Neurokinin-1 receptor deletion modulates behavioural and neurochemical alterations in an animal model of depression

The substance P/NK1 receptor system plays an important role in the regulation of stress and emotional responding and as such had been implicated in the pathophysiology of anxiety and depression. The present study investigated whether alterations in the substance P/NK1 receptor system in brain areas which regulate emotional responding accompany the depressive behavioural phenotype observed in the olfactory bulbectomised (OB) mouse. The effect of NK1 receptor deletion on behavioural responding and monoamine levels in discrete brain regions of the OB model, were also examined. Substance P levels in the frontal cortex and NK1 receptor expression in the amygdala and hippocampus were enhanced following olfactory bulbectomy. Although NK1 receptor knockout (NK1−/−) mice did not exhibit altered behavioural responding in the open field test, noradrenaline levels were enhanced in the frontal cortex, amygdala and hippocampus, as were serotonin levels in the frontal cortex. Locomotor activity and exploratory behaviour were enhanced in wild type OB mice, indicative of a depressive-like phenotype, an effect attenuated in NK1−/− mice. Bulbectomy induced a decrease in noradrenaline and 5-HIAA in the frontal cortex and an increase in serotonin in the amygdala, effects attenuated in OB NK1−/− mice. The present studies indicate that alterations in substance P/NK1 receptor system underlie, at least in part, the behavioural and monoaminergic changes in this animal model of depression.     

Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids

Several studies have shown anxiolytic effects of cannabinoids after systemic or central injections. The periaqueductal gray matter is a midbrain structure involved in the control of anxiety states. Intra-cerebral administration of cannabidiol, a phytocannabinoid, or anandamide, an endocannabinoid, into the dorsolateral portion of periaqueductal gray (dlPAG) promotes anxiolytic-like effects in several animal models of anxiety with bell-shaped dose–response curves. The reasons for these curves are still unclear, but since these drugs can also activate TRPV1 receptors and increase glutamate release, we hypothesized that, at high doses, cannabidiol and WIN 55,212-2, a CB1 receptor agonist, could activate TRPV1 receptors, facilitating glutamate neurotransmission and anxiety responses. To test this hypothesis male Wistar rats with cannulae aimed toward the dlPAG were submitted to the following intra-dlPAG treatments: Experiment 1. Vehicle (0.2 µL) or WIN 55,212-2 (3–30 pmol); Experiment 2. Capsazepine (CPZ, 10 nmol, a TRPV1 receptor antagonist) or vehicle followed, 5 min later, by vehicle or WIN 55, 212-2 (10 or 30 pmol); Experiment 3. CPZ (10 nmol) or vehicle followed, 5 min later, by cannabidiol (30 or 60 nmol). Ten minutes after the last injection the animals were tested in the elevated plus maze (EPM). WIN 55,212-2 and cannabidiol induced anxiolytic effects at lower doses that disappeared at the higher dose. Although CPZ + WIN 10 or CPZ + WIN 30 pmol groups were not different from control (CPZ + V), capsazepine prevented the decrease in open arm exploration caused by the higher of dose of WIN 55,212-2 (30 nmol) relative to the lower dose of WIN 55,212-2 (10 nmol) and, in the case of cannabidiol (60 nmol), increased open arm exploration (V + CBD 60 group versus CPZ + CBD 60 group). These results suggest that TRPV1 receptors in the dlPAG modulate anxiety and that activation of these receptors by high doses of cannabinoids could be involved in the bell-shaped dose–response curves observed with these compounds.     

Potential peripheral biological predictors of suicidal behavior in major depressive disorder

Previous studies have shown that dysfunctions in the serotonin system and hypothalamic-pituitary-adrenal axis (HPA) are associated strongly with suicidal behavior and suicide, especially among individuals with major depressive disorder. Suicidal behavior has been explained using both the stress-diathesis model and the state-trait interaction model. Specifically, diatheses, or trait-dependent risk factors, are associated with dysfunctions in the serotonin system; however, stress responses, or state-dependent factors, are associated with HPA hyperactivity. Decreases in cholesterol and brain-derived neurotrophic factor (BDNF) levels have been associated with impaired brain plasticity among individuals with suicidal behavior. Decreased serotonin functioning has been measured using cerebral spinal fluid (CSF) 5-HIAA, fenfluramine challenge studies, and platelet 5-HT2A receptors. HPA axis dysfunction has been evaluated with the dexamethasone suppression test. Cholesterol and BDNF levels have been measured in blood serum or plasma.Nevertheless, challenges to finding promising and accessible neurobiological predictors of suicide and suicidal behavior remain. As suicide behavior is a complex phenomenon, a combined or multidimensional approach, including each of the aforementioned methods, may be required to predict suicide risk among individuals with major depressive disorder.     

