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1.  Depression after status epilepticus: behavioural and biochemical deficits and effects of fluoxetine 
Brain  2008;131(8):2071-2083.
Depression represents one of the most common comorbidities in patients with epilepsy. However, the mechanisms of depression in epilepsy patients are poorly understood. Establishment of animal models of this comorbidity is critical for both understanding the mechanisms of the condition, and for preclinical development of effective therapies. The current study examined whether a commonly used animal model of temporal lobe epilepsy (TLE) is characterized by behavioural and biochemical alterations involved in depression. Male Wistar rats were subjected to LiCl and pilocarpine status epilepticus (SE). The development of chronic epileptic state was confirmed by the presence of spontaneous seizures and by enhanced brain excitability. Post-SE animals exhibited increase in immobility time under conditions of forced swim test (FST) which was indicative of despair-like state, and loss of taste preference in saccharin solution consumption test which pointed to the symptomatic equivalence of anhedonia. Biochemical studies revealed compromised serotonergic transmission in the raphe-hippocampal serotonergic pathway: decrease of serotonin (5-HT) concentration and turnover in the hippocampus, measured by high performance liquid chromatography, and decrease of 5-HT release from the hippocampus in response to raphe stimulation, measured by fast cyclic voltammetry. Administration of fluoxetine (FLX, 20 mg/kg/day for 10 days) to naive animals significantly shortened immobility time under conditions of FST, and inhibited 5-HT turnover in the hippocampus. In post-SE rats FLX treatment led to a further decrease of hippocampal 5-HT turnover; however, performance in FST was not improved. At the same time, FLX reversed SE-induced increase in brain excitability. In summary, our studies provide initial evidence that post-SE model of TLE might serve as a model of the comorbidity of epilepsy and depression. The finding that behavioural equivalents of depression were resistant to an antidepressant medication suggested that depression in epilepsy might have distinct underlying mechanisms beyond alterations in serotonergic pathways.
doi:10.1093/brain/awn117
PMCID: PMC2587254  PMID: 18559371
comorbidity; depression; epilepsy; hippocampus; serotonin
2.  Comorbidity between epilepsy and depression: Experimental evidence for the involvement of serotonergic, glucocorticoid and neuroinflammatory mechanisms 
Epilepsia  2010;51(Suppl 3):110-114.
Summary
Depression represents one of the most common comorbidities of temporal lobe epilepsy (TLE), and has profound negative impact on the quality of life of TLE patients. However, causes and mechanisms of depression in TLE remain poorly understood, and its effective therapies are lacking. We examined whether a commonly used model of TLE in rats can be used as a model of comorbidity between epilepsy and depression suitable for both mechanistic studies and for the development mechanism-based antidepressant therapies. We established that animals which had been subjected to LiCl and pilocarpine status epilepticus (SE) and developed spontaneous recurrent seizures, exhibited set of impairments congruent with depressive state: behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo-pituitary adrenocortical (HPA) axis; compromised raphe-hippocampal serotonergic transmission. Pharmacological studies suggested that depressive impairments following SE develop as a result of the enhanced interleukin-1β signaling in the hippocampus, which leads to depression via inducing perturbations in the HPA axis and subsequent deficit in the raphe-hippocampal serotonergic transmission.
doi:10.1111/j.1528-1167.2010.02623.x
PMCID: PMC2909020  PMID: 20618414
Temporal lobe epilepsy; depression; comorbidity; serotonin; hypothalamo-pituitary-adrenocortical axis; interleukin-1β
3.  Comorbidity between epilepsy and depression: role of hippocampal interleukin-1β 
Neurobiology of disease  2009;37(2):461.
Depression is a frequent comorbidity of temporal lobe epilepsy (TLE); however its mechanisms remain poorly understood and effective therapies are lacking. Augmentation of hippocampal interleukin-1β (IL-1β) signaling may be a mechanistic factor of both TLE and clinical depression. We examined whether pharmacological blockade of hippocampal interleukin-1 receptor exerts antidepressant effects in an animal model of comorbidity between TLE and depression, which developed in Wistar rats following pilocarpine status epilepticus (SE). In post-SE animals, depression-like state was characterized by behavioral equivalents of anhedonia and despair; dysregulation of the hypothalamo-pituitary-adrenocortical axis; compromised raphe-hippocampal serotonergic transmission. Two-week long bilateral intrahippocampal infusion of human recombinant Interleukin-1 Receptor antagonist (IL-1ra) improved all of the examined depressive impairments, without modifying spontaneous seizure frequency and without affecting normal parameters in naïve rats. These findings implicate hippocampal IL-1β in epilepsy-associated depression, and provide a rationale for the introduction of IL-1β blockers in the treatment of depression in TLE.
doi:10.1016/j.nbd.2009.11.001
PMCID: PMC2818460  PMID: 19900553
Temporal lobe epilepsy; depression; comorbidity; brain inflammation; Interleukin-1β; hippocampus
4.  Plasticity of presynaptic and postsynaptic serotonin 1A receptors in an animal model of epilepsy – associated depression 
Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients’ quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo-pituitary-adrenocortical (HPA) axis and/or diminished raphe-hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin-1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naïve subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naïve and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naïve and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.
doi:10.1038/npp.2011.18
PMCID: PMC3077437  PMID: 21346733
Epilepsy; depression; comorbidity; serotonin 1A receptors; dorsal raphe; hypothalamo-pituitary-adrenocortical axis
5.  Plasticity of Presynaptic and Postsynaptic Serotonin 1A Receptors in an Animal Model of Epilepsy-Associated Depression 
Neuropsychopharmacology  2011;36(6):1305-1316.
Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo–pituitary–adrenocortical (HPA) axis and/or diminished raphe–hippocampal serotonergic transmission. We examined possible involvement of presynaptic and postsynaptic serotonin 1A (5-HT1A) receptors in epilepsy-associated depression. Based on their performance in the forced swim test (FST), post-SE animals were classified as those with moderate and severe depressive impairments. In moderately impaired rats, the activity of the HPA axis (examined using plasma corticosterone radioimmunoassay) was higher than in naive subjects, but the functional capacity of presynaptic 5-HT1A receptors (measured in raphe using autoradiography) remained unaltered. In severely depressed animals, both the activity of the HPA axis and the function of presynaptic 5-HT1A receptors were increased as compared with naive and moderately depressed rats. Pharmacological uncoupling of the HPA axis from raphe nucleus exerted antidepressant effects in severely impaired rats, but did not modify behavior in both naive and moderately depressed animals. Further, the function of postsynaptic 5-HT1A receptors was diminished in the hippocampus of post-SE rats. Pharmacological activation of postsynaptic 5-HT1A receptors improved depressive deficits in epileptic animals. We suggest that under the conditions of chronic epilepsy, excessively hyperactive HPA axis activates presynaptic 5-HT1A receptors, thus shifting the regulation of serotonin release in favor of autoinhibition. Downregulation of postsynaptic 5-HT1A receptors may further exacerbate the severity of epilepsy-associated depression.
doi:10.1038/npp.2011.18
PMCID: PMC3077437  PMID: 21346733
epilepsy; depression; comorbidity; serotonin 1A receptors; dorsal raphe; hypothalamo–pituitary–adrenocortical axis; mood / anxiety / stress disorders; serotonin; animal models; neurology; epilepsy; comorbidity; dorsal aphe; hippocampus; serotonin 1A receptors
6.  Different Emotional Disturbances in Two Experimental Models of Temporal Lobe Epilepsy in Rats 
PLoS ONE  2012;7(6):e38959.
Affective symptoms such as anxiety and depression are frequently observed in patients with epilepsy. The mechanisms of comorbidity of epilepsy and affective disorders, however, remain unclear. Diverse models are traditionally used in epilepsy research, including the status epilepticus (SE) model in rats, which are aimed at generating chronic epileptic animals; however, the implications of different SE models and rat strains in emotional behaviors has not been reported. To address this issue, we examined the emotional sequelae of two SE models of temporal lobe epilepsy (TLE) – the lithium-pilocarpine (LIP) model and the kainic acid (KA) model – in two different rat strains (Wistar and Sprague-Dawley), which differ significantly in the pattern and extent of TLE-associated brain lesions. We found differences between LIP- and KA-treated animals in tests for depression-like and anxiety-like behaviors, as well as differences in plasma corticosterone levels. Whereas only LIP-treated rats displayed increased motivation to consume saccharin, both SE models led to reduced motivation for social contact, with LIP-treated animals being particularly affected. Evaluation of behavior in the open field test indicated very low levels of anxiety in LIP-treated rats and a mild decrease in KA-treated rats compared to controls. After exposure to a battery of behavioral tests, plasma corticosterone levels were increased only in LIP-treated animals. This hyperactivity in the hypothalamus-pituitary-adrenocortical (HPA) axis was highly correlated with performance in the open field test and the social interaction test, suggesting that comorbidity of epilepsy and emotional behaviors might also be related to other factors such as HPA axis function. Our results indicate that altered emotional behaviors are not inherent to the epileptic condition in experimental TLE; instead, they likely reflect alterations in anxiety levels related to model-dependent dysregulation of the HPA axis.
doi:10.1371/journal.pone.0038959
PMCID: PMC3376131  PMID: 22720001
7.  Omega-3 Fatty Acid Deficiency Does Not Alter the Effects of Chronic Fluoxetine Treatment on Central Serotonin Turnover or Behavior in the Forced Swim Test in Female Rats 
Pharmacology, biochemistry, and behavior  2013;0:10.1016/j.pbb.2013.09.010.
While translational evidence suggests that long-chain omega-3 fatty acid status is positively associated with the efficacy of selective serotonin reuptake inhibitor drugs, the neurochemical mechanisms mediating this interaction are not known. Here we investigated the effects of dietary omega-3 (n-3) fatty acid insufficiency on the neurochemical and behavioral effects of chronic fluoxetine (FLX) treatment. Female rats were fed diets with (CON, n=56) or without (DEF, n=40) the n-3 fatty acids during peri-adolescent development (P21-P90), and one half of each group were administered FLX (10 mg/kg/d) for 30 d (P60-P90) prior to testing. In adulthood (P90), regional brain serotonin (5-HT) and 5-hydroxyindoleacetic (5-HIAA) concentrations, presynaptic markers of 5-HT neurotransmission, behavioral responses in the forced swim test (FST), and plasma FLX and norfluoxetine (NFLX) concentrations were investigated. Peri-adolescent n-3 insufficiency led to significant reductions in cortical docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (−25%, p≤0.0001) and DEF+FLX (−28%, p≤0.0001) rats. Untreated DEF rats exhibited significantly lower regional 5-HIAA/5-HT ratios compared with untreated CON rats, but exhibited similar behavioral responses in the FST. In both CON and DEF rats, chronic FLX treatment similarly and significantly decreased 5-HIAA concentrations and the 5-HIAA/5-HT ratio in the hypothalamus, hippocampus, and nucleus accumbens, brainstem tryptophan hydroxylase-2 mRNA expression, and immobility in the FST. While the FLX-induced reduction in 5-HIAA concentrations in the prefrontal cortex was significantly blunted in DEF rats, the reduction in the 5-HIAA/5-HT ratio was similar to CON rats. Although plasma FLX and NFLX levels were not significantly different in DEF and CON rats, the NFLX/FLX ratio was significantly lower in DEF+FLX rats. These preclinical data demonstrate that n-3 fatty acid deficiency does not significantly reduce the effects of chronic FLX treatment on central 5-HT turnover or behavior in the FST in female rats.
