Bulbectomized Rat Model Of Depression Research Articles

High-frequency ultrasound exposure improves depressive-like behavior in an olfactory bulbectomized rat model of depression.

ObjectivesAccording to previous studies, ultrasound exposure appears to be a noninvasive method for modulating brain activity related to cognition and consciousness; however, its effects on emotional states remain unclear. Therefore, an animal model is required in which the effects and effect mechanisms of ultrasound exposure can be investigated. Thus, we used olfactory bulbectomized rats as an animal model of depression and investigated their emotional state following ultrasound exposure.MethodsIn male Wistar/ST olfactory bulbectomized rats, hyperemotionality was evaluated according to hyperemotionality scoring and the scores before and after 24-h ultrasound exposure were compared. Elevated plus maze (EPM) tests were also conducted after 24-h ultrasound exposure, and blood samples were collected in which plasma corticosterone concentrations were measured.ResultsFollowing exposure to high-frequency (~50 kHz) ultrasound vocalizations (USVs) associated with the pleasant emotions of rats, the hyperemotionality scores of olfactory bulbectomized rats were significantly reduced. Additionally, the latency of the first entry into the open arm of the EPM was significantly decreased in USV-exposed olfactory bulbectomized rats, as were their plasma corticosterone levels. Furthermore, artificial ultrasound (50 kHz) at a similar frequency to that of USV also significantly decreased the hyperemotionality score of olfactory bulbectomized rats.ConclusionsUltrasound exposure improved depressive-like behavior in olfactory bulbectomized rats and reduced their plasma corticosterone levels. Thus, we recommend the use of olfactory bulbectomized rats as an animal model for investigating the effects and effect mechanisms of ultrasound exposure.

Upregulated arachidonic acid signalling in the olfactory bulbectomized rat model of depression

The olfactory bulbectomized rat is an animal model of depression with a number of neurochemical, neuroendocrinological and behavioural features resembling human depression. Arachidonic acid (AA) is a second messenger released from the neuronal membrane phospholipids following the stimulation of the receptors coupled with G-proteins to the cytosolic phospholipase A (cPLA 2) signalling pathway. The signalling of several neurotransmitter systems which are deregulated in OBX rats (serotonergic, dopaminergic, cholinergic, and glutamatergic) converges on the cPLA 2 signalling pathway. The aim of the present study was to assess the incorporation coefficient k* [ml/g/s] of AA in a large number of brain regions in the OBX rat, as a parameter reflecting AA turnover. Male Sprague–Dawley rats (160–200 g) were randomly assigned into an intact Sprague–Dawley (SPD) group, a Sham-operated (SHAM) group or an olfactory bulbectomized (OBX) group ( n = 5 per group). Two weeks following the surgeries (SHAM and OBX rats) or without any prior intervention (SPD rats), the k* was measured using [1- 14C] AA autoradiography. Two-way ANOVA followed by the Newman–Keuls test revealed the following: (1) significantly increased AA turnover in the OBX rats, relative to the SHAM rats, in 17 out of 27 assessed brain regions; and (2) no significant differences in AA turnover between the SHAM and the SPD rats. The results suggest the upregulation of one or more neurotransmitter systems or receptors acting through the PLA 2 signalling pathway, or the components of the cPLA 2 signalling system itself. Taken together with the previous measurements, one can conclude that this elevation is likely related to upregulation in the brain serotonergic system because of the elevated 5-HT synthesis of the OBX rats.

Increased Phospholipase A2 Activity and Inflammatory Response But Decreased Nerve Growth Factor Expression in the Olfactory Bulbectomized Rat Model of Depression: Effects of Chronic Ethyl-Eicosapentaenoate Treatment

An increased inflammatory response and deficient synthesis of neurotrophic factors (NTFs) may contribute to the etiology of depression. However, the interrelationship between inflammation and NTFs is unknown. Recently, ethyl-eicosapentaenoate (EPA) has been used to treat depression. The mechanism by which EPA benefits depression is also unclear. Using the olfactory bulbectomized (OB) rat model of depression, this study evaluated two pathways from bulbectomy to the induction of depression-like changes (the inflammation-hypothalamic-pituitary-adrenal axis-stress response pathway and inflammation-nerve growth factor-memory pathway) and the effect of EPA on these pathways. When compared with sham-operated rats fed a control diet, significantly increased locomotor and rearing activities in an "open field," impaired memory in the Morris water maze, increased expression of corticotrophin-releasing factor (CRF), and increased secretion of corticosterone were found in OB rats. mRNA expression of nerve growth factor (NGF) was significantly lower in the hippocampus, and phospholipase A2 (PLA2) was higher in the hypothalamus; this change was associated with increased interleukin-1beta (IL-1beta) and prostaglandin E2 (PGE2) in the serum and brain. EPA treatments normalized these behavioral impairments and reduced CRF expression and corticosterone secretion. EPA also reduced serum concentrations of IL-1beta and PGE2, but reversed NGF reduction. Similar to the effects of EPA, the anti-inflammatory drug celecoxib significantly reduced blood PGE2, IL-1beta, and corticosterone concentrations and increased NGF expression in OB rats. Furthermore, anti-NGF treatment blocked EPA effects on behavior. These results suggest that an interaction exists between inflammation and NGF in the depression model. EPA may improve depression via its anti-inflammation properties and the upregulation of NGF.

