders are more prevalent in women. Perhaps this contradiction is caused by the use of behavioural models with low external validity. Therefore, we analysed immediate reactions to a sudden 90‐dB white noise in a semi‐natural environment. We observed mixed‐sex groups of rats for the 60 seconds preceding noise onset and the first 60 seconds of exposure. White noise elicited fear‐specific behaviours hiding alone and huddling. It also increased exploratory and ambulatory behaviours, although only in the burrow zone farthest from the open area. Thus, in a semi‐natural environment, white noise enhanced motor activity as a product of fear‐induced general arousal. Then, we compared male and female sexual, social, exploratory and anxiety‐related behaviour, and found little sex difference. This absence of behavioural effect, also observed in other studies, might be a result of our study design, a familiar environment with an ecologically relevant social context. Fear and anxiety responses are modulated by oestrogens through the activation of oestrogen receptors α and β. Thus, in a third part of out study, we analysed how treatment with either oil, oestradiol benzoate (EB), an agonist to the oestrogen receptor α (propylpyrazoletriol [PPT]) or β (diarylpropionitrile [DPN]) influenced female behaviour. The effect of treatment was limited, both EB and PPT stimulated motor activity in the open area before white noise, probably because of sexual activity. PPT increased the probability of fleeing from the noise, and decreased the latency to do so, which is consistent with a pattern of anxiogenic properties found in previous studies. Contrary to reports in classical procedures, we failed to detect any effect of DPN on immediate fear reactions in a semi‐natural environment. [ABSTRACT FROM AUTHOR]

The germ theory of disease and the attendant public health initiatives, including sanitation, vaccination, and antibiotic treatment, led to dramatic increases in global life expectancy. As the prevalence of infectious disease declines, mental disorders are emerging as major contributors to the global burden of disease. Scientists understand little about the etiology of mental disorders, however, and many of the most popular psychopharmacological treatments, such as antidepressants and antipsychotics, have only moderate‐to‐weak efficacy in treating symptoms and fail to target biological systems that correspond to discrete psychiatric syndromes. Consequently, despite dramatic increases in the treatment of some mental disorders, there has been no decrease in the prevalence of most mental disorders since accurate record keeping began. Many researchers and theorists are therefore endeavoring to rethink psychiatry from the ground‐up. Anthropology, especially biological anthropology, can offer critical theoretical and empirical insights to combat mental illness globally. Biological anthropologists are unique in that we take a panhuman approach to human health and behavior and are trained to address each of Tinbergen's four levels of analysis as well as culture. The field is thus exceptionally well‐situated to help resolve the mysteries of mental illness by integrating biological, evolutionary, and sociocultural perspectives. [ABSTRACT FROM AUTHOR]

Antidepressant drugs are associated with many challenges due to their adverse impacts. Seeking alternatives through medicinal plants could have a great merit in overcoming these deleterious effects. This study was designed to investigate the potential mechanism of curcumin (CUR) in modifying the depression-like behaviour in ovariectomised (OVX) rats, inference with fluoxetine (FLX) and oestradiol (E2 ). The treatments of OVX rats started after 1 month post ovariectomy and proceeded for 1 month. The experimental animals were divided into five groups: sham-operated, OVX-, OVX-FLX (20 mg kg-1 , i.p., daily), OVX-E2 (100 μg kg-1 , i.m., every other day), and OVX-CUR- (100 mg kg-1 , p.o., daily) treated groups. The results showed that CUR modulated the depression-like behaviour using forced swimming test. It improved the serotonin content in many brain regions by upregulating tryptophan hydroxylase-2 and 5-hydroxytryptamine1A,2A receptor messenger RNA (mRNA) and downregulating monoamine oxidase A mRNA in the limbic system. Furthermore, it upregulated aromatase, brain-derived neurotropic factor mRNA, and extracellular-regulated kinase 1/2 protein in the limbic system, relative to FLX and E2, compared with OVX group. In conclusion, CUR appears to be safe and efficient agent as serotonin modulator similar to FLX and neurotrophic agent like E2 , in improving the depression-like behaviour in OVX rats. [ABSTRACT FROM AUTHOR]

