Repeated Sulforaphane Treatment Reverses Depressive-like Behavior and Exerts Antioxidant Effects in the Olfactory Bulbectomy Model in Mice.

Growing evidence suggests that activators of nuclear factor erythroid-derived 2-like 2 (Nrf2), such as sulforaphane, may represent promising novel pharmacological targets for conditions related to oxidative stress, including depressive disorder. Therefore, we conducted a study to explore the behavioral and biochemical effects of repeated (14 days) sulforaphane (SFN) treatment in the olfactory bulbectomy (OB) animal model of depression. An open field test (OFT), splash test (ST), and spontaneous locomotor activity test (LA) were used to assess changes in depressive-like behavior and the potential antidepressant-like activity of SFN. The OB model induced hyperactivity in mice during the OFT and LA as well as a temporary loss of self-care and motivation in the ST. The repeated administration of SFN (10 mg/kg) effectively reversed these behavioral changes in OB mice across all tests. Additionally, a biochemical analysis revealed that SFN (10 mg/kg) increased the total antioxidant capacity in the frontal cortex and serum of the OB model. Furthermore, SFN (10 mg/kg) significantly enhanced superoxide dismutase activity in the serum of OB mice. Overall, the present study is the first to demonstrate the antidepressant-like effects of repeated SFN (10 mg/kg) treatment in the OB model and indicates that these benefits may be linked to improved oxidative status.

Neonatal olfactory bulbectomy causes dendritic spine retraction in dorsal hippocampal CA3 neurons in female rats and spatial learning deficits in male rats.

Olfactory bulbectomy (OBX) is an experimental strategy that is widely employed because it produces changes at different levels (from behavioral to molecular) that can be related to symptoms of depression in humans. This procedure has been widely studied in adult rats, but little information has been obtained of its effect in neonatal rats. The objective of the present study was to evaluate learning and memory capacity and dendritic spine density in dorsal hippocampal CA3 neurons. Seven-day-old male and female Wistar rats were subjected to nOBX by suction, we included an intact group as a control (CON) and a sham-operated group (SHAM), too. Spatial learning and memory were measured at 56 days of age using a Morris water maze. A different cohort of experimental groups was used to measure dendritic spine density by Golgi-Cox impregnation. Male rats with nOBX showed a pronounced spatial learning deficit than female rats. Also, there was a significant decrease in basilar dendritic spine density in female rats with nOBX compared to the CON group. No changes were observed in this variable in male rats with nOBX. Our results allow us to suggest that there is sexual dimorphism in the effect of nOBX on the dorsal hippocampus and its relationship with spatial learning and memory processes.

Antidepressant-like effects of Jieyu Chufan capsules in the olfactory bulbectomy rat model.

The olfactory bulbectomy (OBX) animal model of depression reproduces the behavioral and neurochemical changes observed in depressed patients. We assessed the therapeutic effects of the Jieyu Chufan (JYCF) capsule on OBX rats. JYCF ameliorated the hedonic and anxiety-like behavior of OBX rats and attenuated the cortical and hippocampal damage. JYCF enhanced the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2), and adiponectin (ADPN) in the cortex and hippocampus of OBX rats. JYCF also reduced cortisol levels and restored the levels of excitatory neurotransmitters, such as 5-hydroxytryptamine (5-HT), acetylcholine (ACH), and glutamic acid (Glu), in the brain tissue of OBX rats. Our results suggest that JYCF preserves the synaptic structure by increasing the levels of synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) and alleviates the histological alterations of brain tissue by activating AKT/PKA-CREB-BDNF pathways, and by upregulating ADPN and FGF2 expression in OBX rats. JYCF exerts multiple therapeutic effects on depression, including modulating neurotransmitters, repairing neuronal damage, and maintaining synaptic integrity. These findings support the potential of JYCF as a novel antidepressant agent with therapeutic effects on depression and related neurological disorders.

Olfactory bulbectomy leads to prolonged induction phase of sevoflurane anesthesia in rats.

