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Abstract: Melatonin is involved in the control of circadian and seasonal rhythmicity, possesses potent antioxidant activity, and exerts a neuroprotective and anticonvulsant effect. Spontaneously hypertensive rats (SHRs) are widely accepted as an experimental model of essential hypertension with hyperactivity, deficient sustained attention, and alterations in circadian autonomic profiles. The purpose of the present study was to determine whether melatonin treatment during epileptogenesis can prevent the deleterious consequences of status epilepticus (SE) in SHRs in the kainate (KA) model of temporal lobe of epilepsy (TLE). Spontaneous recurrent seizures (SRSs) were EEG- and video-recorded during and after the treatment protocol. Melatonin (10mg/kg diluted in drinking water, 8weeks) increased the seizure-latent period, decreased the frequency of SRSs, and attenuated the circadian rhythm of seizure activity in SHRs. However, melatonin was unable to affect the disturbed diurnal rhythms and behavioral changes associated with epilepsy, including the decreased anxiety level, depression, and impaired spatial memory. Melatonin reduced neuronal damage specifically in the CA1 area of the hippocampus and piriform cortex and decreased hippocampal serotonin (5-HT) levels both in control and epileptic SHRs. Although long-term melatonin treatment after SE shows a potential to attenuate seizure activity and neuronal loss, it is unable to restore epilepsy-associated behavioral abnormalities in SHRs. [Copyright &y& Elsevier]

Abstract: Attention deficit/hyperactivity disorder (ADHD) is encountered among patients with epilepsy at a significantly higher rate than in the general population. Mechanisms of epilepsy–ADHD comorbidity remain largely unknown. We investigated whether a model of chronic epilepsy in rats produces signs of ADHD, and thus, whether it can be used for studying mechanisms of this comorbidity. Epilepsy was induced in male Wistar rats via pilocarpine status epilepticus. Half of the animals exhibited chronic ADHD-like abnormalities, particularly increased impulsivity and diminished attention in the lateralized reaction-time task. These impairments correlated with the suppressed noradrenergic transmission in locus coeruleus outputs. The other half of animals exhibited depressive behavior in the forced swimming test congruently with the diminished serotonergic transmission in raphe nucleus outputs. Attention deficit/hyperactivity disorder and depressive behavior appeared mutually exclusive. Therefore, the pilocarpine model of epilepsy affords a system for reproducing and studying mechanisms of comorbidity between epilepsy and both ADHD and/or depression. [Copyright &y& Elsevier]

Highlights: [•] Systemic administration of LP-211 increases wakefulness and reduces REM sleep. [•] Microinjection of LP-211 into the DRN, LC, BFB or LDT suppresses REM sleep. [•] Similar changes were described after administration of other 5-HT receptor agonists. [ABSTRACT FROM AUTHOR]

Highlights: [•] Prenatal LPS exposure increases depression-like behaviors in adult offspring. [•] Affected offspring also show reduced adult neurogenesis and BDNF concentration in the hippocampus. [•] The spine density in prenatal LPS exposed offspring is reduced comparing to controls. [•] Chronic selective serotonin reuptake inhibitor FLX treatment reverses the depression-like behaviors in LPS rats. [•] Prenatal LPS exposure may be used as an animal model for depression research. [ABSTRACT FROM AUTHOR]

Abstract: Dopamine (DA) replacement therapy with l-DOPA is the standard treatment for Parkinson's disease (PD). Unfortunately chronic treatment often leads to the development of abnormal involuntary movements (AIMs) referred to as l-DOPA-induced dyskinesia (LID). Accumulating evidence has shown that compensatory plasticity in serotonin (5-HT) neurons contributes to LID and recent work has indicated that acute 5-HT transporter (SERT) blockade provides anti-dyskinetic protection. However neither the persistence nor the mechanism(s) of these effects have been investigated. Therefore the current endeavor sought to mimic a prolonged regimen of SERT inhibition in l-DOPA-primed and -naïve hemi-parkinsonian rats. Rats received 3 weeks of daily co-treatment of the selective 5-HT reuptake inhibitors (SSRIs) citalopram (0, 3, or 5 mg/kg) or paroxetine (0, 0.5, or 1.25 mg/kg) with l-DOPA (6 mg/kg) during which AIMs and motor performance were monitored. In order to investigate potential mechanisms of action, tissue levels of striatal monoamines were monitored and the 5-HT1A receptor antagonist WAY100635 (0.5 mg/kg) was used. Results revealed that prolonged SSRIs attenuated AIMs expression and development in l-DOPA-primed and -naïve subjects, respectively, without interfering with motor performance. Neurochemical analysis of striatal tissue indicated that a 3 week SERT blockade increased DA levels in l-DOPA-treated rats. Pharmacologically, anti-dyskinetic effects were partially reversed with WAY100635 signifying involvement of the 5-HT1A receptor. Collectively, these findings demonstrate that prolonged SERT inhibition provides enduring anti-dyskinetic effects in part via 5-HT1A receptors while maintaining l-DOPA's anti-parkinsonian efficacy by enhancing striatal DA levels. [Copyright &y& Elsevier]

Highlights: [•] The cholinergic agonist, carbachol, strengthens the inhibition of dorsal raphe neurons. [•] Removal of dorsal but not ventral regions of the slice abolishes this effect. [•] Carbachol depolarizes GABAergic neurons in the ventrolateral periaqueductal gray. [•] Both nicotinic and muscarinic receptors are involved in the effect of carbachol. [ABSTRACT FROM AUTHOR]