Animal model and neurobiology of suicide

Animal models are formidable tools to investigate the etiology, the course and the potential treatment of an illness. No convincing animal model of suicide has been produced to date, and despite the intensive study of thousands of animal species naturalists have not identified suicide in nonhuman species in field situations. When modeling suicidal behavior in the animal, the greatest challenge is reproducing the role of will and intention in suicide mechanics. To overcome this limitation, current investigations on animals focus on every single step leading to suicide in humans. The most promising endophenotypes worth investigating in animals are the cortisol social-stress response and the aggression/impulsivity trait, involving the serotonergic system. Astroglia, neurotrophic factors and neurotrophins are implied in suicide, too. The prevention of suicide rests on the identification and treatment of every element increasing the risk.     

The neuroendocrinology of primate maternal behavior

In nonhuman primates and humans, similar to other mammals, hormones are not strictly necessary for the expression of maternal behavior, but nevertheless influence variation in maternal responsiveness and parental behavior both within and between individuals. A growing number of correlational and experimental studies have indicated that high circulating estrogen concentrations during pregnancy increase maternal motivation and responsiveness to infant stimuli, while effects of prepartum or postpartum estrogens and progestogens on maternal behavior are less clear. Prolactin is thought to play a role in promoting paternal and alloparental care in primates, but little is known about the relationship between this hormone and maternal behavior. High circulating cortisol levels appear to enhance arousal and responsiveness to infant stimuli in young, relatively inexperienced female primates, but interfere with the expression of maternal behavior in older and more experienced mothers. Among neuropeptides and neurotransmitters, preliminary evidence indicates that oxytocin and endogenous opioids affect maternal attachment to infants, including maintenance of contact, grooming, and responses to separation. Brain serotonin affects anxiety and impulsivity, which in turn may affect maternal behaviors such as infant retrieval or rejection of infants' attempts to make contact with the mother. Although our understanding of the neuroendocrine correlates of primate maternal behavior has grown substantially in the last two decades, very little is known about the mechanisms underlying these effects, e.g., the extent to which these mechanisms may involve changes in perception, emotion, or cognition.     

Effects of 8-OH-DPAT, a 5-HT1A receptor agonist, and DOI, a 5-HT2A/2C agonist, on monosynaptic transmission in spinalized rats

We investigated the effect of the 5-HT_1A receptor agonist (±)-8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT) and the 5-HT_2A/2C receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) on monosynaptic transmission in spinalized rats. 8-OH-DPAT significantly inhibited the excitation of α-motoneurons evoked by monosynaptic transmission without a direct effect on α-motoneuron excitation. DOI potentiated the excitation of α-motoneurons by both direct stimulation and monosynaptic transmission. These results indicate that activation of 5-HT_1A receptors inhibits monosynaptic transmission, whereas activation of 5-HT_2A/2C receptors enhances it.     

Unraveling the biological mechanisms in Alzheimer's disease--lessons from genomics

Alzheimer's disease (AD) is the most common form of dementia and the most common neurodegenerative disease, with a complex genetic background. Genome-wide association studies (GWAS) have yielded important new insights into genetic mechanisms of AD pathology. Current results unequivocally confirm apolipoprotein E (APOE) as a major genetic risk factor for development of late onset AD. Additional associations of more than twenty genes have also been identified and replicated in subsequent genetic studies. Despite the exciting new GWAS data which have emerged in the last few years, it has become clear that common variants within the genome cannot fully explain the underlying genetic risk for AD. Novel approaches such as genome-wide analysis of copy number variations (CNV) or low-frequency rare functional gene variants may provide additional insight into genetic basis of AD. In this review we summarize the findings of eighteen GWAS studies in AD performed to date, with an emphasis on potential future developments in the quest for genetic risk factors of AD.     