The effect of olfactory bulb lesions on the induction time of sevoflurane has never been studied. We aimed to investigate this issue. In this study, we found that the volume of olfactory bulbs and the pore of the fila olfactoria were significantly lower with the fibrosis of olfactory bulbs in animals subjected to olfactory bulbectomy. Volatile anesthetics induction times were measured in all groups. Prolonged induction was observed in olfactory bulbectomy group. It was concluded that increased induction times of sevoflurane may be due to the olfactory bulb lesion.

Olfactory Bulbectomy Model of Depression Lowers Responding for Food in Male and Female Rats: The Modulating Role of Caloric Restriction and Response Requirement.

Depression is a psychiatric disorder characterized by a marked decrease in reward sensitivity. By using the olfactory bulbectomy (OBX) model of depression, it was shown that OBX rats display enhanced drug-taking and seeking behaviors in a self-administration paradigm than sham-operated (SHAM) controls, and sex is an important regulating factor. To reveal potential strain effects, we compared the operant behavior of male and female Sprague-Dawley and Wistar OBX and SHAM rats trained to self-administer palatable food pellets. Results showed that Sprague-Dawley OBX rats of both sexes exhibited lower operant responding rates and food intake than SHAM controls. Food restriction increased responding in both OBX and SHAM groups. Female rats responded more than males, but the OBX lesion abolished this effect. In Wistar rats, bulbectomy lowered food self-administration only during the last training days. Food self-administration was not significantly affected in Wistar rats by sex. In summary, this study showed that bulbectomy significantly reduces operant responding and food intake in male and female Sprague-Dawley rats while inducing a mild reducing effect only in the Wistar strain. Strain-dependent effects were also observed in the modulating role of sex and food restriction on operant responding and palatable food intake.

From Nose to Lumbar Spinal Cord - Reduced Sperm Numbers Occur by Olfactory Bulbectomy-Related Onuf's Nucleus Degeneration: New Experimental Evidence for Kallmann Syndrome.

INTRODUCTION: Olfaction and its relation to human health is an area of growing interest. Although olfaction disorders have been considered a part of Kallmann syndrome, the role of olfactory dysfunction on spermatogenesis has not been studied yet. We studied if olfactory bulbectomy (OBX) causes dysfunction in spermatogenesis as a result of Onuf's nucleus damage. METHODS: Twenty-eight male rats were divided into three groups: six as the control (G-1; n = 6), six as the only frontal burr hole applied animals SHAM (G-2; n = 6), and 16 as the study group (G-3; n = 16) in which OBX was performed. The animals were followed for 2 months. After the decapitation of the animals, olfactory bulb (OB) volumes (mm3), the neuron density of the Onuf's nucleus (n/mm3), and sperm density (n/mm3) were estimated stereologically and analyzed. RESULTS: OB volumes (mm3), degenerated neuron density of Onuf's nucleus (n/mm3), and sperm numbers of control, SHAM, and study groups were estimated as: 4 ± 0.5; 6 ± 2 and 103.245 ± 10.841 in G-1; 3.5 ± 0.7; 14 ± 4 and 96.891 ± 9.569 in G-2; and 1.3 ± 0.3; 91 ± 17 and 73.561 ± 6.324 in G-3. The statistical results of degenerated neuron density of Onuf's nucleus and sperm numbers between groups are p < 0.005 for G-1/G-2; p < 0.0005 for G-2/G-3; and p < 0.00001 for G-1/G-3. DISCUSSION: This study first time indicates that Onuf's nucleus degeneration secondary to OBX seems to be responsible for reduced sperm numbers.

Olfactory bulbectomy induces nociceptive alterations associated with gliosis in male rats.