doi:10.1016/j.pbb.2013.09.010
PMCID: PMC3845450  PMID: 24090922
Omega-3 fatty acid; Docosahexaenoic acid; Fluoxetine; Serotonin; Female; Forced swim test
8.  Mesolimbic effects of the antidepressant fluoxetine in Holtzman rats, a genetic strain with increased vulnerability to stress 
Brain research  2011;1387:71-84.
This is the first metabolic mapping study of the effects of fluoxetine after learned helplessness training. Antidepressants are the most commonly prescribed medications, but the regions underlying treatment effects in affectively disordered brains are poorly understood. We hypothesized the antidepressant action of fluoxetine would produce adaptations in mesolimbic regions after two weeks of treatment. We used Holtzman rats, a genetic strain showing susceptibility to novelty-evoked hyperactivity and stress-evoked helplessness, to map regional brain metabolic effects caused by fluoxetine treatment. Animals underwent learned helplessness, and subsequently immobility time was scored in the forced swim test (FST). On the next day, animals began receiving two weeks of fluoxetine (5 mg/kg/day) or vehicle and were retested in the FST at the end of drug treatment. Antidepressant behavioral effects of fluoxetine were analyzed using a ratio of immobility during pre- and post-treatment FST sessions. Brains were analyzed for regional metabolic activity using quantitative cytochrome oxidase histochemistry as in our previous study using congenitally helpless rats. Fluoxetine exerted a protective effect against FST-induced immobility behavior in Holtzman rats. Fluoxetine also caused a significant reduction in the mean regional metabolism of the nucleus accumbens shell and the ventral hippocampus as compared to vehicle-treated subjects. Additional networks affected by fluoxetine treatment included the prefrontal-cingulate cortex and brainstem nuclei linked to depression (e.g. habenula, dorsal raphe and interpeduncular nucleus). We concluded that corticolimbic regions such as the prefrontal-cingulate cortex, nucleus accumbens, ventral hippocampus and key brainstem nuclei represent important contributors to the neural network mediating fluoxetine antidepressant action.
doi:10.1016/j.brainres.2011.02.080
PMCID: PMC3081853  PMID: 21376019
Cytochrome oxidase; Brain mapping; Depression; Fluoxetine; Antidepressant effect; Animal model
9.  Age differences in the impact of forced swimming test on serotonin transporter levels in lateral septum and dorsal raphe 
Background
Forced swimming test (FST) is an animal model which evaluates behavioral despair and the effect of antidepressants such as the selective serotonin reuptake inhibitors; the FST modifies the expression of some receptors related to antidepressant response, but it is not known whether serotonin transporter (SERT), their main target, is affected by this test in animals of different ages. Antidepressant response has shown age-dependent variations which could be associated with SERT expression. The aim of the present study was to analyze changes in the SERT immunoreactivity (SERT-IR) in dorsal raphe and lateral septum of male rats from different age groups with or without behavioral despair induced by their exposure to the FST, since these two structures are related to the expression of this behavior.
Methods
Prepubertal (24 PN), pubertal (40 PN), young adult (3–5 months) and middle-aged (12 months) male rats were assigned to a control group (non-FST) or depressed group (FST, two sessions separated by 24 h). Changes in SERT-IR in dorsal raphe and lateral septum were determined with immunofluorescence.
Results
Pubertal and middle-aged rats showed higher levels of immobility behavior compared to prepubertal rats on the FST. SERT-IR showed an age-dependent increase followed by a moderate decrease in middle-aged rats in both structures; a decreased in SERT-IR in lateral septum and dorsal raphe of pubertal rats was observed after the FST.
Conclusions
Age differences were observed in the SERT-IR of structures related to behavioral despair; SERT expression was modified by the FST in lateral septum and dorsal raphe of pubertal rats.
doi:10.1186/1744-9081-10-3
PMCID: PMC3922148  PMID: 24490994
Despair; Forced swimming test; Rats; Serotonin transporter; Age differences
10.  Interleukin-1beta Causes Fluoxetine Resistance in an Animal Model of Epilepsy-Associated Depression 
Neurotherapeutics  2012;9(2):477-485.