Region-specific dysregulation of allopregnanolone brain content in the olfactory bulbectomized rat model of depression

Allopregnanolone (ALLO) is one of the most potent positive endogenous allosteric modulators of the type A γ-aminobutyric acid (GABA A) receptors. While the robust anxiolytic profile of ALLO has been extensively characterized in rodents and its antidepressant-like effect was recently demonstrated in mice, there have been only few reports on alterations of brain ALLO levels in putative animal models of depression and anxiety. Removal of the olfactory bulbs of rats produces one of the most predictive animal models with which to screen for drugs with potential antidepressant activity following repeated treatment. We therefore investigated whether the olfactory bulbectomized (OB) rat model of depression may be associated with alterations of ALLO levels in whole brain tissue and in different brain regions. We determined ALLO levels in whole brain, amygdala, frontal cortex, hippocampus, and whole cerebral cortex of OB or sham-operated rats at 7, 14, or 28 days following bulbectomy or sham surgery. We observed a significant increase of whole brain ALLO content at 7 and 28 days post-surgery in the OB rats. At days 7 and 14 following olfactory bulb removal, ALLO levels were significantly decreased in amygdala and frontal cortex and significantly increased in whole cerebral cortex. In the hippocampus we observed only a tendency for decreased ALLO levels at day 14. Our data indicates a strong region-specific dysregulation of ALLO homeostasis in brains of OB rats which may contribute to the formation of the bulbectomy syndrome via a sustained reduction in physiological GABA-ergic tone in amygdala and frontal cortex.

Effects of reboxetine and sertraline treatments alone and in combination on the binding properties of cortical NMDA and beta1-adrenergic receptors in an animal model of depression.

Changes to the binding properties of cortical N-methyl-D-aspartic acid (NMDA) and beta-adrenergic receptors have both been reported as potential indicators of antidepressant activity. In the present investigation we examined the effects of the noradrenaline reuptake inhibitor, reboxetine, the serotonin reuptake inhibitor, sertraline, alone and in combination on the binding properties of cortical NMDA receptors and cortical beta1-adrenoceptors following 14 days of treatment in the olfactory bulbectomized rat model of depression. A decrease in the potency of glycine to displace the strychnine insensitive glycine antagonist [3H] 5,7 dichlorokynurenic acid (5,7 DCKA) was observed in cortical homogenates of OB rats when compared to sham-operated controls. Similarly, treatment with the combination of reboxetine and sertraline for 14 days produced a decrease in the potency of glycine when compared to vehicle treated controls. By contrast neither olfactory bulbectomy or drug treatment significantly altered basal or glycine enhanced binding of the non-competitive NMDA antagonist [3H] MK-801 in cortical homogenates. Reboxetine alone, and in combination with sertraline, down-regulated [3H]-CGP 12177 (a selective beta-adrenoceptor antagonist) binding in both OB and sham-operated animals. The lack of a bulbectomy effect in the [3H] CGP-12177 binding assay, and the fact that olfactory bulbectomy and antidepressant treatments produce a similar change to the potency of glycine at the NMDA receptor, suggests that these tests do not provide a neurochemical marker for either the behavioral hyperactivity deficit or antidepressant response in the model.

An in-vivo magnetic resonance imaging study of the olfactory bulbectomized rat model of depression

The olfactory bulbectomized (OB) rat is a well-accepted animal model of depression. The present magnetic resonance imaging (MRI) investigation demonstrates alterations in signal intensities in cortical, hippocampal, caudate and amygdaloid regions in OB animals, but not in sham operated controls. Ventricular enlargement was also evident in OB animals. These alterations have implications with regard to the face and construct validity of this model.

Metyrapone displays antidepressant-like properties in preclinical paradigms.

