Hippocampal Receptors Research Articles

REMOVED: Postnatal exposure of decabromodiphenyl ether (PBDE-209) impairs working and reference memory in young mice: Expression and regulation of NMDA receptor in hippocampus and frontal cortex

This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our‐business/policies/article‐withdrawal)This meeting abstract has been removed by the Publisher. Due to an administrative error, abstracts that were not presented at the ISDN 2014 meeting were inadvertently published in the meeting's abstract supplement. The Publisher apologizes to the authors and readers for this error.

Regulation of hippocampal Fas receptor and death-inducing signaling complex after kainic acid treatment in mice.

Kainic acid (KA)-induced brain neuronal cell death (especially in the hippocampus) was shown to be mainly mediated by the intrinsic (mitochondrial) apoptotic pathway. This study investigated the regulation of the extrinsic apoptotic pathway mediated by Fas ligand/Fas receptor and components of the indispensable death-inducing signaling complex (DISC) in the hippocampus (marked changes) and cerebral cortex (modest changes) of KA-treated mice. KA (45mg/kg) induced a severe behavioral syndrome with recurrent motor seizures (scores; maximal at 60-90min; minimal at 72h) with activation of hippocampal pro-apoptotic JNK (+2.5 fold) and increased GFAP (+57%) and nuclear PARP-1 fragmentation (+114%) 72h post-treatment (delayed neurotoxicity). In the extrinsic apoptotic pathway (hippocampus), KA (72h) reduced Fas ligand (-92%) and Fas receptor aggregates (-24%). KA (72h) also altered the contents of major DISC components: decreased FADD adaptor (-44%), reduced activation of initiator caspase-8 (-47%) and increased survival FLIP-S (+220%). Notably, KA (72h) upregulated the content of anti-apoptotic p-Ser191 FADD (+41%) and consequently the expression of p-FADD/FADD ratio (+1.9-fold), a neuroplastic index. Moreover, the p-FADD dependent transcription factor NF-κB was also increased (+61%) in the hippocampus after KA (72h). The convergent adaptation of the extrinsic apoptotic machinery 72h after KA in mice (with otherwise normal gross behavior) is a novel finding which suggests the induction of survival mechanisms to partly counteract the delayed neuronal death in the hippocampus.

The neuroenergetics of stress hormones in the hippocampus and implications for memory.

Acute stress causes rapid release of norepinephrine (NE) and glucocorticoids (GCs), both of which bind to hippocampal receptors. This release continues, at varying concentrations, for several hours following the stressful event, and has powerful effects on hippocampally-dependent memory that generally promote acquisition and consolidation while impairing retrieval. Several studies have characterized the brain's energy usage both at baseline and during memory processing, but there are few data on energy requirements of memory processes under stressful conditions. Because memory is enhanced by emotional arousal such as during stress, it is likely that molecular memory processes under these conditions differ from those under non-stressful conditions that do not activate the hypothalamic-pituitary-adrenal (HPA) axis. Mobilization of peripheral and central energy stores during stress may increase hippocampal glucose metabolism that enhances salience and detail to facilitate memory enhancement. Several pathways activated by the HPA axis affect neural energy supply and metabolism, and may also prevent detrimental damage associated with chronic stress. We hypothesize that alterations in hippocampal metabolism during stress are key to understanding the effects of stress hormones on hippocampally-dependent memory formation. Second, we suggest that the effects of stress on hippocampal metabolism are bi-directional: within minutes, NE promotes glucose metabolism, while hours into the stress response GCs act to suppress metabolism. These bi-directional effects of NE and GCs on glucose metabolism may occur at least in part through direct modulation of glucose transporter-4. In contrast, chronic stress and prolonged elevation of hippocampal GCs cause chronically suppressed glucose metabolism, excitotoxicity and subsequent memory deficits.