Depression represents a common comorbidity of epilepsy and is frequently resistant to selective serotonin reuptake inhibitors (SSRI). We tested the hypothesis that the SSRI resistance in epilepsy associated depression may be a result of a pathologically enhanced interleukin-1β (IL1-β) signaling, and consequently that the blockade of IL1-β may restore the effectiveness of SSRI. Epilepsy and concurrent depression-like impairments were induced in Wistar rats by pilocarpine status epilepticus (SE). The effects of the 2-week long treatment with fluoxetine, interleukin-1 receptor antagonist (IL-1ra), and their combination were examined using behavioral, biochemical, neuroendocrine, and autoradiographic assays. In post-SE rats, depression-like impairments included behavioral deficits indicative of hopelessness and anhedonia; the hyperactivity of the hypothalamo-pituitary-adrenocortical axis; the diminished serotonin output from raphe nucleus; and the upregulation of presynaptic serotonin 1-A (5-HT1A) receptors. Fluoxetine monotherapy exerted no antidepressant effects, whereas the treatment with IL-1ra led to the complete reversal of anhedonia and to a partial improvement of all other depressive impairments. Combined administration of fluoxetine and IL-1ra completely abolished all hallmarks of epilepsy-associated depressive abnormalities, with the exception of the hyperactivity of the hypothalamo-pituitary-adrenocortical axis, the latter remaining only partially improved. We propose that in certain forms of depression, including but not limited to depression associated with epilepsy, the resistance to SSRI may be driven by the pathologically enhanced interleukin-1β signaling and by the subsequent upregulation of presynaptic 5-HT1A receptors. In such forms of depression, the use of interleukin-1β blockers in conjunction with SSRI may represent an effective therapeutic approach.
Electronic supplementary material
The online version of this article (doi:10.1007/s13311-012-0110-4) contains supplementary material, which is available to authorized users.
doi:10.1007/s13311-012-0110-4
PMCID: PMC3337012  PMID: 22427156
Epilepsy; depression; comorbidity; cytokines; selective serotonin reuptake inhibitors
11.  Raphe-mediated signals control the hippocampal response to SRI antidepressants via miR-16 
Translational Psychiatry  2011;1(11):e56-.
Serotonin reuptake inhibitor (SRI) antidepressants such as fluoxetine (Prozac), promote hippocampal neurogenesis. They also increase the levels of the bcl-2 protein, whose overexpression in transgenic mice enhances adult hippocampal neurogenesis. However, the mechanisms underlying SRI-mediated neurogenesis are unclear. Recently, we identified the microRNA miR-16 as an important effector of SRI antidepressant action in serotonergic raphe and noradrenergic locus coeruleus (LC). We show here that miR-16 mediates adult neurogenesis in the mouse hippocampus. Fluoxetine, acting on serotonergic raphe neurons, decreases the amount of miR-16 in the hippocampus, which in turn increases the levels of the serotonin transporter (SERT), the target of SRI, and that of bcl-2 and the number of cells positive for Doublecortin, a marker of neuronal maturation. Neutralization of miR-16 in the hippocampus further exerts an antidepressant-like effect in behavioral tests. The fluoxetine-induced hippocampal response is relayed, in part, by the neurotrophic factor S100β, secreted by raphe and acting via the LC. Fluoxetine-exposed serotonergic neurons also secrete brain-derived neurotrophic factor, Wnt2 and 15-Deoxy-delta12,14-prostaglandin J2. These molecules are unable to mimic on their own the action of fluoxetine and we show that they act synergistically to regulate miR-16 at the hippocampus. Of note, these signaling molecules are increased in the cerebrospinal fluid of depressed patients upon fluoxetine treatment. Thus, our results demonstrate that miR-16 mediates the action of fluoxetine by acting as a micromanager of hippocampal neurogenesis. They further clarify the signals and the pathways involved in the hippocampal response to fluoxetine, which may help refine therapeutic strategies to alleviate depressive disorders.
doi:10.1038/tp.2011.54
PMCID: PMC3309472  PMID: 22833211
antidepressant; hippocampus; locus coeruleus; microRNA; neurogenesis; raphe
12.  Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression 
PLoS ONE  2011;6(7):e22133.
Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.
doi:10.1371/journal.pone.0022133
PMCID: PMC3132782  PMID: 21760962
13.  Antidepressant-Like Effects of Shuyusan in Rats Exposed to Chronic Stress: Effects on Hypothalamic-Pituitary-Adrenal Function 
This study was to investigate antidepressant activities of Shuyusan (a Chinese herb), using a rats model of depression induced by unpredictable chronic mild stress (UCMS). The administration groups were treated with Shuyusan decoction for 3 weeks and compared with fluoxetine treatment. In order to understand the potential antidepressant-like activities of Shuyusan, tail suspension test (TST) and forced swimming test (FST) were used as behavioral despair study. The level of corticotropin-releasing factor (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT) and hippocampus glucocorticoid receptor expression were examined. After modeling, there was a significant prolongation of immobility time in administration groups with the TST and FST. High-dose Shuyusan could reduce the immobility time measured with the TST and FST. The immobility time in high-dose herbs group and fluoxetine group was increased significantly compared with the model group. After 3 weeks herbs fed, the serum contents level of CRH, ACTH, and CORT in high-dose herb group was significantly decreased compared to the model group. The result indicated that Shuyusan had antidepressant activity effects on UCMS model rats. The potential antidepressant effect may be related to decreasing glucocorticoid levels activity, regulating the function of HPA axis, and inhibiting glucocorticoid receptor expression in hippocampus.
doi:10.1155/2012/940846
PMCID: PMC3449151  PMID: 23008744
14.  Inter-individual differences in novelty-seeking behavior in rats predict differential responses to desipramine in the forced swim test 
Psychopharmacology  2008;198(3):333-340.