Abstract: Two‐dimensional (2D) metal‐organic layers (MOLs) are the 2D version of metal‐organic frameworks (MOFs) with nanometer thickness in one dimension. MOLs are also known as 2D‐MOFs, 2D coordination polymers, ultrathin MOF nanosheets (UMOFNs) or coordination nanosheets in literature. This new category of 2D materials has attracted a lot of interests because of the opportunity in combining molecular chemistry, surface/interface chemistry and material chemistry of low dimensional materials in these systems. Several synthetic strategies have been developed for the construction of 2D MOLs, but the general synthesis of MOLs still presents a challenge. This tutorial level review summarizes the recent progress in the fabrication of novel 2D MOLs and aims to highlight challenges in this field. [ABSTRACT FROM AUTHOR]

Abstract: The serotonin reuptake is mainly regulated by the serotonin transporters (SERTs), which are abundantly found in the raphe nuclei, located in the brainstem. Previous studies have shown that dysfunction in the SERT has been associated with several disorders, including depression and cardiovascular diseases. In this manuscript, we aimed to investigate how gender and the treatment with a serotonin selective reuptake inhibitor (SSRI) could affect mitochondrial bioenergetics and oxidative stress in the brainstem of male and female rats. Fluoxetine, our chosen SSRI, was used during the neonatal period (i.e., from postnatal Day 1 to postnatal Day 21—PND1 to PND21) in both male and female animals. Thereafter, experiments were conducted in adult rats (60 days old). Our results demonstrate that, during lactation, fluoxetine treatment modulates the mitochondrial bioenergetics in a sex‐dependent manner, such as improving male mitochondrial function and female antioxidant capacity. [ABSTRACT FROM AUTHOR]

Abstract: Background and Aim: Progesterone receptor, inflammation, neurotransmitter expression, and fibrosis are involved in slow‐transit constipation. The aim of the present study was to examine whether patients with slow‐transit constipation have an overexpression of progesterone receptor and serotonin, which may impair the fibrosis of muscularis propria in colorectal wall. Methods: High‐resolution colon manometry was used to record the colorectal peristaltic contractions of the proximal ascending and sigmoid colon in patients. Protein samples prepared from frozen sigmoid colon tissue and the proximal margin of the ascending colon of four female patients were compared using isobaric tags for relative and absolute quantification labeling technique coupled to 2D liquid chromatography–tandem mass spectrometry analysis. Immunohistochemical staining of progesterone receptor, serotonin, and fibronectin was performed in paraffin‐embedded sigmoid colon tissues and the proximal margin of the ascending colon or ileum from 43 patients with slow‐transit constipation. Results: Among these differentially regulated proteins based on isobaric tags for relative and absolute quantification and liquid chromatography–tandem mass spectrometry analysis, 56 proteins involved in the response to progesterone, inflammation, matrix remodeling, fibrosis, and muscle metabolism. Immunohistochemical staining confirmed that there was significantly higher expression of progesterone receptor (t = 19.19, P = 0.000) and serotonin (t = 13.52, P = 0.004) in sigmoid colon than in the proximal margin of the ascending colon and ileum. Progesterone receptor and fibronectin expression in the outer layer of muscularis propria were higher than in the middle layer. Conclusions: These results demonstrate that progesterone receptor, along with inflammation and fibrosis, may take part in slow‐transit constipation development. [ABSTRACT FROM AUTHOR]