Major depressive disorder (MDD) is a major health concern worldwide with a wide array of symptoms. Emerging evidence suggests a high comorbidity between MDD and chronic pain, however, the relationship between these two diseases is not completely understood. Growing evidence suggests that glial cells play a key role in both disorders. Hence, we examined the effect of olfactory bulbectomy (OBX), a well-known model of depression-related behavior, on nociceptive behaviors and the number and morphology of astrocytes and glial cells in brain regions involved in the control of nociceptive processes in male rats. The brain regions analyzed included the basolateral amygdala (BLA), central amygdala (CeA), prefrontal cortex (PFC), and CA1 subregion of the hippocampus. A battery of behavioral tests, mechanical allodynia, thermal cold allodynia and mechanical hyperalgesia, was evaluated before and four weeks after OBX. Quantitative morphological analysis, as well as assessment of the number of glial fibrillary acidic protein (GFAP) and ionizing calcium-binding adaptor molecule 1 (Iba1) positive astrocytes and microglia were carried out to characterize glial remodeling and density, respectively. OBX caused mechanical and cold allodynia in an asynchronous pattern. The cold allodynia was noticeable one week following surgery, while mechanical allodynia became apparent two weeks after surgery. In the BLA, CeA and CA1, OBX caused significant changes in glial cells, such as hypertrophy and hypotrophy in GFAP-positive astrocytes and Iba1-positive microglia, respectively. Iba1-positive microglia in the PFC underwent selective hypotrophy due to OBX and OBX enhanced both GFAP-positive astrocytes and Iba1-positive microglia in the BLA. In addition, OBX increased the number of GFAP-positive astrocytes in the CeA and CA1. The amount of Iba1-positive microglia in the PFC also increased as a result of OBX. Furthermore, we found that there was a strong link between the observed behaviors and glial activation in OBX rats. Overall, our work supports the neuroinflammatory hypothesis of MDD and the comorbidity between pain and depression by demonstrating nociceptive impairment and significant microglial and astrocytic activation in the brain.

Neonatal olfactory bulbectomy induces anxiety-related behavior and modifies dopaminergic receptor expression in post-pubertal rats.

Olfaction is a complex physiological process producing effects in the central nervous system (CNS) and implicated in emotional processes. Indeed, the olfactory bulbs (OB) send projections to various CNS regions including the nucleus accumbens (NAcc) and caudate-putamen (CPu). Both the NAcc and CPu receive important dopaminergic input. Emerging evidence suggests that dopamine (DA) is related to anxiety-related behaviors. Therefore, we aimed to investigate the consequences of neonatal olfactory bulbectomy (nOBX) to anxiety-related behavior as assayed in the elevated plus maze (EPM) as well as the expression of dopaminergic receptors (D1-like, D2-like, and D3) in the NAcc and CPu at pre- and post-pubertal ages in the rat. The results show that nOBX increased the number of entries in the open arm of the EPM post-pubertally, suggesting an anxiolytic-related effect. nOBX increased the D2-like binding in the NAcc shell and D3 binding in the NAcc core pre-pubertally. At post-pubertal ages, the D3 binding was reduced at the olfactory tubercle and islands of Calleja in nOBX rats. Alterations in the DA receptor expression may be one mechanism responsible for the observed behavioral modifications in nOBX rats.

Comparison of the Effect on Heart Rate Variability for Modeling Septoplasty and Modeling Deprivation of the Olfactory Analyzer in Rats.

Modeling septoplasty and modeling sensory deprivation of the olfactory analyzer in rats were compared for the effect on the frequency domain of heart rate variability (HRV). Bulbectomy provoked more pronounced changes in HRV as compared with septoplasty simulation.

Evaluation of the 5-HT2C receptor drugs RO 60-0175, WAY 161503 and mirtazepine in a preclinical model of comorbidity of depression and cocaine addiction.

