Olfactory Bulbectomized Rats Research Articles

Chronic antidepressant-like effect of EMD386088, a partial 5-HT6 receptor agonist, in olfactory bulbectomy model may be connected with BDNF and/or CREB signalling pathway.

The removal of the olfactory bulbs has been attributed to behavioral changes and neuroplasticity manifesting themselves among others like increases in brain neurotrophin expression and neurogenesis. Earlier data presented that EMD386088, a 5-HT6 receptor partial agonist, exerts antidepressant-like properties after chronic administration in olfactory bulbectomy (OB) model as was it compared with amitriptyline (AMI). The aim of this study was to compare acute and chronic biochemical effects of EMD386088, administered in its antidepressant active (2.5mg/kg) and non-active (1.25mg/kg) doses, found in the open field test in OB rats, with those of AMI (10mg/kg). The levels of 5-HT6 receptor protein and selected neurotrophins in prefrontal cortex (PFC) and hippocampus (Hp) of rats have been examined. 5-HT6 receptor protein and selected neurotrophins: brain-derived neurotrophic factor (BDNF), cAMP-response element binding protein (CREB), the product of the immediate early gene c-fos (cFos) protein levels were assessed using a Western blot analysis in PFC and Hp of bulbectomized rats after acute or chronic (14-day) EMD386088 or AMI intraperitoneal (ip) treatment. The acute treatment with EMD386088 caused significant increases in CREB and BDNF protein levels in PFC, and an increase in BDNF in Hp of OB rats, while AMI injection decreased CREB and did not change BDNF levels. After the chronic administration of EMD386088, the increasing levels of BDNF and CREB were still observed in PFC and Hp. The antidepressant-like effect of EMD386088 may be associated with the neuroplasticity activation in PFC and Hp in rats.

Antidepressant effect of Hedyotis corymbosa extract in olfactory bulbectomy rats

Background: Hedyotis corymbosa Linn. (family: Rubiaceae) has been used in the Indian indigenous system of medicine, Ayurveda, for treatment of various health aliments. Objectives: The present study was undertaken to evaluate the antidepressant activity of methanolic extract of whole plant of H. corymbosa (MHC) in olfactory bulbectomy rats. Materials and Methods: MHC was prepared and standardized to gallic acid by high-performance thin-layer chromatograph method. Effects of 14 days oral treatment of fluoxetine (30 mg/kg) and three doses of MHC (50, 100, and 200 mg/kg) were evaluated on olfactory bulbectomy (OBX)-induced alterations in behavioral and biochemical parameters in rats. Results: MHC treatment reversed the OBX-induced behavioral abnormalities such as increased exploratory activity in open-field paradigm and decreased feeding latency time in novelty-suppressed feeding test. Serum cortisol levels were restored near to normal by the MHC treatment. Further, treatment of MHC prevented the OBX-induced decline of brain levels of serotonin and nor-adrenaline in dose-dependent manner. Conclusion: MHC prevents behavioral and neurochemical changes in OBX-induced depression in rats. These results demonstrate the antidepressant effect of H. corymbosa and support its folklore claim. Abbreviations Used: ANOVA: one-way analysis of variance; CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals; ELIZA: Enzyme-linked immunosorbent assay; HPTLC: High-performance thin-layer chromatography; MHC: Methanolic extract of Hedyotis corymbosa; NA: Noradrenaline; OBX: Olfactory bulbectomy; SEM: Standard error of mean; TLC: Thin layer chromatography; 5-HT: 5-hydroxytryptamine; 5-HIAA: 5-hydroxyindoleacetic acid.

The olfactory bulbectomized rat model is not an appropriate model for studying depression based on morphological/stereological studies of the hippocampus.

Bilateral olfactory bulbectomy (OBX) has been used as an animal model for major depression that results in behavioral, neurochemical, and neuroendocrinological changes were reversed by chronic treatment with antidepressants, including fluoxetine. However, both etiological and construct validities are lacking in OBX for rats. In the present study, we investigated the morphological changes in the hippocampi of rats undergoing OBX that were treated with fluoxetine (10mg/kg, p.o. once daily for 4 and 12 weeks) using stereological techniques. Our results revealed that OBX caused a reduction in the volumes of the CA1/2, CA3, and dentate gyrus regions 4 weeks after OBX without fluoxetine treatment. With fluoxetine treatment, these reductions were achieved 12 weeks after OBX and the volumes were comparable to normal control rats. Nevertheless, fluoxetine treatment did not reverse neuron loss in all hippocampal regions 12 weeks after OBX. Therefore, we suggest that the OBX rat model should not be used to detect the antidepressant activity of various pharmacological agents such as fluoxetine.