Highlights: [•] Rats were exposed to stress and 24h to 4 days of amphetamine withdrawal. [•] Changes in serotonin 2A receptor expression in prefrontal cortex were examined. [•] 24h withdrawal decreased expression in anterior cingulate and prelimbic cortices. [•] 4 days withdrawal increased expression in anterior cingulate and prelimbic cortices. [•] Stress decreased expression in anterior cingulate and prelimbic cortices [ABSTRACT FROM AUTHOR]

Elevated levels of serotonin (5-HT) and endothelin-1 (ET-1) may be involved in cardiovascular complications of diabetes mellitus. Data suggest supraphysiological concentrations of 5-HT (10-6 M) potentiate the ability of ET-1 to stimulate DNA synthesis and vascular smooth muscle cell (VSMC) proliferation in vitro via activation of mitogen-activated protein kinase (p42/44 MAPK) and Janus kinase 2 (JAK2) pathways. Additionally, 5-HT enhances agonist-induced contractions via p42/44 MAPK and an unknown tyrosine kinase. However, the exact mechanisms of the 5-HT/ET-1 interactions and whether these effects occur at physiological levels (10-9 M) are unknown. Therefore, we hypothesized that interactions between 5-HT and ET-1 at physiological concentrations in VSMC enhanced activation of both p42/44 MAPK and JAK2 pathways contributing to vascular growth and contractile responses. With the use of rat VSMC and Western blot analysis, our data suggest no effect of acute (30 min) preincubation with 5-HT (10-9 M) and/or ET-1 (10-9 M) on the activation of either pathway in normal or high glucose conditions. To determine if there was altered vascular reactivity in intact vessels we tested the effects of 5-HT and ET-1 interaction using myographs to measure isometric contractions of rat thoracic aortic rings. 5-HT (10-9 M) and ET-1 (10-12 M) stimulate enhanced contractile responses to each other that were inhibited by JAK2 and p42/44 MAPK antagonists. Our findings demonstrate that both 5-HT and ET-1 at physiological concentrations could interact with each other and activate p42/44 MAPK and JAK2 signaling pathways to cause an increase in smooth muscle contraction that could lead to altered vascular function. [ABSTRACT FROM AUTHOR]

Highlights: [•] Peripheral chemerin administration decreased food intake and body weight. [•] Chemerin decreased AgRP and orexin A mRNA in the hypothalamus. [•] Chemerin increased hypothalamic serotonin synthesis and release. [ABSTRACT FROM AUTHOR]

Highlights: [•] Peripherally restricted immunomodulatory agent could confer behavioral benefits. [•] Rg1 modulated the peripheral as well as central immune disturbance induced by central LPS. [•] Rg1 attenuated behavioral and neurochemical disturbances without entering the brain. [•] The data supported a novel therapeutic avenue to inflammation-associated psychiatric disorders. [ABSTRACT FROM AUTHOR]

Abstract: Recently, studies show that intermittent fasting and caloric restriction may improve symptoms of depression. However, there is little scientific evidence regarding the literature on the antidepressant-like effects of acute fasting. The present study aims to investigate the antidepressant-like effects and its influence on brain levels of the transcription factor cAMP response element-binding protein (CREB) and its phosphorylated form (p-CREB) in different time periods of fasting mice. Furthermore, the additive antidepressant-like effects of fasting with imipramine and the possible involvement of the 5-HT2 receptors were examined. In the present study 9h, but not 3h and 18h of fasting significantly reduced immobility time in the forced swimming test (FST) without alteration in locomotor activity in the open field test. 9h fasting also enhanced the ratio of p-CREB/CREB in the frontal cortex and hippocampus. Co-administration of 9h of fasting and imipramine (30mg/kg, i.p) produced the additive antidepressant-like effects in the FST and increased the ratio of p-CREB/CREB. Meanwhile, the additive effects were partially reversed by treatment with a 5-HT2A/2C receptor agonist, (±)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI) (5mg/kg, s.c). Furthermore, the antidepressant-like effects of 9h fasting was also blocked by DOI compared to the non-fasting control group. Serum corticosterone level, but not 5-HT and noradrenaline, was significantly increased in a time-dependent manner following different time periods of fasting. Taken together, these results suggest that acute fasting produces antidepressant-like effects via enhancement of the p-CREB/CREB ratio, and additive antidepressant-like effects of fasting with imipramine may be related to modulating 5-HT2 receptors. [Copyright &y& Elsevier]

Abstract: A disturbed metabolism of catecholamines and other neurotransmitters appears to play a major role in the pathogenesis of neurospychiatric symptoms, such as changes in mood and depression. This symptomatology is common in patients with chronic inflammatory disorders such as infections, autoimmune diseases, or cancer. The pathogenesis of these symptoms is still unclear. Pro-inflammatory stimuli interfere not only with the neural circuits and neurotransmitters of the serotonergic system but also with those of the adrenergic system. The pro-inflammatory cytokine interferon-γ stimulates the biosynthesis of 5,6,7,8-tetrahydrobiopterin (BH4), which is a co-factor for several aromatic amino acid mono-oxygenases and is rate-limiting for the biosynthesis of the neurotransmitter serotonin and the catecholamines dopamine, epinephrine (adrenaline) and norepinephrine (noradrenaline). Interferon-γ triggers the high output of reactive oxygen species in macrophages, which can destroy the oxidation-labile BH4. Recent data suggests that oxidative loss of BH4 in chronic inflammatory conditions can reduce the biosynthesis of catecholamines, which may relate to disturbed adrenergic neurotransmitter pathways in patients. [Copyright &y& Elsevier]