Effects of Kaixin Powder on Expression of 5-HT Receptor in Hippocampus of Depressed Rats Induced by CUMS

ObjectiveTo observe the influence of Kaixin Powder on ethology, content of 5-HT in the hippocampus, expression of mRNA, and protein in 5-HT1A and 5-HT2A receptors in the hippocampus of depressed rats induced by chronic unpredictable mild stress (CUMS). MethodsTwenty-four male Wistar rats were randomly divided into blank, model, Trazodone, and Kaixin Powder groups, six rats in each group. In addition to the blank control group, other groups were established the depression model induced by CUMS combined with isolated feeding. At the same time, Trazodone group and Kaixin Powder group were treated with corresponding drugs for 3 weeks. After 3 weeks of administration, the rats were sacrificed, and a series of indexes were measured such as the contents of 5-HT, mRNA expression levels of 5-HT1A and 5-HT2A receptors, protein expression levels of 5-HT1A and 5-HT2A receptors, and so on. ResultsA series of indexes in the model group were decreased significantly such as the body weight growth, the sugar water intake, the score of Open Field Test, the content of 5-HT in the hippocampus, expression of mRNA, and protein in 5-HT1A receptor, while the expression of mRNA and protein in 5-HT2A receptor were increased significantly. Compared with the model group, the indexes were ameliorated in Trazodone and Kaixin Powder groups. Kaixin Powder is better than Trazodone in decreasing the level of protein in 5-HT2A receptor. ConclusionThe result indicated that the depression performance of depressed rats induced by CUMS can be ameliorated by Kaixin Powder, and the mechanism maybe concerned with increasing the contents of 5-HT, exciting 5-HT1A receptor, and antagonising 5-HT2A receptor.

Facilitation of fear extinction by novelty depends on dopamine acting on D1-subtype dopamine receptors in hippocampus

Extinction is the learned inhibition of retrieval. Recently it was shown that a brief exposure to a novel environment enhances the extinction of contextual fear in rats, an effect explainable by a synaptic tagging-and-capture process. Here we examine whether this also happens with the extinction of another fear-motivated task, inhibitory avoidance (IA), and whether it depends on dopamine acting on D1 or D5 receptors. Rats were trained first in IA and then in extinction of this task. The retention of extinction was measured 24 h later. A 5-min exposure to a novel environment 30 min before extinction training enhanced its retention. Right after exposure to the novelty, animals were given bilateral intrahippocampal infusions of vehicle (VEH), of the protein synthesis inhibitor anisomycin, of the D1/D5 dopaminergic antagonist SCH23390, of the PKA inhibitor Rp-cAMP or of the PKC inhibitor Gö6976, and of the PKA stimulator Sp-cAMP or of the PKC stimulator PMA. The novelty increased hippocampal dopamine levels and facilitated the extinction, which was inhibited by intrahippocampal protein synthesis inhibitor anisomysin, D1/D5 dopaminerdic antagonist SCH23390, or PKA inhibitor Rp-cAMP and unaffected by PKC inhibitor Gö6976; additionally, the hippocampal infusion of PKA stimulator Sp-cAMP reverts the effect of D1/D5 dopaminergic antagonist SCH 23390, but the infusion of PKC stimulator PMA does not. The results attest to the generality of the novelty effect on fear extinction, suggest that it relies on synaptic tagging and capture, and show that it depends on hippocampal dopamine D1 but not D5 receptors.

Dynamic increases in AMPA receptor phosphorylation in the rat hippocampus in response to amphetamine