Treadmill exercise improves depression-like symptoms by enhancing serotonergic function through upregulation of 5-HT1A expression in the olfactory bulbectomized rats.

The olfactory bulbectomy (OBX) is a well-known method inducing animal model of depression. Depression is associated with dysfunction of serotonin (5-hydroxytryptamine, 5-HT) system. In the present study, antidepressive effect of treadmill exercise was investigated using olfactory bulbectomized rats. After bilateral bulbectomy, the rats in the treadmill exercise groups were subjected to run on a treadmill for 30 min once a day during 28 days. Increased immobility time and decreased fast time in the forced swim test were observed in the olfactory bulbectomized rats. Sucrose preference in the sucrose preference test was decreased and activity in the open field test was also increased in the olfactory bulbectomized rats. Treadmill exercise decreased immobility time and activity and increased fast time and sucrose preference in the olfactory bulbectomized rats. Expressions of 5-HT and tryptophan hydroxylase (TPH) in the dorsal raphe of rats were suppressed by OBX and treadmill exercise increased the expressions of 5-HT and TPH in the olfactory bulbectomized rats. Serotonin receptor type 1A (5-HT1A) expression in the dorsal raphe was reduced by OBX and treadmill exercise increased 5-HT1A expression in the olfactory bulbectomized rats. In the present study, treadmill exercise ameliorated OBX-induced depressive symptoms. The antidepressive effect of treadmill exercise might be ascribed to the enhancement of serotonergic function through upregulation of 5-HT1A expression in the dorsal raphe.

Sarsasapogenin reverses depressive-like behaviors and nicotinic acetylcholine receptors induced by olfactory bulbectomy

Cholinergic signalling in the hippocampus may contribute to the aetiology of mood regulation. Antidepressants can reverse the increase in acetylcholinesterase (AChE) activity induced by olfactory bulbectomy. The activation of nicotinic acetylcholine receptors (nAChRs) also alleviates the symptoms of depression. This study advances the development of sarsasapogenin, which interacts with cholinergic signalling and has a favourable antidepressant profile in olfactory bulbectomised (OB) rats. We examined OB-induced changes in cholinergic signalling, as well as AChE, α4-nAChR, and α7-nAChR expression in the hippocampus. The results indicate that abnormal cholinergic signalling in the hippocampus contributes to the development of depression in the OB rat model. This depression may be alleviated following treatment with sarsasapogenin.

Effects of repeated treatment with a delta opioid receptor agonist KNT-127 on hyperemotionality in olfactory-bulbectomized rats

We previously demonstrated that a single treatment of a non-peptidic delta opioid receptor agonist, KNT-127, has an antidepressant-like effect in rodents in the forced swim test. Here we evaluated the effect of repeated administration of the potential antidepressant KNT-127 in an olfactory-bulbectomized (OBX) rat model. Male Wistar rats (8–12 weeks old) underwent olfactory bulbectomy. From 14days after surgery each was weighed and administered either KNT-127 (3mgkg−1/day), the selective serotonin reuptake inhibitor (SSRI) fluoxetine (10mgkg−1/day), or vehicle, daily for 14 days. Hyperemotionality was measured on days 3, 5, 7, 10, and 14. Repeated administration of KNT-127 significantly decreased total and individual hyperemotionality scores (attack, startle, struggle and fight) over the entire period. Conversely, fluoxetine did not show any significant effect on days 3, 5, 7, or 14 but significantly reduced the total score on day 10. The inhibitory effects of KNT-127 were greater than those of fluoxetine. The KNT-127 and control groups both gained weight, while the fluoxetine group lost weight. Our results suggest that KNT-127 is a potential lead compound for antidepressant therapy, with high efficacy, a relatively rapid onset of therapeutic effect, and without the possible adverse effects of weight loss caused by SSRIs.