Antidepressant medications are effective only in a subpopulation of patients with depression, and some patients respond to certain drugs but not others. The biological bases for these clinical observations remain unexplained. To investigate individual differences in response to antidepressants, we have examined the effects of the norepinephrine reuptake inhibitor desipramine (DMI) and the selective serotonin reutake inhibitor fluoxetine (FLU) in the forced swim test (FST) in rats that differ for their emotional behavior. After FST, animals with higher locomotor activity in a novel environment (HR) showed higher c-fos mRNA levels than their counterpart (LR) in the locus coeruleus (LC). No group differences in c-fos mRNA expression were present in the dorsal raphe nucleus or nucleus of the solitary tract (NTS). When behavioral effects of DMI or FLU were compared in HR vs. LR animals in the FST, DMI caused a significant decrease in immobility in LR animals only, while FLU caused a significant reduction in immobility regardless of the animals’ phenotype. Moreover, our results showed a decrease in FST-induced c-fos mRNA levels in prefrontal cortex (PFC) and paraventricular nucleus of the hypothalamus (PVN) in LR but not HR animals after DMI treatment, and a significant decrease in FST-induced corticosterone secretion in DMI-treated LR but not HR rats. Taken together, our results suggest that the HR-LR model is a useful tool to investigate individual differences in responses to norepinephrine reutake inhibitors (NRIs) and that a diffential activation of PFC and/or PVN could underlie some of the inter-individual differences in NRIs efficacy.
doi:10.1007/s00213-008-1126-7
PMCID: PMC3101263  PMID: 18438645
15.  Impaired emotional-like behavior and serotonergic function during protracted abstinence from chronic morphine 
Biological psychiatry  2010;69(3):236-244.
Background
Opiate abuse is a chronic relapsing disorder and maintaining prolonged abstinence remains a major challenge. Protracted abstinence is characterized by lowered mood and clinical studies show elevated co-morbidity between addiction and depressive disorders. At present, their relationship remains unclear and has been little studied in animal models. Here we investigated emotional alterations during protracted abstinence, in mice with a history of chronic morphine exposure.
Methods
C57BL6J mice were exposed to a chronic intermittent escalating morphine regimen (20-100mg/kg). Physical dependence (naloxone-precipitated withdrawal), despair-related (tail suspension test) and social behaviors were examined after 1 or 4 weeks of abstinence. Stress hormones and forebrain bioamine levels were analyzed at the end of morphine regimen and after 4 weeks abstinence. Finally, we examined the effects of chronic fluoxetine during abstinence on morphine-induced behavioral deficits.
Results
Acute naloxone-induced withdrawal was clearly measurable after 1 week, and became undetectable after 4 weeks. In contrast, social and despair-related were unchanged after 1 week, but low sociability and despair-like behavior became significant after 4 weeks. Chronic morphine regimen increased both corticosterone levels and forebrain serotonin turnover, but only serotonergic activity in the dorsal raphe remained impaired after 4 weeks. Remarkably, chronic fluoxetine prevented depressive-like behavioral deficits in 4-week abstinent mice.
Conclusions
During protracted abstinence, the immediate consequences of morphine exposure attenuate while fluoxetine-sensitive emotional alterations strengthen with time. Our study establishes a direct link between morphine abstinence and depressive-like symptoms, and strongly suggests that serotonin dysfunction represents a main mechanism contributing to mood disorders in opiate abstinence.
doi:10.1016/j.biopsych.2010.08.021
PMCID: PMC3014999  PMID: 20947067
Opiates; incubation; depression; serotonin; fluoxetine; dorsal raphe
16.  Forced swim test induces divergent global transcriptomic alterations in the hippocampus of high versus low novelty-seeker rats 
Human Genomics  2014;8(1):4.
Background
Many neuropsychiatric disorders, including stress-related mood disorders, are complex multi-parametric syndromes. Susceptibility to stress and depression is individually different. The best animal model of individual differences that can be used to study the neurobiology of affect regards spontaneous reactions to novelty. Experimentally, when naive rats are exposed to the stress of a novel environment, they display a highly variable exploratory activity and are classified as high or low responders (HR or LR, respectively). Importantly, HR and LR rats do not seem to exhibit a substantial differentiation in relation to their ‘depressive-like’ status in the forced swim test (FST), a widely used animal model of ‘behavioral despair’. In the present study, we investigated whether FST exposure would be accompanied by phenotype-dependent differences in hippocampal gene expression in HR and LR rats.
Results
HR and LR rats present a distinct behavioral pattern in the pre-test session but develop comparable depressive-like status in the second FST session. At 24 h following the second FST session, HR and LR rats (stressed and unstressed controls) were sacrificed and hippocampal samples were independently analyzed on whole rat genome Illumina arrays. Functional analysis into pathways and networks was performed using Ingenuity Pathway Analysis (IPA) software. Notably, hippocampal gene expression signatures between HR and LR rats were markedly divergent, despite their comparable depressive-like status in the FST. These molecular differences are reflected in both the extent of transcriptional remodeling (number of significantly changed genes) and the types of molecular pathways affected following FST exposure. A markedly higher number of genes (i.e., 2.28-fold) were statistically significantly changed following FST in LR rats, as compared to their HR counterparts. Notably, genes associated with neurogenesis and synaptic plasticity were induced in the hippocampus of LR rats in response to FST, whereas in HR rats, FST induced pathways directly or indirectly associated with induction of apoptotic mechanisms.