Altered serotonergic neurotransmission has been found to cause impulsive and aggressive behavior, as well as increased motor activity, all exemplifying key symptoms of ADHD. The main objectives of this positron emission tomography (PET) study were to investigate the serotonin transporter binding potential (SERT BPND) in patients with ADHD and to assess associations of SERT BPND between the brain regions. 25 medication-free patients with ADHD (age ± SD; 32.39 ± 10.15; 10 females) without any psychiatric comorbidity and 25 age and sex matched healthy control subjects (33.74 ± 10.20) were measured once with PET and the highly selective and specific radioligand [11C]DASB. SERT BPND maps in nine a priori defined ROIs exhibiting high SERT binding were compared between groups by means of a linear mixed model. Finally, adopted from structural and functional connectivity analyses, we performed correlational analyses using regional SERT binding potentials to examine molecular interregional associations between all selected ROIs. We observed significant differences in the interregional correlations between the precuneus and the hippocampus in patients with ADHD compared to healthy controls, using SERT BPND of the investigated ROIs ( P < 0.05; Bonferroni corrected). When correlating SERT BPND and age in the ADHD and the healthy control group, we confirmed an age-related decline in brain SERT binding in the thalamus and insula ( R2 = 0.284, R2 = 0.167, Ps < 0.05; Bonferroni corrected). The results show significantly different interregional molecular associations of the SERT expression for the precuneus with hippocampus in patients with ADHD, indicating presumably altered functional coupling. Altered interregional coupling between brain regions might be a sensitive approach to demonstrate functional and molecular alterations in psychiatric conditions. Hum Brain Mapp 38:792-802, 2017. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Aim: Studies using S- and R-enantiomers of the SSRI citalopram have shown that R-citalopram exerts an antagonistic effect on the efficacy of the antidepressant S-citalopram (escitalopram) through an interaction at an allosteric modulator site on the serotonin transporter (SERT). Here, we show that protein kinase signaling systems are involved in the allosteric modulation of the SERT in vivo and in vitro. Methods: We assessed the effects of nonspecific protein kinase inhibitor staurosporine in the action of escitalopram and/or Rcitalopram using electrophysiological and behavioral assays in rats and cell surface SERT expression measures in serotoninergic cells. Results: Acute administration of R-citalopram counteracted the escitalopram-induced suppression of the serotonin (5-HT) neuronal firing activity and increase of the head twitches number following L-5-hydroxytryptophan injection. Importantly, these counteracting effects of R-citalopram were abolished by prior systemic administration of staurosporine. Interestingly, the preventing effect of staurosporine on 5-HT neuronal firing activity was abolished by direct activation of protein kinase C with phorbol 12-myristate 13-acetate. Finally, in vitro, quantification of the amount of cell surface- expressed SERT molecules revealed that R-citalopram prevented escitalopram-induced SERT internalization that was completely altered by staurosporine. Conclusion: Taken together, these results highlight for the first time an involvement of protein kinases in the allosteric modulation of SERT function. [ABSTRACT FROM AUTHOR]

Crystal engineering can be described as the understanding of intermolecular interactions in the context of crystal packing and the utilization of such understanding to design new solids with desired physical and chemical properties. Free-energy differences between supramolecular isomers are generally small and minor changes in the crystallization conditions may result in the occurrence of new isomers. The study of supramolecular isomerism will help us to understand the mechanism of crystallization, a very central concept of crystal engineering. Two supramolecular isomers of dichloridobis(1,10-phenanthroline-κ2 N, N′)cobalt(II), [CoCl2(C12H8N2)2], i.e. (I A) (orthorhombic) and (I B) (monoclinic), and two supramolecular isomers of dichloridobis(1,10-phenanthroline-κ2 N, N′)cobalt(II) N, N-dimethylformamide monosolvate, [CoCl2(C12H8N2)2]·C3H7NO, i.e. (II A) (orthorhombic) and (II B) (monoclinic), were synthesized in dimethylformamide (DMF) and structurally characterized. Of these, (I A) and (II A) have been prepared and structurally characterized previously [Li et al. (2007). Acta Cryst. E 63, m1880-m1880; Cai et al. (2008). Acta Cryst. E 64, m1328-m1329]. We found that the heating rate is a key factor for the crystallization of (I A) or (I B), while the temperature difference is responsible for the crystallization of (II A) or (II B). Based on the crystallization conditions, isomerization behaviour, the KPI (Kitajgorodskij packing index) values and the density data, (I B) and (II A) are assigned as the thermodynamic and stable kinetic isomers, respectively, while (I A) and (II B) are assigned as the metastable kinetic products. The 1,10-phenanthroline (phen) ligands interact with each other through offset face-to-face (OFF) π-π stacking in (I B) and (II B), but by edge-to-face (EF) C-H...π interactions in (I A) and (II A). Meanwhile, the DMF molecules in (II B) connect to neighbouring [CoCl2(phen)2] units through two C-H...Cl hydrogen bonds, whereas there are no obvious interactions between DMF molecules and [CoCl2(phen)2] units in (II A). Since OFF π-π stacking is generally stronger than EF C-H...π interactions for transition-metal complexes with nitrogen-containing aromatic ligands, (II A) is among the uncommon examples that are stable and densely packed but that do not following Etter's intermolecular interaction hierarchy. [ABSTRACT FROM AUTHOR]