The level of the zinc homeostasis regulating proteins in the brain of rats subjected to olfactory bulbectomy model of depression

BackgroundZinc transporters (ZnTs) and metallothioneins (MT) are important in maintaining Zn homeostasis in the brain. The present study was designed to find out whether alterations in ZnTs and MTs are associated with the pathophysiology of depression and the mechanism of antidepressant action. MethodsMessenger RNA and proteins of ZnT1, ZnT3, ZnT4, ZnT5, ZnT6 and MT1/2 were measured in the prefrontal cortex (PFC) and hippocampus (Hp) of rats subjected to olfactory bulbectomy (OB) (a model of depression) and chronic amitriptyline (AMI) treatment by Real Time PCR and Western Blot/Immunohistochemistry (IHP). ResultsResults in the OB rats showed: increases in the protein levels of ZnT1 in the PFC and Hp and MT1/2 in the PFC; a decrease in ZnT3 protein level in the PFC; no changes in ZnT4, ZnT5 and ZnT6 in the PFC and Hp. IHP labeling revealed increases in the optical densities of ZnT1-IR in the PFC and Hp and decreases in ZnT3 and ZnT4-IR in the PFC of OB rats. Although OB had no effects on gene expression of ZnTs, mRNAs for MT1/2 were increased. Chronic AMI treatment did not influence protein levels of ZnTs and MT1/2 in Sham and OB rats; however decreased mRNA levels of ZnT4 and ZnT5 in PFC and ZnT1, ZnT3, ZnT4 and ZnT6 in Hp of Sham rats and normalized OB induced increase in MT1/2 gene expression. ConclusionsChanges in ZnTs and MT1/2 suggest altered cortical distribution of Zn in the OB model which further supports the hypothesis that Zn dyshomeostasis may be involved in the pathophysiology of depression.

Adenosine A2A receptors in the olfactory bulb suppress rapid eye movement sleep in rodents.

Rapid eye movement (REM) sleep behavior disorder in humans is often accompanied by a reduced ability to smell and detect odors, and olfactory bulbectomized rats exhibit increased REM sleep, suggesting that the olfactory bulb (OB) is involved in REM-sleep regulation. However, the molecular mechanism of REM-sleep regulation by the OB is unknown. Adenosine promotes sleep and its A2A receptors (A2AR) are expressed in the OB. We hypothesized that A2AR in the OB regulate REM sleep. Bilateral microinjections of the A2AR antagonist SCH58261 into the rat OB increased REM sleep, whereas microinjections of the A2AR agonist CGS21680 decreased REM sleep. Similar to the A2AR antagonist, selective A2AR knockdown by adeno-associated virus carrying short-hairpin RNA for A2AR in the rat OB increased REM sleep. Using chemogenetics on the basis of designer receptors exclusively activated by designer drugs, we demonstrated that the inhibition of A2AR neurons increased REM sleep, whereas the activation of these neurons decreased REM sleep. Moreover, using a conditional anterograde axonal tract-tracing approach, we found that OB A2AR neurons innervate the piriform cortex and olfactory tubercle. These novel findings indicate that adenosine suppresses REM sleep via A2AR in the OB of rodents.

N-acetylcysteine amide (AD4) reduces cocaine-induced reinstatement.

Chronic exposure to drugs of abuse changes glutamatergic transmission in human addicts and animal models. N-acetylcysteine (NAC) is a cysteine prodrug that indirectly activates cysteine-glutamate antiporters. In the extrasynaptic space, NAC restores basal glutamate levels during drug abstinence and normalizes increased glutamatergic tone in rats during reinstatement to drugs of abuse. In initial clinical trials, repeated NAC administration seems to be promising for reduced craving in cocaine addicts. In this study, NAC-amide, called AD4 or NACA, was examined in intravenous cocaine self-administration and extinction/reinstatement procedures in rats. We investigated the behavioral effects of AD4 in the olfactory bulbectomized (OBX) rats, considered an animal model of depression. Finally, we tested rats injected with AD4 or NAC during 10-daily extinction training sessions to examine subsequent cocaine seeking. AD4 (25-75mgkg(-1)) given acutely did not alter the rewarding effects of cocaine in OBX rats and sham-operated controls. However, at 6.25-50mgkg(-1), AD4 decreased dose-dependently cocaine seeking and relapse triggered by cocaine priming or drug-associated conditioned cues in both phenotypes. Furthermore, repeated treatment with AD4 (25mgkg(-1)) or NAC (100mgkg(-1)) during daily extinction trials reduced reinstatement of drug-seeking behavior in sham-operated controls. In the OBX rats only, AD4 effectively blocked cocaine-seeking behavior. Our results demonstrate that AD4 is effective at blocking cocaine-seeking behavior, highlighting its potential clinical use toward cocaine use disorder.