Increasing evidence supports the critical role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors in psychostimulant action. These receptors are regulated via a phosphorylation-dependent mechanism in their trafficking, distribution, and function. The hippocampus is a brain structure important for learning and memory and is emerging as a critical site for processing psychostimulant effects. To determine whether the hippocampal pool of AMPA receptors is regulated by stimulants, we investigated and characterized the impact of amphetamine (AMPH) on phosphorylation of AMPA receptors in the adult rat hippocampus in vivo. We found that AMPH markedly increased phosphorylation of AMPA receptor GluA1 subunits at serine 845 (S845) in the hippocampus. The effect of AMPH was dose dependent. A single dose of AMPH induced a rapid and transient increase in S845 phosphorylation. Among different hippocampal subfields, AMPH primarily elevated S845 phosphorylation in the Cornu Ammonis area 1 and dentate gyrus. In contrast to S845, serine 831 phosphorylation of GluA1 and serine 880 phosphorylation of GluA2 were not altered by AMPH. In addition, surface expression of hippocampal GluA1 was up-regulated, while the amount of intracellular GluA1 fraction was concurrently reduced in response to AMPH. GluA2 protein levels in either the surface or intracellular pool were insensitive to AMPH. These data demonstrate that the AMPA receptor in the hippocampus is sensitive to dopamine stimulation. Acute AMPH administration induces dose-, time-, site-, and subunit-dependent phosphorylation of AMPA receptors and facilitates surface trafficking of GluA1 AMPA receptors in hippocampal neurons in vivo. Acute injection of amphetamine increased phosphorylation of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluA1 subunits at a protein kinase A (PKA)-sensitive site (S845) in the rat hippocampus. This increase was dose- and time-dependent and correlated with an increase in surface GluA1 expression. Thus, amphetamine can upregulate GluA1 phosphorylation and surface trafficking of GluA1 in hippocampal neurons in vivo.

Pregnenolone sulfate normalizes schizophrenia-like behaviors in dopamine transporter knockout mice through the AKT/GSK3β pathway.

Pregnenolone sulfate, an endogenous neurosteroid in the central nervous system, is a positive allosteric modulator of the NMDA receptor, and plays a role in the modulation of learning and memory. Here, we study the actions of pregnenolone sulfate using the dopamine transporter knockout (DAT-KO) mice, which exhibit endophenotypes that recapitulate certain symptoms of schizophrenia, including the psychomotor agitation, stereotypy, prepulse inhibition (PPI) deficits and cognitive impairments. We found that acute treatment with pregnenolone sulfate normalized the hyperlocomotion and stereotypic bouts, and rescued the PPI deficits of DAT-KO mice. In addition, long-term treatment with pregnenolone sulfate rescued the cognitive deficits of DAT-KO mice in the novel object recognition and social transmission of food preference tests. We also showed that pregnenolone sulfate normalized behavioral abnormalities in MK801-treated wild-type mice, whereas pregnenolone, its precursor, only partially rescued MK801-induced behavioral abnormalities. This indicates that there are distinct mechanisms of action between pregnenolone sulfate and pregnenolone, and the involvement of NMDA receptor signaling in the action of pregnenolone sulfate. Moreover, we found that acute treatment with pregnenolone sulfate increased the phosphorylation levels of striatal AKT and GSK3β in DAT-KO mice, and that long-term treatment with pregnenolone sulfate increased expression levels of NR1 subunit of the NMDA receptor in hippocampus. Thus, pregnenolone sulfate was able to rescue the behavioral anomalies of DAT-KO mice through the NMDA receptor-mediated, AKT/GSK3β signaling pathway.

Effects of low-dose ketamine combined with propofol on phosphorylation of AMPA receptor GluR1 subunit and GABAA receptor in hippocampus of stressed rats receiving electroconvulsive shock.