Recent preclinical studies have revealed a functionally important role for the drug efflux pump P-glycoprotein (P-gp) at the blood-brain barrier in limiting brain levels and thus antidepressant-like activity of certain antidepressant drugs. Specifically, acute administration of P-gp inhibitors, such as verapamil and cyclosporin A (CsA), has been shown to augment brain concentrations and functional activity of the antidepressant escitalopram in rodents. However, depression is a chronic disorder and current treatments require prolonged administration to elicit their full therapeutic effect. Thus, it is important to investigate whether acute findings in relation to P-gp inhibition translate to chronic paradigms. To this end, the present study investigates whether chronic treatment with the P-gp inhibitor verapamil and the antidepressant escitalopram results in enhanced brain distribution and antidepressant-like effects of escitalopram. Verapamil (10 mg·kg-1 i.p.) and escitalopram (0.1 mg·kg-1 i.p.) were administered once daily for 22 days. On the final day of treatment, brain regions and plasma were collected for analysis of cortical and plasma escitalopram concentrations, and to determine the hippocampal expression of genes previously reported to be altered by chronic antidepressant treatment. Verapamil treatment resulted in a greater than twofold increase in brain levels of escitalopram, without altering plasma levels. Neither gene expression analysis nor behavioral testing revealed an augmentation of responses to escitalopram treatment due to verapamil administration. Taken together, these data demonstrate for the first time that P-gp inhibition can yield elevated brain concentrations of an antidepressant after chronic treatment. The functional relevance of these increased brain levels requires further elaboration. [ABSTRACT FROM AUTHOR]

Preclinical animal models implicate serotonin neurons in the pathophysiology of levodopa ( l-dopa)-induced dyskinesias in Parkinson's disease (PD), but effective treatment remains elusive. We examined the relationship between serotonin and l-dopa-induced dyskinesias in a pathologically confirmed cohort of PD patients. We obtained brain tissue from 44 PD cases and 17 age-matched controls and assessed monoamine levels and the serotonin and dopamine transporters in the striatum, and the extent of dopaminergic and serotonergic cell preservation in the substantia nigra (SN) and the dorsal raphe nuclei (DRN), respectively. As expected, PD patients demonstrated a severe loss of all dopaminergic markers, including dopamine ( P < 0.0001) and the dopamine transporter ( P < 0.0001) in the striatum, and dopaminergic neurons ( P < 0.001) in the SN, compared with controls. Marked serotonin loss was observed in the caudate (but not putamen) in PD patients compared with controls ( P < 0.001), but no difference was found in the levels of the serotonin transporter in the striatum or density of serotonergic neurons in the DRN between these groups, suggesting a functional but not structural change in the serotonergic system in PD. No difference was seen in levels of serotonergic and dopaminergic markers in the striatum between PD patients with and without dyskinesias, or between cases separated according to the clinical severity of their dyskinesias. The absence of a correlation between striatal serotonin markers and the incidence and severity of l-dopa-induced dyskinesias suggests that an intact and functioning serotonergic system is not a risk factor for developing dyskinesias in PD. © 2015 International Parkinson and Movement Disorder Society [ABSTRACT FROM AUTHOR]