Rhodioloside ameliorates depressive behavior via up-regulation of monoaminergic system activity and anti-inflammatory effect in olfactory bulbectomized rats

Rhodioloside, a major constituent from roots of Rhodiola rosea, has been previously confirmed to alleviate the hyperactivity in olfactory bulbectomized (OBX) rats exposed to the open field and to decrease the immobility time in the forced swimming test (FST) and tail suspension test (TST). However, its antidepressant effects and mechanisms remain unclear. This study aimed to evaluate the antidepressant effect and the potential mechanisms of rhodioloside in OBX rats. ELISA kits, HPLC-MS and western blot analysis were applied to explore the underlying antidepressant mechanisms of rhodioloside. Rhodioloside (20, 40mg/kg) significantly reversed OBX-induced reduction in sucrose consumption. It was also observed that administration of rhodioloside (20, 40mg/kg) decreased pro-inflammatory cytokines interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) levels and inhibits nuclear factor-kappa B (NF-κB) activation, as well as normalized the monoaminergic system changes in prefrontal cortex (PFC) of OBX rats. These results confirmed the antidepressant-like effect of rhodioloside, which might be primarily based on its up-regulation of the monoaminergic system activity and anti-inflammatory effect.

Behavioral, neurochemical and molecular changes after acute deep brain stimulation of the infralimbic prefrontal cortex

Deep brain stimulation (DBS) is a treatment that has shown some efficacy in treatment-resistant depression. In particular, DBS of the subcallosal cingulate gyrus (Brodmann's area 25, Cg25) has been successfully applied to treat refractory depression. In the rat, we have demonstrated that DBS applied to infralimbic (IL) cortex elevates the levels of glutamate and monoamines in the prefrontal cortex, and requires the stimulation of cortical α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors for its antidepressant-like effects. However, the molecular targets of IL DBS are not fully known. To gain insight into these pathways, we have investigated whether IL DBS is able to reverse the behavioral, biochemical and molecular changes exhibited by the olfactory bulbectomized (OBX) rat. Our results revealed that 1 h IL DBS diminished hyperlocomotion, hyperemotionality and anhedonia, and increased social interaction shown by the OBX rats. Further, IL DBS increased prefrontal efflux of glutamate and serotonin in both sham-operated and OBX rats. With regard to molecular targets, IL DBS increases the synthesis of brain-derived neurotrophic factor (BDNF) and the GluA1 AMPA receptor subunit, and stimulates the Akt/mammalian target of rapamycin (mTOR) as well as the AMPA receptor/c-AMP response element binding (CREB) pathways. Temsirolimus, a known in vivo mTOR blocker, suppressed the antidepressant-like effect of IL DBS in naïve rats in the forced swim test, thus demonstrating for the first time that mTOR signaling is required for the antidepressant-like effects of IL DBS, which is in line with the antidepressant response of other rapid-acting antidepressant drugs.

Neuropeptide Trefoil Factor 3 Reverses Depressive-Like Behaviors by Activation of BDNF-ERK-CREB Signaling in Olfactory Bulbectomized Rats.

The trefoil factors (TFFs) are a family of three polypeptides, among which TFF1 and TFF3 are widely distributed in the central nervous system. Our previous study indicated that TFF3 was a potential rapid-onset antidepressant as it reversed the depressive-like behaviors induced by acute or chronic mild stress. In order to further identify the antidepressant-like effect of TFF3, we applied an olfactory bulbectomy (OB), a classic animal model of depression, in the present study. To elucidate the mechanism underlying the antidepressant-like activity of TFF3, we tested the role of brain-derived neurotrophic factor (BDNF)-extracellular signal-related kinase (ERK)-cyclic adenosine monophosphate response element binding protein (CREB) signaling in the hippocampus in the process. Chronic systemic administration of TFF3 (0.1 mg/kg, i.p.) for seven days not only produced a significant antidepressant-like efficacy in the OB paradigm, but also restored the expression of BDNF, pERK, and pCREB in the hippocampal CA3. Inhibition of BDNF or extracellular signal-related kinase (ERK) signaling in CA3 blocked the antidepressant-like activity of TFF3 in OB rats. Our findings further confirmed the therapeutic effect of TFF3 against depression and suggested that the normalization of the BDNF-ERK-CREB pathway was involved in the behavioral response of TFF3 for the treatment of depression.