Background Previous studies on male rodents found that prenatal alcohol exposure ( PAE) decreases the number of serotonin immunoreactive (5- HT-ir) neurons in the brainstem. However, data on the effects of PAE in females are lacking. In light of known sex differences in responsiveness of the 5-HT system and known effects of estrogen ( E2) and progesterone ( P4) in the brain, we hypothesized that sex steroids will modulate the adverse effects of PAE on 5- HT neurons in adult females. Methods Adult females from 3 prenatal groups (Prenatal alcohol-exposed [ PAE], Pair-fed [ PF], and ad libitum-fed Controls [ C]) were ovariectomized ( OVX), with or without hormone replacement, or underwent Sham OVX. 5- HT-ir cells were examined in key brainstem areas. Results Our data support the hypothesis that PAE has long-term effects on the 5-HT system of females and that ovarian steroids have a modulatory role in these effects. Intact ( Sham OVX) PAE females had marginally lower numbers of 5- HT-ir neurons in the dorsal raphe nucleus of the brainstem compared with PF and C females. This marginal difference became significant following removal of hormones by OVX. Replacement with E2 restored the number of 5- HT-ir neurons in PAE females to control levels, while P4 reversed the effects of E2. Importantly, despite these differential responses of the 5-HT system to ovarian steroids, there were no differences in E2 and P4 levels among prenatal treatment groups. Conclusions These data demonstrate long-term, adverse effects of PAE on the 5-HT system of females, as well as differential sensitivity of PAE compared with control females to the modulatory effects of ovarian steroids on 5-HT neurons. Our findings have important implications for understanding sex differences in 5-HT dysfunction in depression/anxiety disorders and the higher rates of these mental health problems in individuals with fetal alcohol spectrum disorder. [ABSTRACT FROM AUTHOR]

Ciliary and nerve structures were described in juvenile female Dinophilus gyrociliatus (O. Schmidt, 1848) after immunochemical staining with tubulin, serotonin, and FMRFamide antibodies. Anti-tubulin antibodies revealed the following external structures: two head and seven body ciliary bands, a ventral ciliary band, and head ciliary fields. Gut cilia and five pairs of protonephridia were detected inside the body. The nervous system consists of an oval headed neuropile with anterior and posterior nerves extending from it, seven longitudinal nerve cords, commissures, and circular nerves. Anti-serotonin antibodies revealed the head neuropile, neurons at the base of the ventral ciliary band, an oesophageal ring, and seven longitudinal ventral cords. Anti-FMRFamide antibodies revealed approximately ten neurons in the cerebral ganglion, five longitudinal cords, and the oesophageal and caudal-nerve rings. The presented data suggest the simplification of the nervous system structure in D. gyrociliatus, which probably reflects pedomorphosis. [ABSTRACT FROM AUTHOR]

Highlights: [•] Early environmental enrichment equally affects visual tissues in both sexes during prepuberty. [•] Early environmental enrichment increases serotonergic activity in the adult female retina. [•] Late environmental enrichment increases dopaminergic activity in the male visual cortex. [•] Visual adaptation concerns the female retina and the male visual cortex. [Copyright &y& Elsevier]

Highlights: [•] Morphine decreased BDNF, TrkB and 5-HT1A mRNA expression in the serotonergic DRN. [•] Morphine decreased CRF-R1 and increased CRF-R2 mRNA expression in the DRN. [•] Opiate history and swim stress interact to reduce DRN TPH2 mRNA expression. [•] Opiate modulation of DRN circuits may promote 5-HT hypofunction. [•] 5-HT hypofunction may contribute to vulnerability to stress-induced opiate relapse. [Copyright &y& Elsevier]

Highlights: [•] Chronic L-DOPA induces robust contralateral rotations in 6-OHDA-lesioned rats. [•] NO donor molsidomine administered at low dose modulates L-DOPA induced rotations. [•] Molsidomine improves L-DOPA effects on DA level in the striatum and SN. [•] Chronic L-DOPA decreases 5-HT level in the striatum and SN of 6-OHDA-lesioned rats. [•] Molsidomine modulates L-DOPA induced effects on 5-HT level and its catabolism. [ABSTRACT FROM AUTHOR]

Highlights: [•] We provide a genetic mouse model with an isolated cortex to study the spinal cord. [•] Mice with an isolated cortex maintain basic motor function but are hyperactive. [•] No cortex input results in abnormalities of spinal motor neurons, muscles and NMJs. [•] Mutants have increased dopaminergic and serotoninergic spinal projections. [ABSTRACT FROM AUTHOR]