Conclusions
The markedly divergent gene expression signatures exposed herein support the notion that the hippocampus of HR and LR rats undergoes distinct transcriptional remodeling in response to the same stress regimen, thus yielding a different FST-related ‘endophenotype’, despite the seemingly similar depressive-like phenotype.
doi:10.1186/1479-7364-8-4
PMCID: PMC3941591  PMID: 24568636
Stress; Gene expression; Rats; Depression; Individual differences; Hippocampus; FST; Neurogenesis; Neuroplasticity; Apoptosis
17.  Antidepressant-like effects of the aqueous macerate of the bulb of Gladiolus dalenii Van Geel (Iridaceae) in a rat model of epilepsy-associated depression 
Background
In Cameroonian traditional medicine various extracts of Gladiolus dalenii Van Geel (Iridaceae) have been used as a cure for various ailments that include headaches, digestive problems, muscle and joint aches, and some central nervous system disorders such as epilepsy, schizophrenia and mood disorders. Owning to this background, the aim of the study was to investigate whether an aqueous macerate of the bulb of Gladiolus dalenii has any antidepressant activity focusing specifically on depression-like behaviours associated with epilepsy.
Method
We used the combined administration of atropine and pilocarpine to rats as our animal model of epilepsy. The forced swim test and spontaneous locomotor activity in the open field test were the two tools used to assess the presence of depression-like behaviour in epileptic and control animals. The following depression-related parameters were determined: plasma ACTH, plasma corticosterone, adrenal gland weight and hippocampal levels of brain-derived neurotrophic factor (BDNF). The effects of Gladiolus dalenii were compared to that of fluoxetine.
Results
Our results showed that we had a valid animal model of epilepsy-induced depression as all 3 measures of construct, predictive and face validity were satisfied. The data indicated that Gladiolus dalenii significantly reduced the immobility times in the forced swim test and the locomotor activity as assessed in the open field. A similar pattern was observed when the HPA axis parameters were analysed. Gladiolus dalenii significantly reduced the levels of ACTH, corticosterone, but not the adrenal gland weight. Gladiolus dalenii significantly increased the level of BDNF in the hippocampus. In all parameters measured the effects of Gladiolus dalenii were significantly greater than those of fluoxetine.
Conclusion
The results show that Gladiolus dalenii has antidepressant-like properties similar to those of fluoxetine in epilepsy-associated depressive states. The antidepressant activity of Gladiolus dalenii is likely to be mediated by restoring the activity of the HPA axis and increasing the levels of BDNF in the hippocampus.
doi:10.1186/1472-6882-13-272
PMCID: PMC3854025  PMID: 24138845
Depression; Epilepsy; HPA axis; BDNF; Gladiolus dalenii
18.  Effect of Saraswatarishta in animal models of behavior despair 
Background:
Saraswatarishta (SA) is a herbo-mineral formulation consisting of 18 plants some of which are Medhyarasayanas. It has been claimed to be useful in treating central nervous system disorders.
Objective:
To evaluate antidepressant effect of ‘Saraswatarishta’(SA) alone and in combination with imipramine and fluoxetine in animal models of depression.
Materials and Methods:
After obtaining IAEC permission, 144 rats (n = 36/part) were randomized into 6 groups- Group 1: Distilled water (1 mL), Group 2: Imipramine (30 mg/kg), Group 3: Fluoxetine (10 mg/kg), Group 4: SA (1.8 mL/kg), Group 5: Imipramine + SA, Group 6: Fluoxetine + SA. Effects of study drugs were evaluated in forced swim test (FST) with single exposure to FST (Part 1) and repeated exposure for 14 days (Part 2). In Part 3, reserpine was used with FST and effects of study drugs were evaluated against single exposure to FST. Same model was used with repeated exposures to FST (Part 4). In each part, rats were subjected to open field test (OFT) for 5 min prior to final FST. The variables measured: Immobility time in FST; line crossing, rearing and defecation in the OFT.
Results:
In all four parts, individual drugs and combinations thereof produced significant decrease in immobility time as compared to control, and extent of decrease was comparable amongst these groups. However, values for combination of fluoxetine with SA group were found to be lesser than that for individual agents in Parts 2 and 3. Combination of SA with imipramine did not enhance its anti-depressant effect in any of the parts. OFT findings did not vary significantly amongst the study groups.
Conclusion:
Decreased immobility in FST and absence of generalized stimulation or depression of motor activity in OFT point towards potential antidepressant effect of Saraswatarishta. Its co-administration with fluoxetine showed more promising effects.
doi:10.4103/0975-9476.140469
PMCID: PMC4204283  PMID: 25336844
Depression; forced swimming test; reserpine; saraswatarishta
19.  Alzheimer’s disease and epilepsy: insight from animal models 
Future neurology  2012;7(2):177-192.
Alzheimer’s disease (AD) and epilepsy are separated in the medical community, but seizures occur in some patients with AD, and AD is a risk factor for epilepsy. Furthermore, memory impairment is common in patients with epilepsy. The relationship between AD and epilepsy remains an important question because ideas for therapeutic approaches could be shared between AD and epilepsy research laboratories if AD and epilepsy were related. Here we focus on one of the many types of epilepsy, temporal lobe epilepsy (TLE), because patients with TLE often exhibit memory impairment, depression and other comorbidities that occur in AD. Moreover, the seizures that occur in patients with AD may be nonconvulsive, which occur in patients with TLE. Here we first compare neuropathology in TLE and AD with an emphasis on the hippocampus, which is central to both AD and TLE research. Then we compare animal models of AD pathology with animal models of TLE. Although many aspects of the comparisons are still controversial, there is one conclusion that we suggest is clear: some animal models of TLE could be used to help address questions in AD research, and some animal models of AD pathology are bona fide animal models of epilepsy.
doi:10.2217/fnl.12.8
PMCID: PMC3378058  PMID: 22723738
amyloid precursor protein; dentate gyrus; hilus; mossy fiber sprouting; neurodegeneration; presenilin-1; seizure; temporal lobe
20.  Toluene Induces Depression-Like Behaviors in Adult Mice 
Toxicological Research  2010;26(4):315-320.