Antidepressant-like activity of EMD 386088, a 5-HT6 receptor partial agonist, following systemic acute and chronic administration to rats.

The study was designed to examine the potency of EMD 386088, a 5-HT6 receptor partial agonist, to exert antidepressant-like properties in animal models following acute and chronic intraperitoneal administration to rats. The modified rat forced swim test (FST) was utilized to examine a potential antidepressant effect of EMD 386088 after acute treatment (30min before the test) and three times in a 24-h administration scheme (24h, 5h, and 30min prior to the FST). The olfactory bulbectomy (OB) model was used to assess its antidepressant-like properties after chronic treatment (the drug was administered once daily for 14days). EMD 386088 showed an antidepressant-like effect in all conducted tests. Its activity in FST after its acute administration (5mg/kg) was blocked by the selective 5-HT6 receptor antagonist SB 271046. The obtained results seem to be specific, as there was no observed locomotor stimulation by the drug given at a lower/antidepressant dose. In the three times in the 24-h treatment scheme, EMD 386088 (2.5mg/kg) exerted antidepressant properties in FST as well as increased locomotor activity in the open field test. Chronic administration of EMD 386088 (2.5mg/kg) significantly improved the learning deficit in OB rats without affecting performance in Sham-operated (SH) animals in the passive avoidance test, and reduced OB-related rats' locomotor hyperactivity, but did not change the number of rearing + peeping episodes. The obtained findings suggest that EMD 386088 produces antidepressant-like activity after systemic acute and chronic administration which may result from direct stimulation of 5-HT6 receptors.

Antidepressant effects of standardized extract of Commiphora mukul Engl. in olfactory bulbectomized rats

The objective of this work was to evaluate the effects of standardized hydroalcholic extract of Commiphora mukul (HECM) in animal model of chronic stress medicated depression, namely olfactory bulbectomy (OBX) model in rats. Effects of 14-day (subacute) oral pretreatment of HECM (50, 100 and 200 mg/kg) were evaluated on depression and stress related parameters on OBX rats. Separate groups for sham control, OBX control and positive controls namely imipramine (20 mg/kg), fluoxetine (30 mg/kg) and desipramine (15 mg/kg) were also maintained. Behavioral and physiological parameters in open field and elevated plus maze were recorded. HECM showed dose-dependent reversal of OBX-induced physiological effects such as reduction of body weight, body temperature, heart rate and serum sodium concentration. HECM also showed reversal effects on OBX induced food intake increase and hyperactivity in open field and elevated plus maze paradigm. In conclusion, HECM demonstrated restorative effects in OBX induced depression model in rats probably due to stress reliving mechanisms.

Effects of 4-hydroxyisoleucine from Fenugreek Seeds on Depression-like Behavior in Socially Isolated Olfactory Bulbectomized Rats.