Abstract: Methamphetamine use disorders remain a significant public health concern. Methamphetamine produces its behavioral effects by facilitating release of monoamines like dopamine (DA) and serotonin (5-HT). Results from animal studies show that acute pretreatment with DA and 5-HT antagonists attenuates the effects of methamphetamine, but this area remains largely unexplored in humans. This study sought to assess whether aripiprazole, a partial agonist at D2/5-HT1A receptors and an antagonist at 5-HT2A receptors, would attenuate the reinforcing and subject-rated effects of oral methamphetamine. Seven subjects with histories of recreational stimulant use completed a placebo-controlled, crossover, double-blind protocol in which they first sampled doses of oral methamphetamine (0, 4, 8 or 16mg) following acute pretreatment with aripiprazole (0 and 15mg). During each Sampling Session, subjects also completed a battery of subject-rated, cardiovascular, and other performance measures. In subsequent Self-Administration Sessions, subjects were provided the opportunity to earn the previously sampled methamphetamine dose on a progressive-ratio procedure. Methamphetamine functioned as a reinforcer, and produced prototypical stimulant-like subject-rated and cardiovascular effects (e.g., increased ratings of Stimulated; elevated blood pressure). Aripiprazole reduced methamphetamine self-administration and attenuated some of the positive subject-rated effects of methamphetamine (e.g., ratings of Like Drug). These results indicate that acute aripiprazole pretreatment attenuates the abuse-related effects of methamphetamine. [Copyright &y& Elsevier]

Previous studies have reported that selective serotonin reuptake inhibitors (SSRIs) may induce or exacerbate rapid eye movement (REM) sleep without atonia (RSWA) and increase the risk of developing REM sleep behavior disorder (RBD). However, most of these studies are retrospective and cross-sectional and employed small sample sizes and a mixture of SSRIs. In this 8-week open-label trial of sertraline in depressed patients (n=31), depressed patients were administered 50mg sertraline at 8am on the 1st day and subsequently titrated up to a maximum of 200mg/day. All patients underwent repeated video-polysomnography (vPSG) (baseline, 1st day, 14th day, 28th day, and 56th day). Both tonic (submental) and phasic (submental and anterior tibialis) RSWA events were visually counted. Tonic RSWA increased from 3.2±1.8% at baseline to 5.1±2.3% on the 1st day and 10.4±2.7% on the 14th day; after that, measurements were stable until the 56th day. A similar profile was observed for phasic RSWA. The increases in tonic RSWA (r =0.56, P=0.004) and phasic RSWA (submental: r =−0.51, P=0.02; anterior tibialis: r =0.41, P=0.04) were correlated with the degree of the prolonging of REM latency. All of RSWAs were not correlated with patients' demographic and clinical characteristics. Sertraline may induce or exacerbate RSWA. In contrast to idiopathic RBD, sertraline-related RSWA had the specific characteristics of being correlated with the degree of the prolonging of REM latency and no predominance of male sex and elder age, suggesting different pathophysiological mechanisms. The antidepressant-related RSWA should be a potential public health problem in the depressed patients. [ABSTRACT FROM AUTHOR]

Abstract: Numerous reports have highlighted the role of the endocannabinoid system in the addictive potential of MDMA (3,4-methylenedioxy-methamphetamine). A previous report showed that CB1 knockout (KOCB1) mice do not acquire MDMA self-administration, despite developing conditioned place preference (CPP). This contradiction could be due to the particular procedure of place conditioning used. The present work compares MDMA-induced CPP in KOCB1 mice using unbiased and biased procedures of place conditioning. In the unbiased procedure, MDMA induced CPP and reinstatement of the extinguished preference in wild type (WT) mice, but not in KOCB1 mice. In contrast, in a biased protocol of CPP, MDMA produced preference in both types of mice. The anxiolytic response induced by MDMA in the elevated plus maze (EPM) was observed only in KOCB1 mice and may have been responsible, at least partially, for the CPP in the biased procedure. A neurochemical analysis revealed that KOCB1 mice presented higher striatal DA and DOPAC levels in response to MDMA, but no alterations in their levels of monoamine transporters. In line with previous self-administration studies, our data suggest that CB1 receptors play an important role in the reinforcing effects of MDMA, and that the experimental procedure of CPP employed should be taken into account when drawing conclusions. [Copyright &y& Elsevier]

Abstract: Olanzapine is widely used in treating multiple domains of schizophrenia symptoms but induces serious metabolic side-effects. Recent evidence has showed that co-treatment of betahistine (a histaminergic H1 receptor agonist and H3 receptor antagonist) is effective for preventing olanzapine-induced weight gain/obesity, however it is not clear whether this co-treatment affects on the primary therapeutic receptor binding sites of olanzapine such as serotonergic 5-HT2A receptors (5-HT2AR) and dopaminergic D2 receptors (D2R). Therefore, this study investigated the effects of this co-treatment on 5-HT2AR, 5-HT transporter (5-HTT) and D2R bindings in various brain regions involved in antipsychotic efficacy. Female Sprague Dawley rats were administered orally (t.i.d.) with either olanzapine (1mg/kg), betahistine (2.7mg/kg), olanzapine plus betahistine (O+B), or vehicle (control) for 2weeks. Quantitative autoradiography was used to detect the density of [3H]ketanserin, [3H]paroxetine and [3H]raclopride binding site to 5-HT2AR, 5-HTT and D2R. Compared to the controls, olanzapine significantly decreased [3H]ketanserin bindings to 5-HT2AR in the prefrontal cortex, cingulate cortex, and nucleus accumbens. Similar changes in 5-HT2AR bindings in these nuclei were also observed in the O+B co-treatment group. Olanzapine also significantly decreased [3H]paroxetine binding to 5-HTT in the ventral tegmental area and substantia nigra, however, both olanzapine only and O+B co-treatment did not affect [3H]raclopride binding to D2R. The results confirmed the important role of 5-HT2AR in the efficacy of olanzapine, which is not influenced by the O+B co-treatment. Therefore, betahistine co-treatment would be an effective combination therapy to reduce olanzapine-induced weight gain side-effects without affecting olanzapine's actions on 5-HT2AR transmissions. [Copyright &y& Elsevier]