Association of the ADRA1A gene and the severity of metabolic abnormalities in patients with schizophrenia

Patients with schizophrenia have a higher risk of developing metabolic abnormalities and their associated diseases. Some studies found that the accumulative number of metabolic syndrome components was associated with the severity of metabolic abnormalities. The purpose of this study was to examine the roles of the ADRA1A, ADRA2A, ADRB3, and 5HT2A genes in the risk of having more severe metabolic abnormalities among patients with schizophrenia. We studied a sample of 232 chronic inpatients with schizophrenia (120 males and 112 females) to explore the associations between the four candidate genes and the severity of metabolic syndrome by accumulative number of the components. Four single nucleotide polymorphisms in the candidate genes were genotyped, including the Arg347Cys in ADRA1A, the C1291G in ADRA2A, the Try64Arg in ADRB3, and the T102C in 5HT2A. An association between the accumulative number of metabolic syndrome components and the ADRA1A gene was found after adjusting age, sex, and other related variables (p-value = 0.036). Presence of the Arg347 allele in the ADRA1A gene is a risk factor for having more severe metabolic abnormalities. These findings suggest a medical attention of closely monitoring metabolic risks for schizophrenia patients with high-risk genotypes.     

Somato-dendritic distribution of 5-HT(1A) and 5-HT(1B) autoreceptors in the BDNF- and cAMP-differentiated RN46A serotoninergic raphe cell line

The rapid differentiating effects of brain-derived neurotrophic factor (BDNF) or dibutyryl-cAMP (dBcAMP) were characterized on RN46A, a rat raphe-derived neuronal cell line. After BDNF treatment, RN46A cells were serotonin-immunopositive and bipolar, and expressed the microtubule-associated-protein 2 (Map2). After dBcAMP treatment, the cells often became multipolar, bearing very long processes strongly immunopositive for serotonin and Map2. Under both conditions, the expression and distribution of 5-HT(1A) and 5-HT(1B) autoreceptors remained identical. 5-HT(1A) and Map2 immunolabelings were superimposable, as expected of their somato-dendritic targeting. Surprisingly, the distribution of 5-HT(1B) immunoreactivity was similar, in contrast with its usual localization in axons and nerve terminals in the brain. In conclusion, both BDNF and cAMP-differentiated RN46A cells towards a neuronal serotoninergic-like phenotype without the typical differential targeting of the 5-HT(1) autoreceptors, an interesting model to study the molecular mechanisms ensuing the targeting of 5-HT(1) autoreceptors to somas and dendrites.     

Nucleus incertus--an emerging modulatory role in arousal, stress and memory

A major challenge in systems neuroscience is to determine the underlying neural circuitry and associated neurotransmitters and receptors involved in psychiatric disorders, such as anxiety and depression. A focus of many of these studies has been specific brainstem nuclei that modulate levels of arousal via their ascending monoaminergic projections (e.g. the serotonergic dorsal raphé, noradrenergic locus ceruleus and cholinergic laterodorsal tegmental nucleus). After years of relative neglect, the subject of recent studies in this context has been the GABAergic nucleus incertus,¹ which is located in the midline periventricular central gray in the ‘prepontine’ hindbrain, with broad projections throughout the forebrain. Nucleus incertus neurons express receptors for the stress hormone, corticotropin-releasing factor (CRF), are activated by psychological stressors, and project to key nuclei involved in stress responses and behavioral activation. The nucleus incertus is also a node in neural circuits capable of modulating hippocampal theta rhythm, which is related to control of spatial navigation and memory. A significant population of nucleus incertus neurons express the recently discovered, highly conserved neuropeptide, relaxin-3; and the recent availability of structurally-related, chimeric peptides that selectively activate or inhibit the relaxin-3 receptor, RXFP3, is facilitating studies of relaxin-3/RXFP3 networks and associated GABA and CRF systems. It is predicted that such targeted research will help elucidate the functions of ascending nucleus incertus pathways, including their possible involvement in arousal (sleep/wakefulness), stress reponses, and learning and memory; and in the pathology of related psychiatric diseases such as insomnia, anxiety and depression, and cognitive deficits.     