To investigate the effects of low-dose ketamine combined with propofol on the antidepressant efficacy in stressed rats undergoing electroconvulsive shock (ECS) and its impact on phosphorylation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor subunit glutamate receptor 1 (GluR1) and γ-aminobutyric acid receptor subunit A (GABAAR). Sprague-Dawley rats were stressed by chronic unpredictable mild stress. Fifty stressed rats were randomly divided into 5 groups (n = 10 per group): depression group (with no application, group D), ECS group (applied with ECS after intraperitoneal injection of isotonic sodium chloride solution, 8 mL/kg, group E), ketamine + ECS group (applied with ECS after intraperitoneal injection of ketamine, 10 mg/kg, group KE), propofol + ECS group (applied with ECS after intraperitoneal injection of propofol, 80 mg/kg, group PE), and ketamine + propofol + ECS group (applied with ECS after intraperitoneal injection of ketamine, 10 mg/kg, and propofol, 80 mg/kg, group KPE). All groups except group D underwent ECS once a day for 7 consecutive days. Sucrose preference test, open-field test, and Morris water maze were performed to assess the depressive behavior. Phosphorylation of GluR1 and GABAAR were evaluated by Western blot. Compared with group D, sucrose preference percentage and open-field scores were increased after ECS application in the 4 other groups; rats in group E reported prolonged escape latency and shortened space exploration time, whereas the escape latency were decreased and space exploration time were prolonged in group KPE; the ratio of p-GluR1/p-GABAAR in hippocampus were increased in the 4 other groups. When using group E as control, rats in group KPE exhibited higher sucrose preference percentage and open-field scores; the escape latency was shortened and space exploration time was prolonged in groups KE, PE, and KPE; the ratio of p-GluR1/p-GABAAR in the hippocampus was up-regulated in groups KE and KPE. When compared with groups KE and PE, the rats in group KPE exhibited higher sucrose preference percentage and open-field scores, the escape latency of group KPE was shortened and space exploration time was prolonged, the ratio of p-GluR1/p-GABAAR in the hippocampus of group KEP is between those of groups KE and PE. Low-dose ketamine combined with propofol may play a role in enhancing the antidepressant efficacy of ECS in stressed rats, ameliorating the cognitive impairment associated with ECS by balancing the expression of p-GluR1 and p-GABAAR in the hippocampus of stressed rats.

Interstrain differences of ionotropic glutamate receptor subunits in the hippocampus and induction of hippocampal sclerosis with pilocarpine in mice

Rodent strains used in epilepsy research have various neurological characteristics. These differences were suggested to be attributed to the diverse densities of the ionotropic glutamate receptor (iGluR) subunits. However, previous studies failed to find interstrain differences in the hippocampal receptor levels.We supposed that a detailed layer-to-layer analysis of the iGluR subunits in the hippocampus might reveal strain-dependent differences in their base lines and reactions induced by pilocarpine (PILO) between two mouse strains without documented ancestors.Levels of iGluR subunits in Balb/c and NMRI mice were compared using semiquantitative immunohistochemistry. The alterations in the neuronal circuitry were validated by neuropeptide Y (NPY) and neuronal nuclear antigen (NeuN) immunostainings.Immunohistochemistry showed interstrain laminar differences in some subunits of both the control and PILO-treated animals. The seizure-induced irreversible neuronal changes were accompanied by reduced GluA1 and GluA2 levels. Their changes were inversely correlated in the individual NMRI mice by Pearson's method. Increase in NPY immunoreactivity showed positive correlation with GluA1, and negative correlation with GluA2. The NMRI strain was susceptible to PILO-induced hippocampal sclerosis, while the Balb/c animals showed resistance.Basal levels of iGluRs differ in mouse strains, which may account for the interstrain differences in their reactions to the convulsant.

Effects of acute and sustained administration of vortioxetine on the serotonin system in the hippocampus: electrophysiological studies in the rat brain.