Highlights: [•] This paper is the 35th annual review of research on the endogenous opioid system. [•] It summarizes 2012 behavioral, molecular and pharmacological opioid papers. [•] Topics include opioid analgesic, stress, tolerance and dependence effects. [•] Topics also include learning, ingestion, alcohol and drugs of abuse. [•] Topics also examine sex, mental illness, and neurologic disorders. [ABSTRACT FROM AUTHOR]

Highlights: [•] Rotenone produced PD-like behavioral and neurochemical alterations. [•] Rotenone causes increased oxidative stress and histopathological changes. [•] AESC and AFSC attenuated the rotenone induced behavioral and neurochemical changes. [•] Histopathological and biochemical alterations were also attenuated by AESC and AFSC. [•] AFSC have shown the maximum ameliorative effect against rotenone induced toxicity. [ABSTRACT FROM AUTHOR]

Abstract: The present study was aimed at assessing the influence of noradrenergic innervation of the paraventricular nucleus (PVN) and the arcuate nucleus (ARC) of the brain hypothalamus on cytochrome P450 expression in the liver. DSP-4, a neurotoxin specific to noradrenergic nerve terminals, was administrated locally into the PVN or ARC. One week after neurotoxin injection, the levels of neurotansmitters (noradrenaline/dopamine/serotonin) were measured in the middle part of the hypothalamus, hormone concentrations were estimated in blood plasma, and the activity and the protein levels of CYP isoforms were measured in the liver. A significant decrease in noradrenaline level in the hypothalamus was observed after DSP-4 injection into the PVN or ARC. The levels of dopamine or serotonin remained unchanged or slightly lowered. Simultaneously, significant changes in the plasma concentration of growth hormone were found; its elevation in PVN-lesioned rats and a drop in ARC-lesioned ones. There were no changes in the plasma concentration of the thyroid hormones or corticosterone. The activity and protein levels of isoforms CYP2C11, CYP3A and CYP2A rose in the liver of PVN-lesioned rats, but the activity and protein level of CYP2C11 fell in ARC-lesioned animals such a tendency being also observed in the case of CYP3A. Our study shows that noradrenergic innervation of the PVN and ARC of the hypothalamus exerts an opposite effect on the regulation of cytochrome P450 in the liver. These findings may be important for pharmacological experiments and pharmacotherapy with neuroactive drugs, since cytochrome P450 is responsible for the metabolism of steroids and the majority of drugs. [Copyright &y& Elsevier]

Highlights: [•] Serotonin elevated IL-6 mRNA expression in osteocytic MLO-Y4 cells. [•] Serotonin significantly increased IL-6 secretion in osteocytic MLO-Y4 cells. [•] 5-HT2B receptor mediates serotonin induced IL-6 secretion in MLO-Y4 cells. [•] Serotonin induced IL-6 secretion is depend on activation of ERK1/2 pathway. [ABSTRACT FROM AUTHOR]

Abstract: The respiratory system is immature at birth and significant development occurs postnatally. A critical period of respiratory development occurs in rats around postnatal days 12–13, when enhanced inhibition dominates over suppressed excitation. The mechanisms underlying the heightened inhibition are not fully understood. The present study tested our hypothesis that the inhibition is marked by a switch in glycine receptor subunits from neonatal to adult form around the critical period. An in-depth immunohistochemical and single neuron optical densitometric study was undertaken on four respiratory-related nuclear groups (the pre-Bötzinger complex, nucleus ambiguus, hypoglossal nucleus, and ventrolateral subnucleus of solitary tract nucleus), and a non-respiratory cuneate nucleus in P2–21 rats. Our data revealed that in the respiratory-related nuclear groups: (1) the expressions of GlyRα2 and GlyRα3 were relatively high at P2, but declined after 1–1½ weeks to their lowest levels at P21; (2) the expression of GlyRα1 increased with age and reached significance at P12; and (3) the expression of GlyRβ rose from P2 to P12 followed by a slight decline until P21. No distinct increase in GlyRα1 at P12 was noted in the cuneate nucleus. Thus, there is a switch in dominance of expression from neonatal GlyRα2/α3 to the adult GlyRα1 and a heightened expression of GlyRα1 around the critical period in all respiratory-related nuclear groups, thereby supporting enhanced inhibition at that time. The rise in the expression of GlyRβ around P12 indicates that it plays an important role in forming the mature heteropentameric glycine receptors in these brain stem nuclear groups. [Copyright &y& Elsevier]