A possible involvement of glucocorticoids in the aetiology of depression is suggested by commonly reported hypothalamo-pituitary-adrenocortical (HPA) axis abnormalities in depressed patients, the modulation of the HPA axis by antidepressant drugs and clinical reports of antidepressant efficacy with antiglucocorticoid agents. The effects of treatment with metyrapone, a glucocorticoid synthesis inhibitor, and the tricyclic antidepressant, desipramine, in two rodent models of depression, namely the forced swim test and olfactory bulbectomized (OB) rat, were investigated. In addition, the effect of chronic metyrapone and desipramine treatments on the hypothermic response to a challenge with the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) was assessed. There is experimental evidence to suggest that attenuation of the hypothermic response to this agonist occurs following chronic antidepressant treatment. In the forced swim test, metyrapone (50 mg/kg) and desipramine (10 mg/kg) significantly reduced the immobility time. In the olfactory bulbectomized rat model of depression, chronic administration (14 days) of metyrapone (50 mg/kg b.i.d.) and desipramine (5 mg/kg b.i.d.) attenuated the OB-related hyperactivity in a novel stressful environment. Chronic metyrapone treatment (50 mg/kg b.i.d.) attenuated the hypothermic response to an acute challenge with 8-OH-DPAT (0.05 mg/kg s.c.), indicating a change to the sensitivity of 5-HT1A receptors. These preclinical tests demonstrate an antidepressant-like profile for metyrapone. Further exploration of the therapeutic potential and possible mechanism of action of glucocorticoid antagonism in depression is warranted.

Olfactory bulbectomy increases prepro-enkephalin mRNA levels in the ventral striatum in rats

The effects of bilateral olfactory bulbectomy (OBX) on prepro-enkephalin, thyrotropin-releasing hormone, and D-2 receptor mRNA levels in the ventral striatum were examined by in situ hybridization histochemistry. Pre- pro-enkephalin mRNA levels were significantly increased in the olfactory tubercle (OT), but not in the nucleus accumbens, 14 days following bilateral OBX. Levels of D-2 receptor mRNA were also increased in the OT, though to a lesser degree. Prepro-thyrotropin-releasing hormone mRNA was unaffected by OBX. A separate experiment revealed no effect of OBX on enkephalin gene expression 7 days following surgery but a comparable elevation in pre- pro-enkephalin mRNA 14 and 28 days post-surgery. The findings are consistent with previously-reported effects of dopamine lesions on striatal gene expression, suggesting that the observed effects may be mediated by deafferentation-induced alterations in dopaminergic transmission in the OT. Altered dopaminergic function in the OT may be particularly relevant to the ‘anhedonia’ that has been associated with the olfactory bulbectomized rat model of depression.

The Determination of the Optimal Dose of Milnacipran in the Olfactory Bulbectomized Rat Model of Depression

Olfactory bulbectomy (OB) is associated with a variety of behavioral abnormalities such as hyperactivity in the “open-field” test. Previous studies have shown that chronic administration of antidepressants can reverse this behavioral deficit. The activity of milnacipran (20, 30, and 40 mg/kg, PO bid) administered in two equally divided doses twice daily was assessed in the olfactory bulbectomized rat model of depression. It was found that chronic treatment with milnacipran at the doses of 30 and 40 mg/kg, but not 20 mg/kg, attenuated the lesion-induced hyperactivity of the OB rat in the “open-field” test following 14 days of treatment. In the step-through passive avoidance test, administration of milnacipran at doses of 20, 30, and 40 mg/kg had no effect on the performance deficit associated with olfactory bulbectomy. Olfactory bulbectomy reduced the concentration of noradrenaline (NA) in the frontal cortex. However, chronic milnacipran treatment did not significantly alter this deficit. It is concluded that milnacipran, when administered chronically at doses of 30 and 40 mg/kg, are effective at reversing the “open-field” deficit associated with olfactory bulbectomy, and that a dose of 30 mg/kg is an optimal dose.

Behavioural and Neurochemical Effects of Dizocilpine in the Olfactory Bulbectomized Rat Model of Depression

The activity of dizocilpine (MK-801; 0.1 and 0.3 mg/kg) administered once daily intraperitoneally (IP) was assessed in the olfactory bulbectomized rat model of depression. Olfactory bulbectomy (OB) is associated with a variety of behavioural abnormalities, such as hyperactivity in the “open field” test. Previous studies have shown that chronic administration of antidepressants can reverse this behavioural deficit. In the present study, chronic treatment with 0.1 and 0.3 mg/kg of dizocilpine (IP) antagonized the lesion-induced hyperactivity in the “open field” test. Acute treatment with dizocilpine was associated with an increase in locomotor activity in both sham-operated and OB rats, with a greater response in the sham-operated group. Following chronic treatment, this hyperactivity was found to be greater in the OB-treated animals compared with the sham-treated animals. Olfactory bulbectomy reduced serotonin (5-HT), noradrenaline (NA), and dopamine (DA) concentrations in the frontal cortex. Chronic dizocilpine administration did not alter the 5-HT or NA response. In contrast, chronic administration of dizocilpine to OB animals did attenuate the OB-related deficit in DA. In the OB-operated control animals, there was an increase in DOPAC levels. In conclusion, chronic dizocilpine administration displays antidepressant-like activity in the OB rat model of depression. However, unlike conventional antidepressants, dizocilpine does not correct the 5-HT and NA neurotransmitter deficits that occur in this model.