Objective Antidepressants are at best 50-55% effective. Non-compliance and the antidepressant discontinuation syndrome (ADS) are causally related yet poorly appreciated. While ADS is associated with most antidepressants, agomelatine seems to be devoid of such risk. We review the neurobiology and clinical consequences of antidepressant non-compliance and the ADS. Agomelatine is presented as a counterpoint to learn more on how ADS risk is determined by pharmacokinetics and pharmacology. Design The relevant literature is reviewed through a MEDLINE search via PubMed, focusing on agomelatine and clinical and preclinical research on ADS. Results Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. Conclusions This review raises awareness of the long-term negative aspects of non-compliance and inappropriate antidepressant discontinuation, and suggests possible approaches to 'design-out' a risk for ADS. It reveals intuitive and rational ideas for antidepressant drug design, and provides new thoughts on antidepressant pharmacology, ADS risk and how these affect long-term outcome. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article presents a review of genetic findings in obsessive-compulsive disorder (OCD). It mentions the use of bioinformatics approaches in locating pathways relevant to neuroprotection. It notes that OCD susceptibility gene products affect cyclic adenosine monophosphate response element (CREB)-binding protein (CBP) and other targets.

ABSTRACT To clarify the basis of limited responses in children and adolescents to antidepressant treatments considered standard in the treatment of adult major depressive disorder, juvenile Sprague-Dawley rats were subjected to 21-day treatment with dissimilar antidepressant drugs fluoxetine, imipramine, or vehicle control. Total RNA was extracted from brain frontal cortices and hybridized to the Affymetrix 230.2 chip. A total of 18 microarrays were analyzed (i.e., six biological replicates in three treatment groups). Transcripts identified were validated using Taqman real-time quantitative PCR methodology, and the relative expression of each gene was also determined. In both the imipramine- and fluoxetine-treated animals, expression of six genes was down-regulated (ANOVA-filtered gene expression data using dChip [version 2005]): Gpd1; Lrrn3; Sult1A1; Angptl4; Mt1a; Unknown. Furthermore, four genes were over-expressed: P4Ha1; RDG1311476; Rgc32; and SLC25A18-like by both imipramine and fluoxetine. These data demonstrate that antidepressant drugs interfere with the expression of genes involved in cell signaling, survival, and protein metabolism. Our results show that antidepressants regulate the induction of highly specific transcriptional programs in the developing frontal cortex. These findings provide novel insights into the long-term molecular actions of antidepressant drugs in the developing brain. Synapse 68:209-220, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ABSTRACT Stress influences the development of depression, and depression is associated with structural and functional changes in the hippocampus. The current study sought to determine whether chronic corticosteroid (CORT) treatment influences serotonin transporter (5-HTT) protein expression and function in the CA1, CA3, and dentate gyrus (DG) subregions of the hippocampus. Male CD-1 mice were subcutaneously injected with CORT at a dose of 20 mg/kg once daily for 3 weeks. Behavioral state was assessed using sucrose preference, physical state of the coat, forced swimming test, and tail suspension test. We then determine 5-HTT protein expression and synaptosomal 5-HT uptake in the CA1, CA3 and DG subregions. CORT treatment induced anhedonia and behavioral despair, two core endophenotypes of clinical depression; 5-HTT protein expression levels and synaptosomal 5-HT uptake were both decreased in a subregion-specific manner, with the greatest decrease observed in the DG, a moderate decrease in the CA3, and the CA1 showed no apparent change. In addition, a reduction in tissue mass was detected in the DG following the CORT treatment. These data indicate that subregion-specific decreases in hippocampal 5-HTT protein expression and function are associated with endophenotypes of depression. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Objectives MDAI (5,6-methylenedioxy-2-aminoindane; 6,7-dihydro-5H-cyclopenta[f][1,3]benzodioxol-6-amine; 'sparkle'; 'mindy') is a psychoactive substance, sold primarily over the Internet and in 'head' shops as a 'legal high'. Synthesised and used as a research chemical in the 1990s, MDAI has structural similarities to MDMA (3,4-methylenedioxy- N-methylamphetamine) and shares its behavioural properties. Recreational use of MDAI appears to have started in Europe around 2007, with a noticeable increase after 2009 in the UK and other countries. Calls to National Poisons Information Services started in 2010, although there were few presentations to emergency departments by patients complaining of undesirable physical and psychiatric effects after taking MDAI. Recreational use of this drug has been reported only occasionally by online user fora. There is little scientifically based literature on the pharmacological, physiological, psychopharmacological, toxicological and epidemiological characteristics of this drug. Methods Recent literature (including 'grey') was searched to update what is known about MDAI, especially on its toxicity. Results The resultant information is presented, including on the first three UK deaths involving MDAI use in 2011 and 2012. 'Serotonin syndrome' appears to be a possible factor in these fatalities. Conclusion It is vital that any other cases, including non-fatal overdoses, are documented so that a scientific evidence base can be established for them. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Serotonin (5-hydroxytryptamine; 5- HT) is an important brain neurotransmitter that is implicated in mental and neurodegenerative diseases and is modulated by ovarian hormones. Nevertheless, the effect of oestrogens on 5- HT neurotransmission in the primate caudate nucleus, putamen and nucleus accumbens, which are major components of the basal ganglia, and the anterior cerebral cortex, mainly the frontal and cingulate gyrus, is not well documented. The present study evaluated 5- HT reuptake transporter ( SERT) and 5- HT metabolism in these brain regions in response to 1-month treatment with 17β-oestradiol in short-term (1 month) ovariectomised ( OVX) monkeys ( Macaca fascicularis). SERT-specific binding was measured by autoradiography using the radioligand [3H]citalopram. Biogenic amine concentrations were quantified by high-performance liquid chromatography. 17β-Oestradiol increased SERT in the superior frontal cortex and in the anterior cingulate cortex, in the nucleus accumbens, and in subregions of the caudate nucleus of OVX monkeys. 17β-Oestradiol left [3H]citalopram-specific binding unchanged in the putamen, as well as the dorsal and medial raphe nucleus. 17β-Oestradiol treatment decreased striatal concentrations of the precursor of 5- HT, 5-hydroxytryptophan, and increased 5- HT, dopamine and 3-methoxytyramine concentrations in the nucleus accumbens, caudate nucleus and putamen, whereas the concentrations of the metabolites 5-hydroxyindoleacetic acid, 3,4-dihydroxyphenylacetic acid and homovanillic acid remained unchanged. No effect of 17β-oestradiol treatment was observed for biogenic amine concentrations in the cortical regions. A significant positive correlation was observed between [3H]citalopram-specific binding and 5- HT concentrations in the caudate nucleus, putamen and nucleus accumbens, suggesting their link. These results have translational value for women with low oestrogen, such as those in surgical menopause or perimenopause. [ABSTRACT FROM AUTHOR]