Abstract: This study aimed to investigate the effect of magnolol (5,5′-diallyl-2,2′-biphenyldiol) on contraction in distal colonic segments of rats and the underlying mechanisms. Colonic segments were mounted in organ baths for isometric force measurement. Whole-cell voltage-sensitive L-type Ca2+ currents were recorded on isolated single colonic smooth muscle cells using patch-clamp technique. The spontaneous contractions and acetylcholine (ACh)- and Bay K 8644-induced contractions were inhibited by magnolol (3–100μM). In the presence of Bay K8644 (100nM), magnolol (10–100μM) inhibited the contraction induced by 10μM ACh. By contrast, tetrodotoxin (100nM) and N ώ -nitro-l-arginine methyl ester (l-NAME 100μM) did not change the inhibitory effect of magnolol (10μM). In addition, magnolol (3–100μM) inhibited the L-type Ca2+ currents. The present results suggest that magnolol inhibits colonic smooth muscle contraction through downregulating L-type Ca2+ channel activity. [Copyright &y& Elsevier]

Highlights: [•] Tipepidine inhibited DA D2 receptor-mediated GIRK channel currents in VTA neurons. [•] Tipepidine activated single VTA neurons inhibited by dopamine. [•] Tipepidine increased double immunopositive cells for TH and c-Fos in VTA. [•] The results show a part of mechanisms for novel antidepressant effect of tipepidine. [Copyright &y& Elsevier]

Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the methyl-CpG binding protein 2 (MeCP2) gene. In previous studies, monoaminergic dysfunctions have been detected in patients with RTT and in a murine model of RTT, the Mecp2-null mouse. Therefore, the pathogenesis of RTT is thought to involve impairments in the monoaminergic systems. However, there have been limited data showing that the impairment of monoamines leads to early symptoms during development. We used histochemistry to study the somatosensory barrel cortex in the B6.129P2(C)-Mecp2 tm1.1Bird mouse model of RTT. The barrel cortex is widely used to investigate neuronal development and its regulation by various neurotransmitters including 5-HT. 5-HT levels were measured by high performance liquid chromatography with electrochemical detection (HPLC/EC), and serotonin transporter (SERT) and 5-HT1B receptor mRNAs were measured in the somatosensory cortex, thalamus and striatum on postnatal days (P) 10, P20 and P40. Mecp2-null mice (Mecp2−/y) had significantly smaller barrel fields than age-matched wild-type controls (Mecp2+/y) on P10 and P40, but the topographic map was accurately formed. Levels of 5-HT, and SERT and 5-HT1B receptor mRNA expression in the somatosensory cortex did not differ significantly between the Mecp2-null and wild-type mice on P10. However, thalamic 5-HT was reduced in Mecp2-null mice. Our data indicate that a lack of MeCP2 may disturb the refinement of the barrel cortex in the early postnatal period. Our findings suggest that a decrease in thalamic 5-HT might be involved in this phenomenon. [Copyright &y& Elsevier]

Abstract: Introduction: In vivo positron emission tomography (PET) imaging of the serotonin transporter (SERT) is a valuable tool in drug development and in monitoring brain diseases with altered serotonergic function. We have developed a two-step labeling reaction for the preparation of the high serotonin affinity ligand [18F]FPBM ([18F]2-(2′-((dimethylamino)methyl)-4′-(3-fluoropropoxy)phenylthio)benzenamine, 1). Method: To improve and automate the radiolabeling of [18F]FPBM, 1, an intermediate, [18F]3-fluoropropyltosylate, [18F]4, was prepared first, and then it was reacted with the phenol precursor (4-(2-aminophenylthio)-3-((dimethylamino)methyl)phenol, 3) to afford [18F]FPBM, 1. To optimize the labeling, this O-alkylation reaction was evaluated under different temperatures, using different bases and varying amounts of precursor 3. The desired product was obtained after a solid phase extraction (SPE) purification. Results: This two-step radiolabeling reaction successfully produced the desired [18F]FPBM, 1, with an excellent radiochemical purity (>95%, n=8). Radiochemical yields were between 31% and 39% (decay corrected, total time of labeling: 70min, n=8). The SPE purification cannot completely remove pseudo-carriers in the final dose of [18F]FPBM, 1. The concentrations of major pseudo-carriers were measured by UV-HPLC (476–676, 68–95 and 50–71μg for precursor 3, O-hydroxypropyl and O-allyloxy derivatives, 5 and 6, respectively). To investigate the potential inhibition of SERT binding of these pseudo-carriers, we performed in vitro competition experiments evaluated by autoradiography. Known amounts of ‘standard’ FPBM, 1, of the pseudo-carriers, 5 and 6, were added to the HPLC-purified [18F]1 dose. The inhibition of ‘standard’ FPBM, 1, binding to the SERT binding sites, using monkey brain sections, were measured (EC50 =13, 46, 7.1 and 8.3 nM, respectively for 1, precursor 3, O-hydroxypropyl and O-allyloxy derivative of 3). Conclusion: An improved radiolabeling method by a SPE purification for preparation of [18F]FPBM, 1, was developed. The results suggest that it is feasible to use this labeling method to prepare [18F]FPBM, 1, without affecting in vivo SERT binding. [Copyright &y& Elsevier]

Highlights: [•] Progesterone withdrawal induces depression-like behavior in rat forced swim test. [•] Different classes of antidepressants differently affect depression-like behavior. [•] Depression-like behavior was sensitive to acute 5-HT1A, 5-HT3 and 5-HT7 modulation. [•] Receptor modulation effects were not additive to that of SERT inhibition. [ABSTRACT FROM AUTHOR]