Behavioural and immunological effects of the antihistamine terfenadine in olfactory bulbectomized rats

The effects of chronic treatment with the non-sedative histamine H 1 receptor antagonist terfenadine (5 mg/kg, i.p.) for 16 days on some behavioural and immunological parameters were studied in the olfactory bulbectomized (OB) rat model of depression. In the open field apparatus, OB rats showed a significant increase in ambulation and rearing scores. Following terfenadine treatment, this hyperactivity was significantly attenuated. In untreated OB rats, neutrophils phagocytosis and lymphocyte proliferation were significantly suppressed. Terfenadine administration markedly reversed the suppression of these immunological parameters in the treated OB animals, but did not reverse the abnormalities in the differential white blood cell count caused by bulbectomy. These results suggest that the histamine H, receptor antagonist terfenadine may have antidepressant properties and that terfenadine is effective in reversing some of behavioural and immune changes in the olfactory bulbectomized rat model of depression.

Behavioural and neuropharmacological properties of the dibenzazepines, desipramine and lofepramine: studies on the olfactory bulbectomized rat model of depression

O'Connor, William T. and Brian E. Leonard: Behavioural and Neuropharmacological Properties of the Dibenzazepines, Desipramine and Lofepramine: Studies on the Olfactory Bulbectomized Rat Model of Depression. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1988, 12 : 41–51. 1. 1. Lofepramine was compared with its major desipramine for its effects on adaptation to novel objects in the home cage (neophobia) and exploratory behaviours in both sham operated and olfactory bulbectomized rats. 2. 2. In the test for neophobia (marble burying), the aversive response of bulbecotmized rats differed from that of the sham operated animals, the bulbectomized rats showing a diminished aversive response. This response was unaffected by either antidepressant. 3. 3. Of two tests for exploratory activity, the “open field” test clearly differentiated the bulbectomized rats treated with desipramine from those treated with lofepramine. In the lower doses used (1 and 10 mg/kg), only desipramine treatment significantly attenuated the hypermotility of the bulbectomized rats. In high doses (30 mg/kg), lofepramine also attenuated the hypermotility of the bulbectomized rats; this could have been due to the presence of high concentrations of the desipramine metabolite. In a nonstressful novel environment (‘hole board’), neither drug significantly affected the behaviour of sham operated or olfactory bulbectomized rats. Neither antidepressant had noticeable anticholinergic properties as indicated by the number of faecal boli deposited. 4. 4. Acute clonidine administration was found to attenuate the activity of rats in the ‘open field’ apparatus. This effect was attenuated following the chronic administration of desipramine but not lofepramine. It may be concluded that the pharmacological activity of lofepramine is independent of its metabolism to desipramine in vivo .

Antidepressant properties of the triazolobenzodiazepines alprazolam and adinazolam: studies on the olfactory bulbectomized rat model of depression.

Chronically administered alprazolam and adinazolam attenuated the hyperactivity of bilaterally bulbectomized rats when placed in a stressful, novel environment ('open field' apparatus). These drugs had no effect on the activities of sham operated animals under the same experimental conditions. In other studies in these laboratories, clinically effective antidepressant drugs have been shown to have a qualitatively similar effect to alprazolam and adinazolam. Chronically administered diazepam and phenobarbitone did not affect the hyperactivity of bulbectomized rats in the 'open field' apparatus. No difference could be found between the behaviour of bulbectomized rats and the sham operated controls when the animals were placed in a novel, non-stressful environment ('hole board' apparatus and Y-maze). Chronic treatment of either the lesioned or non-lesioned animals with alprazolam or adinazolam did not cause any change in the behaviour of the animals in these situations. This suggests that the behaviour of the rat on the 'hole board' is not a reliable indication of anti-anxiety activity for chronically administered benzodiazepines. When unstarved lesioned and non-lesioned animals were given a choice of five palatable foods for a period of 1 h, slight differences in preference for the type of food chosen could be detected. Thus unsweetened biscuit ('cream crackers') was the most preferred choice of the sham operated rats while cheese and chocolate were the least preferred. Bulbectomized rats showed a more varied food choice, with processed meat ('corned beef') and raisins being preferred to biscuit in two out of four groups. Chronic treatment with either alprazolam or adinazolam did not appear to affect the food preference.(ABSTRACT TRUNCATED AT 250 WORDS)