Context:Antidepressant-like effects of (2S, 3R, 4S)-4-hydroxyisoleucine (4-HI), a major amino acid from fenugreek seeds, has been reported in the animal model of acute depression.Aims:To evaluate effects of subacute administration of 4-HI in animal model of stress-induced depression namely socially isolated olfactory bulbectomized rats.Materials and Methods:Bilateral olfactory bulbectomy (OBX) were induced in 30 Sprague-Dawley rats. After recovery period of 14 days, rats were randomized into five groups of 6 rats each and stressed with social isolation (individual housing). The rats were orally treated with either vehicle (OBX-Iso), positive control, fluoxetine (30 mg/kg) or 4-HI (10, 30, 100 mg/kg) once a day from day 14 onward. Separate group of rats with social isolation but without OBX (Sham-Iso) was also maintained. The behavioral depression and anxiety related parameters using open field test (OFT), sucrose intake test, novelty suppressed feeding (NSF) and forced swim test (FST), and neurochemical estimation (brain monoamines viz., serotonin and nor-adrenaline, serotonin turnover, and serum cortisol) were performed.Statistical Analysis Used:Data was analyzed by either two-way ANOVA (OFT and FST) or one-way ANOVA (sucrose intake test, NSF, and neurochemical estimation) followed by Dunnett's multiple comparisons test. Differences were considered significant at P < 0.05.Results:The significant and dose-dependent protection from behavioral and neurochemical changes were observed in 4-HI co-administrated OBX-Iso rats.Conclusion:4-HI demonstrated the antidepressant and antianxiety effects in socially isolated stress-induced OBX rats with possible involvement of multiple stress relieving mechanisms.HIGHLIGHTS OF PAPERIn this study, the subacute pretreatment of 4-HI showed strong and dose-dependent prevention of isolation stress related behavioral and neurochemical responses in olfactory bulbectomized rats. The prevention of hyperactive HPA axis in OBX-Iso stress-induced rats can be envisaged as probable mechanism of antidepressant and antianxiety effects of 4-HI.SUMMARY Effect of 4-hydroxyisoleucine (4-HI) in olfactory bulbectomized and socially isolated (Iso) rats was evaluated4-HI showed significant and dose-dependent antidepressant effects during novelty suppressed feeding (NSF) and forced swim test (FST)4-HI showed significant and dose-dependent antianxiety effects during OFT (open field test) and sucrose intake test4-HI showed protection from OBX-Iso stress-induced brain monoamines, serotonin turnover, and serum cortisol level elevation. Abbreviations used: SSRI: Selective Serotonin Reuptake Inhibitor; 4-HI: (2S, 3R, 4S)-4-hydroxyisoleucine; OBX: Olfactory bulbectomy; CPCSEA: Committee for the Purpose of Control and Supervision of Experiments on Animals; OFT: Open Field Test; NSF: Novelty Suppressed Feeding; FST: Forced Swimming Test; 5HT: 5-Hydroxytryptamine; 5-HIAA: 5-Hydroxyindoleacetic Acid; NA: Nor-adrenaline; and HPA: Hypothalamic-Pituitary Adrenal.

Assessment of a major depression animal model for old man established with orchidectomized plus olfactory bulbectomized rat

Objective To evaluate the effectiveness of a major depression animal model for old man established with orchidectomized(ORX) and subsequently olfactory bulbectomized(OBX) rat. Methods Healthy Sprague-Dawley male adult rats were randomly assigned to six groups with ten rats in each group: intact, sham-operated, model, vehicle, fluoxetine plus testosterone propionate(Flu+ TP) and amitriptyline plus testosterone propionate(Ami+ TP) groups. ORX+ OBX rat model was established. Therapy of Flu or Ami (10 mg/kg, i.p.) combined with TP(25 mg/kg, s.c.) was administered. Behavioral changes of rats in each group were detected. Results Open field test: The number of rat crossing lattices in model((124.50±14.25)lattices) or vehicle group( 118.70±10.27) was significantly larger than those of intact(38.20±6.30), sham-operated(33.70±9.58), Flu+ TP (34.00±9.82) and Ami+ TP group (35.20±12.54). The rearing number of model or vehicle group was also significantly larger than those of intact, sham-operated, Flu+ TP and Ami+ TP group.Statistical differences in the above corresponding comparisons of open field test existed (P<0.01). Forced swimming test: The immobility time of model((131.70±32.44)s) or vehicle group ((135.10±34.01)s) was significantly longer than those of intact((66.60±12.06)s), sham-operated((62.00±13.38)s), Flu+ TP((59.60±8.89)s) and Ami+ TP group ((64.80±10.78)s). There were statistical differences in the above corresponding comparisons (P<0.01). Morris water maze test: The escape latency of model((62.00±26.05)s) or vehicle group ((60.52±27.00)s) was significantly longer than those of intact((24.19±9.12)s), sham-operated((21.06±8.13)s), Flu+ TP((22.88±8.01)s) and Ami+ TP group ((27.04±10.11)s); while the time rat swimming in the quadrant originally put a platform of model or vehicle group was significantly shorter than those of intact, sham-operated, Flu+ TP and Ami+ TP group. There were statistical differences in the above corresponding comparisons of Morris water maze test (P<0.01, P<0.05). Conclusion The above data demonstrates that ORX+ OBX rat model is both repeatability and reliability, and can be a major depression animal model of old man for future researches. Key words: Orchidectomy; Olfactory bulbectomy; Old man; Major depression; Androgen; Animal model

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.

Fatty acids rehabilitated long-term neurodegenerative: like symptoms in olfactory bulbectomized rats.