Highlights: [•] Aggression testing occurred in mice with mutations in the TLX gene. [•] TLX homozygotes were uniformly aggressive, while heterozygotes showed a mixed aggressive phenotype. [•] Clozapine and ketanserine reduced aggression in all TLX mice. [•] (+) DOI increased aggression in all TLX mice. [ABSTRACT FROM AUTHOR]

Highlights: [•] There is no consistent procedure to model the serotonin syndrome (SS) in rodents. [•] Provide a comprehensive review of rodent models of the SS. [•] Analyzed behavioral and autonomic responses induced by serotonergic drugs. [•] Standardized test methods will improve future studies using animal models of the SS. [ABSTRACT FROM AUTHOR]

Abstract: Adult-born neurons in crayfish (Procambarus clarkii) are the progeny of 1st-generation precursor cells (functionally analogous to neuronal stem cells in vertebrates) that are located in a neurogenic niche on the ventral surface of the brain. The daughters of these precursor cells migrate along the processes of bipolar niche cells to proliferation zones in the cell clusters where the somata of the olfactory interneurons reside. Here they divide again, producing offspring that differentiate into olfactory local and projection neurons. The features of this neuronal assembly line, and the fact that it continues to function when the brain is isolated and perfused or maintained in organotypic culture, provide opportunities unavailable in other organisms to explore the sequence of cellular and molecular events leading to the production of new neurons in adult brains. Further, we have determined that the 1st-generation precursor cells are not a self-renewing population, and that the niche is, nevertheless, not depleted as the animals grow and age. We conclude, therefore, that the niche is not a closed system and that there must be an extrinsic source of neuronal stem cells. Based on in vitro studies demonstrating that cells extracted from the hemolymph are attracted to the niche, as well as the intimate relationship between the niche and vasculature, we hypothesize that the hematopoietic system is a likely source of these cells. [Copyright &y& Elsevier]

The anatomical factors involved in upper airway closure of obstructive sleep apnea (OSA) have been established. However, the mechanisms of repetitive OSA are not well understood. We found that dorsomedial medullary 5-HT2 receptor activity is compensated for by hypercapnia and elicits the immediate onset of poikilocapnic hypoxic ventilatory airway responses. Therefore, the aim of this study was to test the hypothesis that hypercapnia compensates for the immediate onset of poikilocapnic hypoxic ventilatory airway responses induced by dorsomedial medullary 5-HT2 receptors. Adult male mice (C57BL/6N) were intraperitoneally anesthetized with pentobarbital sodium. Microdialysis probes were inserted into the dorsomedial medulla oblongata of the mice. The mice were placed in a double-chamber plethysmograph and were allowed to acclimatize and recover from anesthesia. Mice were then exposed to hypercapnic hypoxic gases (7 % O/5 % CO in N) with or without 5-HT2-antagonist (10 M LY-53857) perfusion. Respiratory curves through the head and body chambers were recorded to measure ventilatory airway variables. Extracellular fluid was collected every 5 min for HPLC analysis of 5-HT concentration. Hypercapnic hypoxia elicited neither delayed onset of ventilatory augmentation nor immediate airway narrowing with dorsomedial medullary 5-HT2 antagonism. Hypoxic polypnea was shifted downward. The increases in dorsomedial medullary 5-HT release and ventilatory volume were not affected with or without 5-HT2 activity. In conclusion, the onset of poikilocapnic hypoxic ventilatory airway responses mediated via dorsomedial medullary 5-HT2 activity is compensated for by hypercapnia. Maintenance of PCO level and CO responsiveness, especially with lowered 5-HT2 activity, may be important for preventing repetitive OSA. [ABSTRACT FROM AUTHOR]

Introduction: Biological evaluation of [125I]FlipIDAM (2-((2-((dimethylamino)methyl)-4-iodophenyl)thio)phenyl)methanol ([125I] 4 ), a new single-photon emission computed tomography (SPECT) radioligand for imaging the serotonin transporter (SERT) which displayed improved in vivo kinetics for mapping SERT binding sites in the brain. Methods: In vitro binding studies of [125I] 4 were performed with membrane homogenates of LLC-PK1 cells stably transfected and overexpressing one of the monoamine transporter (SERT, DAT or NET) and rat cortical homogenates. Biodistribution and ex vivo autoradiography studies were carried out in rats. In vivo competition experiments were evaluated to determine the SERT selectivity of [125I] 4 vs. [125I]IDAM ([125I] 1 ). Results: In vitro binding studies of 4 showed excellent binding affinity (Ki,SERT =0.90±0.05nM) and excellent selectivity over the other monoamine transporters (100 fold and >4000 fold for NET and DAT respectively). Scatchard analysis of saturation binding of [125I] 4 to rat cortical homogenates gave a Kd value of 0.5±0.09nM and a Bmax value of 801.4±58.08fmol/mg protein. The biodistribution study showed rapid high brain uptake (3.09±0.11% dose/organ at 2min) and a good target to non-target ratio (hypothalamus to cerebellum) at 30min (2.62) compared to [125I] 1 (2.19). Ex vivo autoradiography showed that FlipIDAM localizes in accordance with SERT distribution patterns in the brain. In vivo and ex vivo competition experiments with specific and non-specific SERT compounds also showed that [125I] 4 binds specifically to SERT rich regions. Conclusions: The biological evaluation of [125I] 4 demonstrates that [123I] 4 would be a good candidate for SPECT imaging of SERT. [ABSTRACT FROM AUTHOR]