It has been clinically reported that toluene causes mental depression in humans. However, the detrimental effects of toluene exposure on brain function and the relation between features of mental depression and toluene exposure are poorly understood. This study evaluated depression-like behaviors in adult C57BL/6 mice after administration of toluene, and elucidated the effects of classical antidepressants on the depression-like behaviors. For the estimation of depression-like behaviors, tail suspension test (TST) and forcedswim test (FST) were performed 1, 4 and 16 days after toluene (0~1000 mg/kg bw) treatment. In addition, classical antidepressants such as fluoxetine (FLX, 20 mg/kg bw) and imipramine (IMI, 40 mg/kg bw) were administered 12 h and 1 h before the tests. In the TST and FST, toluene-treated mice exhibited a longer duration of immobility than vehicle-treated mice 1 and 4 days after toluene treatment. The depression-like behaviors were significantly reversed by FLX and IMI. The weight of the adrenal gland and the size of adrenocortical cells were significantly higher in toluene-treated mice compared to vehicle-treated controls. It is suggested that acute toluene exposure of adult mice is sufficiently detrimental to induce depression. In addition, this study has established a mouse model for a depressive state induced by toluene treatment.
doi:10.5487/TR.2010.26.4.315
PMCID: PMC3834495  PMID: 24278539
Toluene; Depression; Behavior; Adrenal gland; Animal model
21.  EFFECTS OF NICOTINE ON DEPRESSIVE-LIKE BEHAVIOR AND HIPPOCAMPAL VOLUME OF FEMALE WKY RATS 
The observed high incidence of smoking amongst depressed individuals has led to the hypothesis of ‘self medication” with nicotine in some of these patients. The inbred Wistar-Kyoto (WKY) rats exhibit depressive-like characteristics as evidenced by exaggerated immobility in the forced swim test (FST). One aim of this study was to investigate whether nicotine may have an antidepressant-like effect in these animals. Moreover, because of human postmortem studies indicating a reduction of the hippocampus volume in depressed patients, it was of interest to determine whether such an anatomical anomaly may also be manifested in WKY rats and whether it would be affected by chronic nicotine treatment. Adult female WKY and their control Wistar rats were administered nicotine consecutively (0.2 mg/kg, ip, once or twice daily for 14 days) and their activity in an open field, as well as their immobility in FST were assessed either 15 min or 18 hr after the last injection. Another set of animals was treated twice daily with 0.2 mg/kg nicotine for 14 days and sacrificed on day 15 for stereological evaluation of the hippocampal volume. When tested 15 min after the last injection, once or twice daily nicotine exacerbated the immobility in the FST in WKY rats only. When tested 18 hr after the last injection, only twice daily nicotine treatment resulted in less immobility in the FST in WKY rats. Open field locomotor activity was not affected by any nicotine regimen. WKY rats had significantly less hippocampal volume (approximately 20%) than Wistar rats which was not altered by nicotine. These findings further validate the use of WKY rats as an animal model of human depression and signify the importance of inherent genetic differences in final behavioral outcome of nicotine.
doi:10.1016/j.pnpbp.2009.09.024
PMCID: PMC2814982  PMID: 19800382
WKY rats; Depression; Hippocampus; Nicotine; Forced Swim Test; Stereology
22.  Concise Review: Prospects of Stem Cell Therapy for Temporal Lobe Epilepsy 
Stem cells (Dayton, Ohio)  2007;25(10):2396-2407.
Certain regions of the adult brain have the ability for partial self-repair after injury through production of new neurons via activation of neural stem/progenitor cells (NSCs). Nonetheless, there is no evidence yet for pervasive spontaneous replacement of dead neurons by newly formed neurons leading to functional recovery in the injured brain. Consequently, there is enormous interest for stimulating endogenous NSCs in the brain to produce new neurons or for grafting of NSCs isolated and expanded from different brain regions or embryonic stem cells into the injured brain. Temporal lobe epilepsy (TLE), characterized by hyperexcitability in the hippocampus and spontaneous seizures, is a possible clinical target for stem cell-based therapies. This is because these approaches have the potential to curb epileptogenesis and prevent chronic epilepsy development and learning and memory dysfunction after hippocampal damage related to status epilepticus or head injury. Grafting of NSCs may also be useful for restraining seizures during chronic epilepsy. The aim of this review is to evaluate current knowledge and outlook pertaining to stem cell-based therapies for TLE. The first section discusses the behavior of endogenous hippocampal NSCs in human TLE and animal models of TLE and evaluates the role of hippocampal neurogenesis in the pathophysiology and treatment of TLE. The second segment considers the prospects for preventing or suppressing seizures in TLE using exogenously applied stem cells. The final part analyzes problems that remain to be resolved before initiating clinical application of stem cell-based therapies for TLE.
doi:10.1634/stemcells.2007-0313
PMCID: PMC3612506  PMID: 17600108
Temporal lobe epilepsy; Adult neurogenesis; Dentate gyrus; Epilepsy; Hippocampal stem cells Hippocampal progenitors; Neural stem cells; Stem cell grafts
23.  Rhythm and blues: animal models of epilepsy and depression comorbidity 
Biochemical pharmacology  2012;85(2):135-146.