BACKGROUND: Epidemiological data indicate a high rate of comorbidity of depression and cocaine use disorder (CUD). The role of serotonin 2C (5-HT2C) receptors in the mechanisms responsible for the coexistence of depression and CUD was not investigated. METHODS: We combined bilateral olfactory bulbectomy (OBX), an animal model of depression, with intravenous cocaine self-administration and extinction/reinstatement in male rats to investigate two 5-HT2C receptor agonists (Ro 60-0175 (RO) and WAY 161503 (WAY)) and the 5-HT2C-receptor preferring antagonist mirtazapine (MIR; an antidepressant), with the goal of determining whether these drugs alter cocaine-induced reinforcement and seeking behaviors. Additionally, neurochemical analyses were performed following cocaine self-administration and its abstinence period in the brain structures in OBX rats and SHAM-operated controls. RESULTS: Acute administration of RO reduced, while WAY non-significantly attenuated cocaine reinforcement in both rat phenotypes. Moreover, RO or WAY protected against cocaine-seeking behavior after acute or after repeated drug administration during extinction training in OBX and SHAM rats. By contrast, acutely administered MIR did not alter cocaine reinforcement in both rat phenotypes, while it's acute (but not repeated) pretreatment reduced cocaine-seeking in OBX and SHAM rats. In neurochemical analyses, cocaine reinforcement increased 5-HT2C receptor levels in the ventral hippocampus; a preexisting depression-like phenotype enhanced this effect. The 10-daily cocaine abstinence reduced 5-HT2C receptor expression in the dorsolateral striatum, while the coexistence of depression and CUD enhanced local receptor expression. CONCLUSION: The results support a key role of 5-HT2C receptors for treating CUD and comorbid depression and CUD. They may be backs the further research of pharmacological strategies with drug targeting receptors.

Depressive-like phenotype enhances relapse of nicotine seeking after forced abstinence in rats.

OBJECTIVE: Comorbidity of depression and drug addiction is common, but effective treatment is missing. A rat model combining the olfactory bulbectomy (OBX) model and IV drug self-administration has provided evidence of differential reactivity of the OBX rats towards drugs of abuse. This study evaluates nicotine taking and seeking behaviour in this model. METHODS: Adult male Wistar rats were used; in one group, the OBX was performed while the other group was sham-operated. After three weeks of nicotine self-administration (fixed ratio-1 schedule), rats underwent two weeks of forced abstinence followed by a drug-free relapse-like session. Two doses of nicotine were studied: 0.019 and 0.030 mg/kg per infusion. The locomotor test took place before the self-administration protocol and on the first day of abstinence. RESULTS: OBX induced characteristic hyperactive locomotor phenotype. OBX rats self-administered more nicotine in the experiment using 0.019 mg/kg per infusion, but they reached lower drug intake in the study using 0.030 mg/kg per infusion. However, relapse of nicotine seeking after forced abstinence was significantly higher in the OBX groups in both cohorts. CONCLUSION: These results are in line with previous studies showing OBX-induced dissimilarities in drug-seeking and drug-taking and represent complementary information to reports on other substances.

Laterality in functional and metabolic state of the bulbectomised rat brain detected by ASL and 1H MRS: A pilot study.

OBJECTIVES: Pilot study validating the animal model of depression - the bilateral olfactory bulbectomy in rats - by two nuclear magnetic resonance methods, indirectly detecting the metabolic state of the brain. Furthermore, the study focussed on potential differences in brain laterality. METHODS: Arterial spin labelling assessed cerebral brain flow in prefrontal, sensorimotor, and piriform cortices, nucleus accumbens, hippocampus, thalamus, circle of Willis, and whole brain. Proton magnetic resonance spectroscopy provided information about relative metabolite concentrations in the cortex and hippocampus. RESULTS: Arterial spin labelling found no differences in cerebral perfusion in the group comparison but revealed lateralisation in the thalamus of the control group and the sensorimotor cortex of the bulbectomized rats. Lower Cho/tCr and Cho/NAA levels were found in the right hippocampus in bulbectomized rats. The differences in lateralisation were shown in the hippocampus: mI/tCr in the control group, Cho/NAA, NAA/tCr, Tau/tCr in the model group, and in the cortex: NAA/tCr, mI/tCr in the control group. CONCLUSION: Olfactory bulbectomy affects the neuronal and biochemical profile of the rat brain laterally and, as a model of depression, was validated by two nuclear magnetic resonance methods.