Highlights: [•] Endomorphin-2 administration into the arcuate nucleus increased food intake. [•] Endomorphin-2 decreased hypothalamic CRH gene expression. [•] Endomorphin-2 increased hypothalamic dopamine and norepinephrine levels. [•] All effects are blocked by μ-opioid antagonist β-funaltrexamine. [ABSTRACT FROM AUTHOR]

Injections of noradrenaline into the lateral parabrachial nucleus (LPBN) increase arterial pressure and 1.8% NaCl intake and decrease water intake in rats treated with the diuretic furosemide (FURO) combined with a low dose of the angiotensin converting enzyme inhibitor captopril (CAP). In the present study, we investigated the influence of the pressor response elicited by noradrenaline injected into the LPBN on FURO+CAP-induced water and 1.8% NaCl intake. Male Holtzman rats with bilateral stainless steel guide-cannulas implanted into LPBN were used. Bilateral injections of noradrenaline (40nmol/0.2μl) into the LPBN increased FURO+CAP-induced 1.8% NaCl intake (12.2±3.5, vs., saline: 4.2±0.8ml/180min), reduced water intake and strongly increased arterial pressure (50±7, vs. saline: 1±1mmHg). The blockade of the α1 adrenoceptors with the prazosin injected intraperitoneally abolished the pressor response and increased 1.8% NaCl and water intake in rats treated with FURO+CAP combined with noradrenaline injected into the LPBN. The deactivation of baro and perhaps volume receptors due to the cardiovascular effects of prazosin is a mechanism that may facilitate water and NaCl intake in rats treated with FURO+CAP combined with noradrenaline injected into the LPBN. Therefore, the activation of α2 adrenoceptors with noradrenaline injected into the LPBN, at least in dose tested, may not completely remove the inhibitory signals produced by the activation of the cardiovascular receptors, particularly the signals that result from the extra activation of these receptors with the increase of arterial pressure. [ABSTRACT FROM AUTHOR]

Abstract: Altered reactivity to stress, either in the direction of exaggerated reactivity or diminished reactivity, may signal a dysregulation of systems intended to maintain homeostasis and a state of good health. Evidence has accumulated that diminished reactivity to psychosocial stress may signal poor health outcomes. One source of diminished cortisol and autonomic reactivity is the experience of adverse rearing during childhood and adolescence. The Oklahoma Family Health Patterns Project has examined a cohort of 426 healthy young adults with and without a family history of alcoholism. Regardless of family history, persons who had experienced high degrees of adversity prior to age 16 had a constellation of changes including reduced cortisol and heart rate reactivity, diminished cognitive capacity, and unstable regulation of affect, leading to behavioral impulsivity and antisocial tendencies. We present a model whereby this constellation of physiological, cognitive, and affective tendencies is consistent with altered central dopaminergic activity leading to changes in brain function that may foster impulsive and risky behaviors. These in turn may promote greater use of alcohol other drugs along with adopting poor health behaviors. This model provides a pathway from early life adversity to low stress reactivity that forms a basis for risky behaviors and poor health outcomes. [Copyright &y& Elsevier]

Abstract: Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) were identified in the mid 90s as a novel peptidergic system structurally related to opioids. A growing body of preclinical evidence suggests that blockade of NOP receptors evokes antidepressant-like actions. These have been explored using a range of compounds (peptide and non peptide antagonists), across different species (rat and mouse) and assays (behavioral despair and chronic mild stress) suggesting a robust and consistent antidepressant-like effect. Moreover, rats and mice knockout for the NOP receptor gene display an antidepressant-like phenotype in behavioral despair assays. Electrophysiological, immunohistochemical and neurochemical studies point to an important role played by monoaminergic systems, particularly 5-HTergic, in mediating the antidepressant-like properties of NOP antagonists. However other putative mechanisms of action, including modulation of the CRF system, circadian rhythm and a possible neuroendocrine-immune control might be involved. A close relationship between the N/OFQ-NOP receptor system and stress responses is well described in the literature. Stressful situations also alter endocrine, behavioral and neurochemical parameters in rats and chronic administration of a NOP antagonist restored these alterations. Interestingly, clinical findings showed that plasma N/OFQ levels were significantly altered in major and post-partum depression, and bipolar disease patients. Collectively, data in the literature support the notion that blockade of NOP receptor signaling could be a novel and interesting strategy for the development of innovative antidepressants. [Copyright &y& Elsevier]

Highlights: [•] Injection of the 5-HT1A receptor agonist 8-OH-DPAT increases plasma cortisol. [•] Serotonin directly stimulates cortisol secretion from the head kidney in vitro. [•] Multiple 5-HT receptor subtypes mediate 5-HT-stimulated cortisol secretion. [•] The chromaffin cells of the head kidney contain 5-HT. [•] Chromaffin cells may be involved in paracrine regulation of cortisol secretion via 5-HT. [ABSTRACT FROM AUTHOR]

Highlights: [•] Review behavioral sensitization in response to noxious stimulation or injury. [•] Review functional, synaptic, and cellular mechanisms of sensitization. [•] Review epigenetic mechanisms in learning- and pain-related sensitization. [ABSTRACT FROM AUTHOR]