The olfactory bulbectomized rat as a model of depression: The hippocampal pathway.

In rodents, the removal of the olfactory bulbs (OBs), i.e. olfactory bulbectomy (OBX), results in numerous alterations in neurotransmitter, endocrine and immune systems, as well as behavioral changes, similar to those observed in depressed patients. Because the behavioral deficits induced in OBX animals are reversed after repeated administration of antidepressants, this is a model often used to test the effectiveness of putative antidepressant agents. Recent evidence suggests that OBX results in the dysfunction of various cellular processes within the hippocampus, including decreases in dentate gyrus neurogenesis, disruption in long-term potentiation in CA1 and CA3 subregions and neuronal atrophy in the CA1 subregion, along with downstream markers, all of which are consistent with abnormal neuronal activity in the hippocampus of clinically depressed populations. Moreover, repeated administration of novel natural and synthetic antidepressant compounds can improve certain aspects of depression-like behavior and hippocampal function. In an effort to bring together the existing literature, this review will focus on the mechanisms by which proposed pharmaceuticals impact hippocampal-dependent processes and behavior.

Effect of Chronic Administration of Resveratrol on Cognitive Performance during Aging Process in Rats.

The increase in the elderly population has generated concern to meet health demands. The research efforts to elucidate the mechanisms of damage associated with aging have also been significantly increased, especially in order to avoid the reduction of the cognitive abilities in geriatric patients, resulting from the damage generated mainly at the level of the hippocampus during old age. At present, many studies describe resveratrol as an antiaging component. There are reports that it can activate the Sirt1 gene related to antiaging, emulating the effects obtained by caloric restriction in rodents. The aim of the study was to evaluate the effect of chronic administration of resveratrol (10 mg/kg) on cognitive performance in behavioral tests after 8 months of treatment and on the preservation of cerebral integrity in the cytoarchitecture of regions CA1 and CA2. Results showed that the cytoarchitecture of the CA1 and CA2 regions in the hippocampus retained their integrity over time in rats treated with resveratrol, and the behavioral test performed revealed that chronic resveratrol administration for 8 months showed improvements in cognitive performance. The results indicate that resveratrol may exhibit therapeutic potential for age-related conditions.

Neonatal olfactory bulbectomy enhances locomotor activity, exploratory behavior and binding of NMDA receptors in pre-pubertal rats.

In this study, we investigated the effect of neonatal olfactory bulbectomy (nOBX) on behavioral paradigms related to olfaction such as exploratory behavior, locomotor activity in a novel environment and social interaction. We also studied the effect of nOBX on the activity of the N-methyl-d-aspartate (NMDA) subtype of glutamate receptors during development. The behavioral effects of nOBX (postnatal day 7, PD7) were investigated in pre- (PD30) and post-pubertal (PD60) Wistar rats. NMDA receptor activity was measured with [(125)I]MK-801 in the brain regions associated with the olfactory circuitry. A significant increase in the novelty-induced locomotion was seen in the pre-pubertal nOBX rats. Although the locomotor effect was less marked than in pre-pubertal rats, the nOBX rats tested post-pubertally failed to habituate to the novel situation as quickly as the sham- and normal- controls. Pre-pubertally, the head-dipping behavior was enhanced in nOBX rats compared with sham-operated and normal controls, while normal exploratory behavior was observed between groups in adulthood. In contrast, social interaction was increased in post-pubertal animals that underwent nOBX. Both pre- and post-pubertal nOBX rats recovered olfaction. Interestingly, pre-pubertal rats showed a significant increase in the [(125)I]MK-801 binding in the piriform cortex, dorsal hippocampus, inner and outer layers of the frontal cortex and outer layer of the cingulate cortex. At post-pubertal age, no significant differences in [(125)I]MK-801 binding were observed between groups at any of the brain regions analyzed. These results suggest that nOBX produces pre-pubertal behavioral disturbances and NMDA receptor changes that are transitory with recovery of olfaction early in adulthood.

Impaired structural hippocampal plasticity is associated with emotional and memory deficits in the olfactory bulbectomized rat.