Study on antidepressant effects of Nrf2/HO-l of volatile oil from Chai Dang Bo drug-group on OB model rats and its mechanism / 中国药理学通报

Aim To confirm the antidepressant effect of the volatile oil part of the disassembled prescription drugs (Chai Hu, Dang Gui and Bo He, referred to as CDB) from Xiaoyao Powder and investigate its mechanism via Nrf2/H0-1 signaling pathway on OB model rats. Methods GC-MS analysis of the main components of volatile oil part of CDB was performed. The rats were randomly divided into sham operation group, model group, fluoxetine hydrochloride group (FLX, 10 mg • kg

Zinc Deficiency Blunts the Effectiveness of Antidepressants in the Olfactory Bulbectomy Model of Depression in Rats.

Currently used antidepressants do not always provide the desired results, and many patients suffer from treatment-resistant depression. Clinical studies suggest that zinc deficiency (ZnD) may be an important risk factor for depression and might blunt the effect of antidepressants. This study aimed to examine whether ZnD might blunt the effectiveness of antidepressants in the olfactory bulbectomy model (OB) of depression in rats. For this purpose, rats were subjected to the OB model, fed a zinc-deficient diet (3 mg Zn/kg) for 3 weeks, and finally treated with escitalopram (Esc), venlafaxine (Ven) 10 mg/kg, i.p., or combined Esc/Ven (1 mg/kg, i.p.) with zinc (5 mg/kg) for another 3 weeks. Open field (OFT), forced swim (FST), and sucrose intake (SIT) tests were used to evaluate depressive-like behavioral changes. In addition, serum, intracellular, and synaptic Zn concentrations and the level of zinc transporter (ZnT) proteins were analyzed. The OB + ZnD model induced hyperactivity in rats in the OFT, increased immobility time in the FST, and anhedonia in the SIT. Chronic treatment with Esc reduced immobility time in the FST in the OB + ZnD model. Esc/Ven +Zn increased sucrose intake in rats from the OB + ZnD group. The OB + ZnD decreased serum zinc levels and intracellular and synaptic Zn concentration in the prefrontal cortex (PFC) and cerebellum. These changes were normalized by chronic administration of Esc/Ven +Zn. Moreover, OB + ZnD decreased levels of the ZnT1 protein in the PFC and Hp and ZnT3 in Hp. Chronic administration of antidepressants did not alter the levels of ZnT proteins. The OB + ZnD model induces more depressive-like effects than either model alone. Our results show that ZnD may induce drug resistance in rats. Normalizing serum or brain zinc concentration is insufficient to reverse behavioral abnormalities caused by the OB + ZnD model. However, zinc supplementation might improve the effectiveness of antidepressants in reversing particular depression symptoms.

Correlation between the reduction in hippocampal SirT2 expression and depressive-like behaviors and neurological abnormalities in olfactory bulbectomized mice.

Reduced activity of hippocampal silent information regulator protein 2 (SirT2) has been associated with the development of depression caused by disturbances in neuronal and synaptic plasticity. However, changes in the hippocampal SirTs in olfactory bulbectomized (OBX) mice, an animal model of depression, remain unknown. Therefore, this study examined depressive-like behaviors, hippocampal SirTs, synaptic plasticity-associated proteins, and cell proliferation in OBX mice. The OBX mice showed depressive-like behaviors; reduced SirT2, synaptophysin, and PSD95 levels; and reduced cell proliferation in the hippocampus. These data indicate that decreased hippocampal SirT2 may contribute to pathophysiological depression and strongly affect the psychological state.

Antidepressant effects of Enterococcus faecalis 2001 through the regulation of prefrontal cortical myelination via the enhancement of CREB/BDNF and NF-κB p65/LIF/STAT3 pathways in olfactory bulbectomized mice.