Amphetamine withdrawal in both humans and rats is associated with increased anxiety states, which are thought to contribute to drug relapse. Serotonin in the ventral hippocampus mediates affective behaviors, and reduced serotonin levels in this region are observed in rat models of high anxiety, including during withdrawal from chronic amphetamine. This goal of this study was to understand the mechanisms by which reduced ventral hippocampus serotonergic neurotransmission occurs during amphetamine withdrawal. Serotonin synthesis (assessed by accumulation of serotonin precursor as a measure of the capacity of in vivo tryptophan hydroxylase activity), expression of serotonergic transporters, and in vivo serotonergic clearance using in vivo microdialysis were assessed in the ventral hippocampus in adult male Sprague Dawley rats at 24 h withdrawal from chronic amphetamine. Overall, results showed that diminished extracellular serotonin at 24 h withdrawal from chronic amphetamine was not accompanied by a change in capacity for serotonin synthesis ( in vivo tryptophan hydroxylase activity), or serotonin transporter expression or function in the ventral hippocampus, but instead was associated with increased expression and function of organic cation transporters (low-affinity, high-capacity serotonin transporters). These findings suggest that 24 h withdrawal from chronic amphetamine reduces the availability of extracellular serotonin in the ventral hippocampus by increasing organic cation transporter-mediated serotonin clearance, which may represent a future pharmacological target for reversing anxiety states during drug withdrawal. [ABSTRACT FROM AUTHOR]