Disturbances in olfactory circuitry have been associated with depression in humans. The olfactory bulbectomized (OBX lesion) has been largely used as a model of depression-like behavior in the rat. However, quantitative neuronal rearrangements in key brain regions in this animal model have not been evaluated yet. Accordingly, we investigated changes in hippocampal plasticity as well as behavioral deficits in this animal model. OBX-induced behavioral deficits were studied in a battery of tests, namely the open field test (OFT), forced swim test (FST), and spatial memory disturbances in the Morris water maze (MWM). To characterize the neuronal remodeling, neuroanatomical rearrangements were investigated in the CA1 hippocampus and piriform cortex (PirC), brain regions receiving inputs from the olfactory bulbs and associated with emotional or olfactory processes. Additionally, cell proliferation and survival of newborn cells in the adult dentate gyrus (DG) of the hippocampus were also determined. OBX induced hyperlocomotion and enhanced rearing and grooming in the OFT, increased immobility in the FST as well as required a longer time to find the hidden platform in the MWM. OBX also induced dendritic atrophy in the hippocampus and PirC. In addition, cell proliferation was decreased while the survival remained unchanged in the DG of these animals. These various features are also observed in depressed subjects, adding further support to the validity and usefulness of this model to evaluate potential novel antidepressants.

Chronic administration of the Y2 receptor antagonist, JNJ-31020028, induced anti-depressant like-behaviors in olfactory bulbectomized rat.

Recent studies from our groups have shown that BIIE0246, a Y2 receptor antagonist, has antidepressant effect in olfactory bulbectomized (OBX) rat. However, its complex structure and high molecular weight limit its usefulness as an in vivo pharmacological tool. Alternatively, the novel and brain penetrant Y2 receptor antagonist, JNJ-31020028 is a useful tool to investigate the in vivo function of the Y2 receptor. In the present study, we evaluated the effect of chronic intracerebroventricular (icv) administration of JNJ-31020028 in a battery of behavioral tests in an animal model that mimics several deficits observed in the human depression, the OBX rat. Chronic administration of JNJ-31020028 induced a decrease in immobility time in the forced swim test in OBX while had no effect in control animals. Additionally, it decreased number of grooming events in OBX animals, but had no effects on some other behavioral deficits observed such as rearing and hyperlocomotion. Furthermore, JNJ-31020028 had no effect on behavior tests that are commonly used to evaluate anxiety, namely the social interaction test in both OBX and control animals. These data indicate that similar to BIIE0246, JNJ-31020028 also has antidepressant like effects in the OBX model.

The selective neuropeptide Y Y5 agonist [cPP(1-7),NPY(19-23),Ala31,Aib32,Gln34]hPP differently modulates emotional processes and body weight in the rat.

The neuropeptide Y (NPY) has been suggested to act as a major regulator of emotional processes and body weight. The full spectrum of biological effects of this peptide is mediated by at least four classes of receptors known as the Y(1), Y(2), Y(4), and Y(5) subtypes. However, the respective contribution of each of these receptor subtypes, especially the Y(5) subtype, in emotional processes is still mostly unknown. In the present study, we investigated the effect of long term administration of a selective Y(5) agonist [cPP(1-7),NPY(19-23),Ala(31),Aib(32),Gln(34)]hPP on emotional processes and body weight using two rat models of emotional dysfunctions, the corticosterone (CORT)-induced anxiety model as well as the olfactory bulbectomized (OBX) model of depression and anxiety in Wistar and Sprague-Dawley rats, respectively. The sub-chronic administration of the Y(5) agonist reversed the high levels of locomotion, rearing and grooming in the open field test and the impaired social activity induced by OBX, while increased the percentage of entries and time in the open arm of the elevated plus maze in CORT-treated rats. Furthermore, this Y(5) agonist increased body weight in both strains of control rats. These data further demonstrate that Y(5) receptors are not only involved in the control of body weight but also mediate emotional processing under challenged conditions. Thus, the pharmacotherapeutic administration of a Y(5) agonist could be considered as a potentially novel strategy to alleviate some forms of anxiety and depression in humans.