A therapeutic strategy through the gut-brain axis has been proven to be effective in treatment for depression. In our previous study, we demonstrated that Enterococcus faecalis 2001 (EF-2001) prevents colitis-induced depressive-like behavior through the gut-brain axis in mice. More recently, we found that demyelination in the prefrontal cortex (PFC) was associated with depressive-like behavior in an animal model of major depressive disorder, olfactory bulbectomized (OBX) mice. The present study investigated the effects of EF-2001 on depressive-like behaviors in OBX mice and the underlying molecular mechanisms from the perspective of myelination in the PFC. OBX mice exhibited depressive-like behaviors in the tail-suspension, splash, and sucrose preference tests, and decreased myelin and paranodal proteins along with mature oligodendrocytes in the PFC. These behavioral and biochemical changes were all prevented by treatment with EF-2001. Further, EF-2001 treatment increased brain-derived neurotrophic factor (BDNF) and leukemia inhibitory factor (LIF) in the PFC. Interestingly, an immunohistochemical analysis revealed enhanced phospho (p) -cAMP-responsive element binding protein (CREB) expression in neurons, p-nuclear factor-kappa B (NFκB) p65 (Ser536) expression in astrocytes, and p-signal transducer and activator of transcription 3 (STAT3) (Ty705) expression in mature oligodendrocytes in the PFC of OBX mice. From these results, we suggest that EF-2001 administration prevents depressive-like behaviors by regulating prefrontal cortical myelination via the enhancement of CREB/BDNF and NFκB p65/LIF/STAT3 pathways. Our findings strongly support the idea that a therapeutic strategy involving the gut microbiota may be a promising alternative treatment for alleviating symptoms of depression.

Galanin (1-15) Enhances the Behavioral Effects of Fluoxetine in the Olfactory Bulbectomy Rat, Suggesting a New Augmentation Strategy in Depression.

BACKGROUND: Selective serotonergic reuptake inhibitors, including fluoxetine (FLX), are the most commonly used for the treatment of major depression. However, they are effective for remission in only 30% of patients. Recently, we observed that Galanin (1-15) [GAL(1-15)] enhanced the antidepressant effects of FLX in naïve animals, suggesting a new augmentation strategy in depression. METHODS: We have analyzed in an animal model of depression, the olfactory bulbectomy (OBX) rats, the effect of GAL(1-15) on FLX-mediated responses in the forced swimming test and the sucrose preference test and the involvement of GAL receptor 2 with its antagonist, M871. We have also studied the corticosterone levels in OBX after the coadministration of GAL(1-15) with FLX. Moreover, we studied whether the effects of GAL(1-15) on FLX actions were mediated via auto- and heteroreceptor 5-HT1A (5-HT1AR), analyzing the binding characteristics, mRNA levels, and functionality of 5-HT1AR in the dorsal hippocampus. RESULTS: GAL(1-15) enhances the antidepressant-like effects induced by FLX in OBX animals in the forced swimming test and the sucrose preference test. The involvement of the GALR2 was demonstrated with M871. Importantly, the mechanism underlying the GAL(1-15)/FLX interactions in the OBX animals involves the 5-HT1AR in the hippocampus at the plasma membrane (increase of affinity and density of 5HT1AR in the DG) and transcriptional (increase of 5HT1AR mRNA levels in DG and CA1) levels. Besides, the coadministration of GAL(1-15) and FLX also reduced OBX-increased corticosterone levels. CONCLUSIONS: The results open the possibility to use GAL(1-15) in combination with FLX as a novel strategy for the treatment of depression.

Oxidative Damage of Proteins Precedes Loss of Cholinergic Phenotype in the Septal Neurons of Olfactory Bulbectomized Mice.

BACKGROUND: The development of cholinergic deficit is considered an early sign of a number of pathological conditions, including Alzheimer's disease. Cholinergic dysfunction underlies cognitive decline associated with both normal aging and Alzheimer's disease. OBJECTIVE: Here, we studied a possible mechanism of functional impairment of cholinergic neurons using an olfactory bulbectomy model. METHODS: Male mice were subjected to olfactory bulbectomy or sham surgery. Three weeks after that they were trained in Morris water maze and then euthanized one month after surgery. The cholinergic indices as well as the indices of oxidative stress were studied using immunohistochemistry, western blot and ELISA. Gene expression was studied using RT-qPCR. RESULTS: The experimental treatment was followed by impaired learning of a standard spatial task in a water maze. This was associated with a decrease in the number of cells containing choline acetyltransferase (ChAT), in relation to total number of neurons in the medial septum and lower ChAT enzymatic activity in the hippocampus. However, the levels of mRNAs of ChAT, vesicular ACh transporter and acetylcholine esterase remained unchanged in bulbectomized mice compared to sham-operated animals. These alterations were preceded by the accumulation of protein-bound carbonyls, indicating oxidative damage of proteins, whereas oxidative damage of nucleic acids was not detected. CONCLUSION: We assume that in olfactory bulbectomy model, oxidative damage of proteins may cause cholinergic dysfunction rather than irreversible neuronal damage. These data indicate that cholinergic neurons of the basal forebrain are very sensitive to oxidative stress, which may be responsible for the appearance of early cognitive decline in Alzheimer's disease.