Our previous study demonstrated that an olfactory bulbectomy in rats induced short-term, multifaceted, devastating Alzheimer's-like effects, which included cognitive impairment, hyperactivity, hyperthermia, and increased levels of homocysteine and pro-inflammatory cytokines, including IL-17A. In addition, the rats exhibited an increase in the hyperphosphorylation of brain Tau proteins and in the number of neurofibrillary tangles. Here, we examined the long-term effects of the surgery and found that olfactory bulbectomy also rendered the rats to become anemic with brain iron overload. Additionally, a significant reduction in the membrane fluidity index in frontal cortex synaptosomes was found. Treatment with a mixture of n-3/n-6 of fatty acids restored the unwanted effect. The beneficial effects of fatty acids are mediated via the effects of fatty acids on the neuronal membrane structure and fluidity. These findings are similar to Alzheimer's symptoms, which suggest this model can be used as an animal model for Alzheimer's disease. We recommend using this model to scan potential new anti-Alzheimer's drugs.

Chronic administration of amitriptyline differentially alters neuropathic pain-related behaviour in the presence and absence of a depressive-like phenotype

Chronic pain and depression share a complex, reciprocal relationship. Furthermore, in addition to treating depression, antidepressants such as amitriptyline are a first-line treatment for chronic pain conditions, indicating possible common neural substrates underlying both depression and pain. However, there is a paucity of studies examining the effect of antidepressant treatment on nociceptive and neuropathic pain responding in the presence of a depressive phenotype. The current study aimed to examine the effect of chronic amitriptyline administration on neuropathic pain-related behaviour and associated neuroinflammatory processes in the olfactory bulbectomised (OB) rat model of depression. Nociceptive responding to mechanical, innocuous cold or noxious heat stimuli in sham or OB rats was not altered by chronic amitriptyline administration. The induction of neuropathic pain following L5–L6 spinal nerve ligation (SNL) resulted in robust mechanical and cold allodynia and heat hyperalgesia in both sham and OB vehicle-treated animals. Chronic amitriptyline administration attenuated SNL-induced mechanical allodynia in both sham and OB rats at day 7 post-SNL, an effect which was enhanced and prolonged in OB rats. In comparison, chronic amitriptyline administration attenuated SNL-induced cold allodynia and heat hyperalgesia in sham, but not OB, rats. Evaluating the affective/motivational aspect of pain using the place escape avoidance paradigm revealed that OB-SNL rats exhibit reduced noxious avoidance behaviour when compared with sham counterparts, an effect not altered by chronic amitriptyline administration. Chronic amitriptyline administration prevented the increased expression of GFAP, IL-10 and CCL5, and enhanced the expression of TNFα, in the prefrontal cortex of OB-SNL rats. In conclusion, these data demonstrate that chronic amitriptyline differentially alters somatic nociceptive responding following peripheral nerve-injury, depending on stimulus modality and the presence or absence of a depressive-like phenotype, an effect which may involve modulation of neuroinflammatory processes.

Modulatory effect of VIP injected into hippocampal CA1 area on anxiety in olfactory bulbectomized rats.

Vasoactive intestinal peptide (VIP) is a neuropeptide, which is widely distributed in the central nervous system and peripheral tissues, acting both as a neurotransmitter and neuromodulator. Despite its extensive expression in the hippocampus, amygdala and other limbic system structures, the effects of VIP on anxiety and depression have not yet been fully investigated. The aim of the present study was to evaluate the involvement of VIP and VIP receptors in the mechanism of anxiety in rats with a model of depression (bilateral olfactory bulbectomy), using the elevated plus-maze test. VIP and a non-specific antagonist of VIP receptors (VIP6-28) were administered unilaterally into the hippocampal CA1 area of bulbectomized (OBX) rats. VIP (10 ng) showed a tendency for an anxiety-modulatory effect upon right side injection, by reducing significantly the closed arm time and increasing the open arm time. VIP (100 ng) injected unilaterally (left or right) into CA1 area induced an anxiolytic-like effect on the activity of OBX rats (increased the number of open arms entries, open arm time and the ratio open/total number of entries). VIP6-28 failed to antagonize the anxiety-related behavior of OBX rats in the plus maze. An unexpected finding in our study was that upon pretreatment with VIP6-28, VIP (10 ng), injected unilaterally (left or right) exerted an anti-anxiety like effect (increased the number of open arm entries, open arm time and the ratio open/total number of entries). Our data point to a possible involvement of hippocampal VIP-ergic neurons in modulating emotional processes or adaptive responses to stressful stimuli in a rat model of depression.