Clinical evidence shows a strong, bidirectional comorbidity between depression and epilepsy that is associated with decreased quality of life and responsivity to pharmacotherapies. At present, the neurobiological underpinnings of this comorbidity remain hazy. To complicate matters, anticonvulsant drugs can cause mood disturbances, while antidepressant drugs can lower seizure threshold, making it difficult to treat patients suffering from both depression and epilepsy. Animal models have been created to untangle the mechanisms behind the relationship between these disorders and to serve as screening tools for new therapies targeted to treat both simultaneously. These animal models are based on chemical interventions (e.g. pentylenetetrazol, kainic acid, pilocarpine), electrical stimulations (e.g. kindling, electroshock), and genetic/selective breeding paradigms (e.g. Genetically Epilepsy-Prone Rats (GEPRs), Genetic Absence Epilepsy Rat from Strasbourg (GAERS), WAG/Rij rats, Swim Lo-Active rats (SwLo)). Studies on these animal models point to some potential mechanisms that could explain epilepsy and depression comorbidity, such as various components of the dopaminergic, noradrenergic, serotonergic, and GABAergic systems, as well as key brain regions, like the amygdala and hippocampus. These models have also been used to screen possible therapies. The purpose of the present review is to highlight the importance of animal models in research on comorbid epilepsy and depression and to explore the contributions of these models to our understanding of the mechanisms and potential treatments for these disorders.
doi:10.1016/j.bcp.2012.08.016
PMCID: PMC4116104  PMID: 22940575
Epilepsy; Depression; Animal Model; Comorbidity
24.  Acute hypoglycemia causes depressive-like behaviors in mice 
Metabolism  2011;61(2):229-236.
Objective
Reports in humans advocate a link between hypoglycemia and altered mood. Such observations, however, have not been mechanistically explored. Here we examined depressive-like behaviors in mice resulting from acute hypoglycemia.
Materials/Methods
Mice were fasted for 12 h then administered intraperitoneal (IP) insulin to induce a blood glucose nadir of 50 mg/dl at 0.75 h after injection which by 2 h post-injection had returned to normal. The behaviors of locomotion, forced swim, saccharin preference and novel object recognition were subsequently examined.
Results
Mice made hypoglycemic showed depressive-like behaviors 24 h after resolution of hypoglycemia as evidenced by increased immobility in the forced swim test (FST) and reduced saccharin preference. Movement and memory were not impacted by hypoglycemia 24 h after its resolution. By 48 h post hypoglycemia, depressive-like behaviors resolved. In contrast, neither peripheral insulin administration without resultant hypoglycemia nor intracerebroventricular (ICV) insulin administration altered performance in the FST. The antidepressants fluoxetine and desipramine prevented hypoglycemia-induced immobility in the FST as did the anti-adrenergic agents phentolamine, metoprolol and butoxamine. Epinephrine and norepinephrine administration caused increased immobility in the FST at 24 h post administration which subsequently resolved by 48 h.
Conclusions
These data indicate that in mice acute hypoglycemia through adrenergic pathways caused depressive-like behaviors that exist well beyond the resolution of hypoglycemia.
doi:10.1016/j.metabol.2011.06.013
PMCID: PMC3245368  PMID: 21820138
insulin; forced swim test; saccharin preference test; antidepressants; catecholamines
25.  ANTIDEPRESSANT-LIKE EFFECTS OF LOW KETAMINE DOSE IS ASSOCIATED WITH INCREASED HIPPOCAMPAL AMPA/NMDA RECEPTOR DENSITY RATIO IN FEMALE WISTAR-KYOTO RATS 
Neuroscience  2012;213:72-80.
Preclinical as well as limited clinical studies indicate that ketamine, a non-competitive glutamate NMDA receptor antagonist, may exert a quick and prolonged antidepressant effect. It has been postulated that ketamine action is due to inhibition of NMDA and stimulation of AMPA receptors. Here, we sought to determine whether ketamine would exert antidepressant effects in Wistar-Kyoto (WKY) rats, a putative animal model of depression and whether this effect would be associated with changes in AMPA/NMDA receptor densities in the hippocampus. Adult female WKY rats and their control Wistar rats were subjected to acute and chronic ketamine doses and their locomotor activity (LMA) and immobility in the forced swim test (FST) were evaluated. Hippocampal AMPA and NMDA receptor densities were also measured following a chronic ketamine dose. Ketamine, both acutely (0.5–5.0 mg/kg ip) and chronically (0.5–2.5 mg/kg daily for 10 days) resulted in a dose-dependent and prolonged decrease in immobility in the FST in WKY rats only, suggesting an antidepressant-like effect in this model. Chronic treatment with an effective dose of ketamine also resulted in an increase in AMPA/NMDA receptor density ratio in the hippocampus of WKY rats. LMA was not affected by any ketamine treatment in either strain. These results indicate a rapid and lasting antidepressant-like effect of a low ketamine dose in WKY rat model of depression. Moreover, the increase in AMPA/NMDA receptor density in hippocampus could be a contributory factor to behavioral effects of ketamine. These findings suggest potential therapeutic benefit in simultaneous reduction of central NMDA and elevation of AMPA receptor function in treatment of depression.
doi:10.1016/j.neuroscience.2012.03.052
PMCID: PMC3367052  PMID: 22521815
Depression; Ketamine; NMDA Receptor; AMPA Receptor; Hippocampus; WKY Rats

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