Dopamine receptor agonist rotigotine-loaded microspheres ameliorates sexual function deteriorated by fluoxetine in depression rats.

Low dopamine levels may cause depressive symptoms. Dopamine is also involved in sexual behavior. Rotigotine is a nonergolinic dopamine agonist. Fluoxetine, an antidepressant that acts as a selective serotonin (5-HT) reuptake inhibitor, may cause moderate or severe sexual dysfunction. This study aims to investigate the effects of rotigotine-loaded microspheres (RoMS) and rotigotine on fluoxetine-induced impairment of sexual function and their efficacy in depression-model rats. Rats with depressive-like behavior, induced by bilateral olfactory bulbectomy, were treated intragastrically with fluoxetine and co-administered RoMS or rotigotine subcutaneously. Then, copulatory behavior and open field tests were conducted. Serum luteinizing hormone and testosterone levels were assayed with enzyme-linked immunosorbent assay kits. The concentrations of 5-HT, dopamine, and norepinephrine were measured in the raphe nucleus and amygdala. The results showed that sexual function was decreased in olfactory bulbectomy rats and significantly deteriorated by fluoxetine. Co-administration of RoMS partly reversed the fluoxetine-induced impairment of sexual function, but rotigotine administration did not produce any improvement. Hyperactivity in olfactory bulbectomy rats was significantly attenuated by fluoxetine but was not influenced by co-administration of RoMS. Compared with the fluoxetine group, RoMS increased the testosterone, luteinizing hormone, dopamine, and norepinephrine levels. These findings indicated that RoMS improved the fluoxetine-induced impairment of sexual function and did not affect its antidepressant efficacy in depressive rats, which provides a potential treatment for patients with depression that can reduce the possibility of sexual dysfunction. Additionally, co-administration of fluoxetine with RoMS may be beneficial for Parkinson's disease patients with depression.

Galanin(1-15) Potentiates the Antidepressant-like Effects Induced by Escitalopram in a Rat Model of Depression.

Selective 5-HT reuptake inhibitor antidepressants (SSRIs) are the first choice in major depressive disorder (MDD), but 50% of affected patients do not show improvement. Galanin(1-15) [GAL(1-15)] enhanced Fluoxetine antidepressant-like effects in an animal model of depression, the olfactory bulbectomy (OBX); however, further detailed analysis of GAL(1-15) effects as augmentation treatment in OBX rats are needed. In OBX rats, we analysed the effect of GAL(1-15) on Escitalopram (ESC)-mediated responses in behavioural tests related to despair. We studied whether GAL(1-15) effects involved 5-HT1AR using an in vivo model siRNA 5-HT1A knockdown rats. Moreover, we analysed by immunohistochemistry the expression of the immediate-early gene c-Fos (c-Fos IR) after the administration of GAL(1-15)+ESC in OBX rats in several nuclei involved in MDD. GAL(1-15) enhances the antidepressant-like effects of ESC, and the GALR2 antagonist M871 blocked GAL(1-15) mediated actions. The downregulation of 5-HT1AR by siRNA was sufficient to block GAL(1-15) effects. Our immunohistochemistry and principal component analysis (PCA) analysis suggest that two functional networks are involved in these effects; one includes the lateral (LHb) and medial (mHb) habenula, dorsal raphe (DR) and ventral tegmental area (VTA), and the other consists of the dentate gyrus (DG), and prefrontal cortex (PFC). The results open up the possibility of using GAL(1-15) in combination with SSRIs as a novel strategy for treating MDD.