Recent evidence underlines the crucial role of neuronal cytoskeleton in the pathophysiology of psychiatric diseases. In this line, the deletion of STOP/ MAP6 (Stable Tubule Only Polypeptide), a microtubule-stabilizing protein, triggers various neurotransmission and behavioral defects, suggesting that STOP knockout ( KO) mice could be a relevant experimental model for schizoaffective symptoms. To establish the predictive validity of such a mouse line, in which the brain serotonergic tone is dramatically imbalanced, the effects of a chronic fluoxetine treatment on the mood status of STOP KO mice were characterized. Moreover, we determined the impact, on mood, of a chronic treatment by epothilone D, a taxol-like microtubule-stabilizing compound that has previously been shown to improve the synaptic plasticity deficits of STOP KO mice. We demonstrated that chronic fluoxetine was either antidepressive and anxiolytic, or pro-depressive and anxiogenic, depending on the paradigm used to test treated mutant mice. Furthermore, control-treated STOP KO mice exhibited paradoxical behaviors, compared with their clear-cut basal mood status. Paradoxical fluoxetine effects and control-treated STOP KO behaviors could be because of their hyper-reactivity to acute and chronic stress. Interestingly, both epothilone D and fluoxetine chronic treatments improved the short-term memory of STOP KO mice. Such treatments did not affect the serotonin and norepinephrine transporter densities in cerebral areas of mice. Altogether, these data demonstrated that STOP KO mice could represent a useful model to study the relationship between cytoskeleton, mood, and stress, and to test innovative mood treatments, such as microtubule-stabilizing compounds. [ABSTRACT FROM AUTHOR]

Dysregulation of glycogen synthase kinase (GSK)-3β contributes to the pathophysiology of mood disorders. However, how its regulation is responsible for the functioning of serotonin (5-HT) requires further investigation. Although enhancement of T-cell function may present an alternative strategy to treat depression, the precise mechanisms have yet to be established. Our previous studies have found that interferon-alpha (IFN-α) up-regulates serotonin transporter (5-HTT) expression and induces 5-HT uptake in T cells. The present study is to examine GSK-3β regulation on IFN-α-induced 5-HTT functions. GSK-3β short hairpin RNAs (shRNAs) or GSK-3β inhibitors decreased IFN-α-induced 5-HT uptake and 5-HTT expression. Src activation and calcium/calcium-activated calmodulin kinase II (CaMKII) were involved in IFN-α-induced phosphorylation of proline-rich tyrosine kinase 2 (Pyk2) (Tyr402) and GSK-3β (Tyr216), which regulated 5-HT uptake. GSK-3β knockdown blocked the IFN-α-induced phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 (Thr202/Tyr204) and signal transducer and transactivator (STAT) 1. In addition to inhibiting ERK, a selective 5-HTT inhibitor fluoxetine blocked IFN-α-induced activations of Src, CaMKII-regulated Pyk2/GSK-3β cascade, as well as STAT1 activation and translocation. These results indicated that calcium/CaMKII- and Src-regulated Pyk2 participated in IFN-α-induced GSK-3β activation and GSK-3β-regulated 5-HT uptake. GSK-3β signaling facilitated IFN-α-activated STAT1 by regulating ERK1/2, which controlled 5-HT uptake. Fluoxetine interfered with the Pyk2/GSK-3β cascade, thereby inhibiting IFN-α-induced 5-HT uptake. J. Cell. Physiol. 227: 2556-2566, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Repeated administration of methamphetamine (mAMPH) to rodents in a single-day 'binge' produces long-lasting damage to dopaminergic and serotonergic terminals. Because previous research has demonstrated that physical activity can ameliorate nigrostriatal injury, this study investigated whether voluntary exercise in rats can alter the monoaminergic damage resulting from a neurotoxic mAMPH binge. Adult male rats were allowed constant access to running wheels or kept in nonwheel cages for three weeks, then given a binge dosing regimen of mAMPH or saline. The rats were returned to their original environments for three additional weeks post-mAMPH. [125I]RTI-55 binding and autoradiography was used to quantify dopamine transporters (DAT), and radioimmunocytochemistry was used to quantify striatal tyrosine hydroxylase (TH). Binge mAMPH treatment significantly reduced striatal DAT and TH in a regionally specific pattern; with greatest effects in ventral caudate-putamen (CP) and relative sparing of the nucleus accumbens septi (NAc). The effects of mAMPH on striatal DAT and TH were ameliorated in the running, compared to the sedentary, animals. Also, mAMPH was found to reduce [125I]RTI-55 binding to serotonin transporters (SERT) in frontoparietal cortex, and this too was significantly attenuated by exercise. Additional correlational analyses showed that the post-mAMPH running of individual animals predicted the amelioration of striatal DAT and TH as well as frontoparietal SERT. Overall, voluntary exercise significantly diminished mAMPH-induced forebrain monoaminergic damage. The significant correlations between post-mAMPH exercise and markers of monoaminergic terminal integrity provide novel evidence that voluntary exercise may exert beneficial effects on behavior in recovering mAMPH addicts. Synapse, 2012. © 2011 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Spontaneous and/or stimulated neural activity of the nigrostriatal dopamine (DA) pathway makes amines run out from the neurons. This DA dynamic follows a rather complex path, running in or out the terminals, and flushing or diffusing into the extracellular space. The location of this leakage is not limited to the axon terminals; it also occurs from the cell bodies and dendrites. This molecular release mechanism was, for a long time, considered as being produced, in part, by the exocytosis of previously stored vesicles. The DA carrier protein (DAT, DA transporter) embedded in the DA cell membrane is known to clear previously released amines through an inward DA influx. The DAT also appears to be an active vector of amine release. Particular local conditions and the presence of numerous psychostimulant substances are able to trigger an outward efflux of DA through the DAT. This process, delivering slowly large amounts of amine could play a major regulatory role in extracellular DA homeostasis. [ABSTRACT FROM AUTHOR]