RationaleVortioxetine is a novel multimodal antidepressant that is a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, an inhibitor of the serotonin (5-HT) transporter, and a 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist in vitro. In vivo studies have shown that vortioxetine enhances levels of 5-HT and desensitizes 5-HT1A autoreceptors.ObjectivesThe aim of the present study was to investigate the effects of acute and long-term administration of vortioxetine on the terminal 5-HT1B receptor and the tonic activation of 5-HT1A receptor in the rat hippocampus.MethodsThese receptors were assessed following vortioxetine administration acutely or subcutaneously using minipumps for 14 days. These studies were carried out using in vivo electrophysiological recording, microiontophoresis, and stimulation of the ascending 5-HT fibers.ResultsVortioxetine enhanced the inhibitory effect of the stimulation of the 5-HT bundle at a high, but not low frequency and reversed the inhibitory effect of the 5-HT1B receptor agonist CP 94253. These results indicate that this compound acted as a 5-HT1B receptor partial agonist. Vortioxetine inhibited 5-HT reuptake but did not dampen the sensitivity of postsynaptic 5-HT1A receptors on pyramidal neurons. Long-term administration of vortioxetine and escitalopram (both at 5 mg/kg/day) induced an increase of tonic activation of the 5-HT1A receptors in CA3 pyramidal neurons, resulting in an increase in 5-HT transmission. In addition, vortioxetine decreased the function of terminal 5-HT1B autoreceptor following its sustained administration.ConclusionsDesensitization of 5-HT1B autoreceptor and an increase of tonic activation of 5-HT1A receptors in the hippocampus may contribute to the antidepressant effect of vortioxetine.

Abstract W P242: Role of Hippocampal Estrogen Receptor α and Src in Sexually Differential Phosphorylation of Tyrosine kinase-B receptors

Introduction: Male neonate brains are more susceptible to the effects of hypoxic ischemic encephalopathy (HI) as compared to females with comparable brain injury. Our recent findings reveal that HI induces an increase in phosphorylation of tyrosine kinase-B receptors (TrkB) in female hippocampi and TrkB agonist, 7,8-dihydroxyflavone (7,8-DHF), exerts profound early and late neuroprotective effects in female but not in male neonates. We hypothesized that differential TrkB phosphorylation seen in females is associated with increased hippocampal estrogen receptor α (ERα) expression and src (Src family kinase) phosphorylation resulting in decreased apoptosis post-HI. Methods: WT (ERα+/+) and KO (ERα-/-) P9 male and female mice pups were subjected to Vannucci’s neonatal HI model by left common carotid artery cauterization and exposure of the pups to 10% O2 at 37°C for 50 min. Pups were either sham or HI operated and given PBS or 7,8-DHF (5 mg/kg in PBS, ip.) starting at 10 min, then at 24 h, and 48 h post HI. Hippocampi were dissected out for either immunoblotting or qRTPCR 3d post-HI. We assessed the effects of sex (M vs F), treatment (PBS vs 7,8-DHF) and HI (sham vs HI) on immunoblotting band densities [pTrkB)/full length TrkB, ERα/actin, p-src/total src, cleaved caspase 3 (cc3)/actin ratios] and qRTPCR results using ANOVA analysis. Results: HI and 7,8-DHF differentially increase p-TrkB and p-src in WT female hippocampi 3 d post-HI (p < 0.0001). HI induces a 2.3 fold increase in ERα mRNA and protein expression in female hippocampi compared to the males 3d post-HI (p=0.002). HI and 7,8-DHF fail to increase p-TrkB and p-src in KO male and female mice suggesting that the TrkB and src phosphorylation are dependent on the ERα signaling in the neonatal hippocampi post-HI. Cc3 levels are found to be increased in KO mice while the 7,8-DHF treated WT female hippocampi had decreased cc3 expression. Conclusion: Sexually differential phosphorylation of TrkB and src are abolished in KO mice suggesting an important role of ERα in TrkB phosphorylation and src activation resulting in decreased apoptosis in female hippocampi post-HI. This mechanism might be one of the mechanisms that makes the male neonate brains more susceptible to the effects of HI.

Hippocampal receptor complexes paralleling LTP reinforcement in the spatial memory holeboard test in the rat