Although nicotine is generally considered to be the main psychoactive component of tobacco, growing evidence highlights the importance of nonnicotine compounds in smoking reinforcement. Monoamine oxidase (MAO) inhibition is a major consequence of smoking and MAO inhibitors, such as tranylcypromine, increase nicotine reinforcement. Tranylcypromine has multiple pharmacological effects, increasing monoamine release for a few hours immediately after its administration and blocking MAO activity for several days. To assess the relative role of these two actions, adult male rats were tested in consecutive daily 3-h sessions for self-administration of nicotine (3 µg kg-1 inj-1, i.v.) either 20 or 1 h following administration of tranylcypromine (3 mg kg-1). Both paradigms were shown to produce highly significant inhibition of MAO activity. However, whereas animals readily acquired self-administration when pretreated with tranylcypromine 1 h prior to testing, they did not with the longer pretreatment interval. Such animals did immediately acquire nicotine self-administration when the tranylcypromine pretreatment interval was switched to 1 h prior to testing on Day 4, indicating that an acute effect of the MAO inhibitor was responsible for enhanced nicotine reinforcement. Several lines of evidence implicate serotonin (5-HT) as the mediator of this enhancement: (1) Tranyclypromine-enhanced nicotine reinforcement was blocked by the 5-HT2 receptor antagonists, ritanserin and ketanserin; (2) parachloroamphetamine (PCA), a 5-HT releaser, also enhanced nicotine self-administration in animals in which MAO activity was inhibited; (3) pretreatment with tranylcypromine increased PCA-induced 5-HT overflow in the nucleus accumbens. These findings suggest that MAO inhibition enhances serotonergic transmission, which serves a critical role in the reinforcing effects of nicotine. [ABSTRACT FROM AUTHOR]

Functional neurotransmitter receptors are expressed in central white matter, where they mediate ischemic damage to glia and may be involved in cell–cell signalling. In this study, we analysed NMDA receptor NR1, NR2B-C and NR3A-B subunit expression in the brain and optic nerve by molecular cloning. In addition to the canonical forms of NR1 and NR2, four previously unknown NR3B variants, generated by alternative splicing, were identified. The variants encoded for isoforms with deletions of 8/15 amino acids in the N-terminal domain or 200/375 amino acids removing one or three transmembrane domains and part of the C-terminal domain, as compared with the previously characterized NR3B isoform. Co-expression of NR3B isoforms with NR1/NR2A-C modulated the amplitude and Mg2+-sensitivity of glutamate responses in a NR2 subunit dependent fashion, with significant variations in the effects produced by different isoforms. These effects were not the result of reduced surface expression of the receptor complex since all NR3B isoforms reduced surface expression by a similar degree. These data reveal previously uncharacterized regulation of NMDA receptor function by alternative splicing of the NR3B subunit. [ABSTRACT FROM AUTHOR]