The current study was designed to examine learning-induced transformation of early-LTP into late-LTP. Recording electrodes were implanted into the dentate gyrus of the hippocampus in male rats and early-LTP was induced by weak tetanic stimulation of the medial perforant path. Dorsal right hippocampi were removed, membrane proteins were extracted, separated by blue-native gel electrophoresis with subsequent immunoblotting using brain receptor antibodies. Spatial training resulted into reinforcement of LTP and the reinforced LTP was persistent for 6h. Receptor complex levels containing GluN1 and GluN2A of NMDARs, GluA1 and GluA2 of AMPARs, nAchα7R and the D(1A) dopamine receptor were significantly-elevated in rat hippocampi of animals underwent spatial learning, whilst levels of GluA3 and 5-HT1A receptor containing complexes were significantly reduced. Evidence for complex formation between GluN1 and D(1A) dopamine receptor was provided by antibody shift assay, co-immunoprecipitation and mass spectrometric analysis.Thus our results propose that behavioural stimuli like spatial learning reinforce early LTP into late LTP and this reinforced LTP is accompanied by changes in certain receptor levels in the membrane fraction of the rat hippocampus.

Histopathological, ultrastructural, and immunohistochemical assessment of hippocampus structures of rats exposed to TCDD and high doses of tocopherol and acetylsalicylic acid.

The effect of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on central nervous system consists of changing expression of estrogen receptors, whereas the result of chronic inflammatory reaction caused by dioxin is occurrence of destructive changes in various organs connected with disturbed metabolism of connective tissue and damage of cells. The aim of the study was to determine the effect of dioxins on function, ultrastructure, and cytological and histological structure of hippocampus, particularly on expression of estrogen receptors in central nervous system as well as to define protective influence of tocopherol (TCP) and acetylsalicylic acid (ASA) on the decrease in activity of proinflammatory effects in central nervous system. It was shown that TCDD contributes to destructive and inflammatory changes along with demyelization of myelin sheaths and atrophy of estrogen receptors in hippocampus. Dioxin contributes to atrophy of estrogen receptors in hippocampus, in which also destructive and inflammatory changes were found along with demyelination of myelin sheaths. Histopathological and ultrastructural image of hippocampus areas in rats, in which both TCP and ASA were used, is characterized by poorly expressed degenerative changes and smaller inflammatory reactivity. Using both TCP and ASA has a protective effect on functions of central nervous system.

The contribution of GABAb circuits in the pro-epileptogenic action of nicotinic acetylcholine receptors in hippocampus

The contribution of GABAb circuits in the pro-epileptogenic action of nicotinic acetylcholine receptors in hippocampus

Report on the two‐phase public consultation on the draft EFSA scientific opinion on bisphenol A (BPA)

Report on the two‐phase public consultation on the draft EFSA scientific opinion on bisphenol A (BPA)

Effect of Repeated Electroacupuncture Intervention on Hippocampal ERK and p38MAPK Signaling in Neuropathic Pain Rats.

Results of our past studies showed that hippocampal muscarinic acetylcholine receptor (mAChR)-1 mRNA and differentially expressed proteins participating in MAPK signaling were involved in electroacupuncture (EA) induced cumulative analgesia in neuropathic pain rats, but the underlying intracellular mechanism remains unknown. The present study was designed to observe the effect of EA stimulation (EAS) on hippocampal extracellular signal-regulated kinases (ERK) and p38 MAPK signaling in rats with chronic constrictive injury (CCI) of the sciatic nerve, so as to reveal its related intracellular targets in pain relief. After CCI, the thermal pain thresholds of the affected hind were significantly decreased compared with the control group (P < 0.05). Following one and two weeks' EAS of ST 36-GB34, the pain thresholds were significantly upregulated (P < 0.05), and the effect of EA2W was remarkably superior to that of EA2D and EA1W (P < 0.05). Correspondingly, CCI-induced decreased expression levels of Ras, c-Raf, ERK1 and p-ERK1/2 proteins, and p38 MAPK mRNA and p-p38MAPK protein in the hippocampus tissues were reversed by EA2W (P < 0.05). The above mentioned results indicated that EA2W induced cumulative analgesic effect may be closely associated with its function in removing neuropathic pain induced suppression of intracellular ERK and p38MAPK signaling in the hippocampus.

Relationship between the level of hippocampal leptin receptor gene expression and learning performance in diabetic rats.

Diabetes mellitus may be associated with impaired cognitive function. Decreased peripheral glucose regulation was associated with decreased general cognitive performance, memory impairments, and atrophy of the hippocampus, a brain area that is key for learning and memory. Leptin that is a peptide hormone, acts in the hippocampus where it facilitates the induction of long-term potentiation and enhances NMDA receptor mediated transmission. The aim of the present study is to investigate possible relationship between the hippocampal leptin receptor gene expression and learning performance in streptozotocin (STZ) induced diabetic rats. In this study was conducted on a total of 40 Winstar albino female rats, including a control group consisting of 20 rats and experimental group comprising of 20 rats in which diabetes was induced by means of STZ administration. Leptin receptor gene expression was detected in hippocampal samples by using real time-PCR. According to the evaluation, the learning performance of rats with induced diabetes was found to be same throughout the first 3 days after STZ in comparison to the control group rats. End of the 45 days the learning performance of the control group was found to be better than the diabetic group (p<0.05). Hipocampal leptin receptor expression was found lower in diabetic group than the control group (p<0.05). The results provide evidence that leptin receptor gene may related to learning performance in diabetic rats. Further, detailed studies are needed to address the exact role of leptin and related molecules in learning performance.

Restoration of serotonin neuronal firing following long-term administration of bupropion but not paroxetine in olfactory bulbectomized rats.

Background:Olfactory bulbectomized rats generally manifest many of the neurochemical, physiological, and behavioral features of major depressive disorder in humans. Another interesting feature of this model is that it responds to chronic but not acute antidepressant treatments, including selective serotonin reuptake inhibitors. The purpose of the present study was first to characterize the firing activity of dorsal raphe serotonin neurons in olfactory bulbectomized rats and then examine the effects of 2 antidepressants, bupropion and paroxetine.Methods:Olfactory bulbectomy was performed by aspirating olfactory bulbs in anesthetized rats. Vehicle and drugs were delivered for 2 and 14 days via subcutaneously implanted minipumps. In vivo electrophysiological recordings were carried out in male anesthetized Sprague-Dawley rats.Results:Following ablation of olfactory bulbs, the firing rate of serotonin neurons was decreased by 36%, leaving those of norepinephrine and dopamine neurons unchanged. In olfactory bulbectomized rats, bupropion (30mg/kg/d) restored the firing rate of serotonin neurons to the control level following 2- and 14-day administration and also induced an increase in the tonic activation of serotonin1A receptors; paroxetine (10mg/kg/d) did not result in a return to normal of the attenuated firing of serotonin neurons in olfactory bulbectomized rats. In the hippocampus, although at a higher dose of WAY 100635 than that required in bupropion-treated animals, paroxetine administration also resulted in an increase in the tonic activation of serotonin1A receptors.Conclusions:The present results indicate that unlike paroxetine, bupropion administration normalized serotonin neuronal activity and increased tonic activation of the serotonin1A receptors in hippocampus.

Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine.

Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders.

Gambogic amide selectively upregulates TrkA expression and triggers its activation

BackgroundGambogic amide is the first identified small molecular agonist for TrkA receptor. It mimics NGF functions by selectively activating TrkA receptor and preventing neuron death. However, its function different from that of NGF remains unknown. MethodsIn the current study, we detect the effect of gambogic amide on TrkA expression using TrkA-expressing cell lines in vitro and hippocampi from mice treated with gambogic amide. ResultsWe have confirmed that gambogic amide displays robust neurotrophic activities in provoking neurite outgrowth in vitro. However, gambiogic amide displays a different kinetics from NGF in activating TrkA signals. NGF swiftly provokes TrkA activation and quickly induces TrkA degradation, while gambogic amid selectively upregulates TrkA protein and mRNA levels in a time-dependent manner. Administration of this compound in mice also activates TrkA receptor in hippocampus and promotes TrkA transcription and expression. ConclusionThis study provides a novel mechanism of how gambogic amide regulates TrkA receptor, other than mimicking NGF in triggering TrkA activation.