Effects of a putative antidepressant with a rapid onset of action in defeated mice with different coping strategies

There is evidence suggesting that stressful social events may result in depressive-like disorders, but the development of these disorders depend on the way in which people cope with stress. Although antidepressants are useful their drawback is a delay in the therapeutic effects, moreover not all the patients show an adequate response to this treatment. The aim of this study was to analyse the effect of RS 67333, which is a 5-HT(4) receptor partial agonist and a putative antidepressant which exhibits a rapid onset of action and to determine whether this drug reverses the behavioural and physiological effects that are generated by chronic defeat in subjects who manifest a more vulnerable profile in their response to stress. Male mice were exposed to defeat for 21 consecutive days using a sensorial contact model. After 18 days of defeat, 2 groups of subjects were established, active and passive, in accordance with the behaviour that was manifested during social confrontation, and drug treatment was initiated for 5 days. Finally, the animals were subjected to a forced swimming test (FST). The results revealed higher corticosterone levels in passive mice after the last defeat. Additionally, 3 days after the last defeat, they showed lower corticosterone levels and higher splenic IL-6 and TNF-α levels and hypothalamic GR mRNA levels when compared to their active and manipulated control counterparts. Passive mice had higher 5-HT(1A) receptor mRNA levels than the manipulated controls and a lower MR/GR ratio than active mice. Similar to stress, the drug increased hypothalamic GR mRNA levels, but it did not affect other measured physiological variables or social behaviour, which suggested that the mechanism of this drug is not the most adequate for reversing stress-induced effects in this model. Nevertheless, the treatment increased swimming and decreased immobility in the FST, suggesting an antidepressant potential for this drug.     

Recent molecular genetic studies and methodological issues in suicide research

Suicide behavior (SB) spans a spectrum ranging from suicidal ideation to suicide attempts and completed suicide. Strong evidence suggests a genetic susceptibility to SB, including familial heritability and common occurrence in twins. This review addresses recent molecular genetic studies in SB that include case-control association, genome gene-expression microarray, and genome-wide association (GWA). This work also reviews epigenetics in SB and pharmacogenetic studies of antidepressant-induced suicide.SB fulfills criteria for a complex genetic phenotype in which environmental factors interact with multiple genes to influence susceptibility. So far, case-control association approaches are still the mainstream in SB genetic studies, although whole genome gene-expression microarray and GWA studies have begun to emerge in recent years. Genetic association studies have suggested several genes (e.g., serotonin transporter, tryptophan hydroxylase 2, and brain-derived neurotrophic factor) related to SB, but not all reports support these findings. The case-control approach while useful is limited by present knowledge of disease pathophysiology. Genome-wide studies of gene expression and genetic variation are not constrained by our limited knowledge. However, the explanatory power and path to clinical translation of risk estimates for common variants reported in genome-wide association studies remain unclear because of the presence of rare and structural genetic variation. As whole genome sequencing becomes increasingly widespread, available genomic information will no longer be the limiting factor in applying genetics to clinical medicine. These approaches provide exciting new avenues to identify new candidate genes for SB genetic studies. The other limitation of genetic association is the lack of a consistent definition of the SB phenotype among studies, an inconsistency that hampers the comparability of the studies and data pooling.In summary, SB involves multiple genes interacting with non-genetic factors. A better understanding of the SB genes by combining whole genome approaches with case-control association studies, may potentially lead to developing effective screening, prevention, and management of SB.     

Modulation of neurotransmitter systems by dehydroepiandrosterone and dehydroepiandrosterone sulfate: mechanism of action and relevance to psychiatric disorders

Dehydroepiandrosterone (DHEA) is synthesized in the brain and several studies have shown that this steroid is a modulator of synaptic transmission. The effect of DHEA, and its sulfate ester DHEAS, on glutamate and GABA neurotransmission has been extensively studied but some effects on other neurotransmitter systems, such as dopamine, serotonin and nitric oxide, have also been reported. This review summarizes studies showing the effect of DHEA and DHEAS on neurotransmitter systems at different levels (metabolism, release, reuptake, receptor activation), as well as the activation of voltage-gated ion channels and calcium homeostasis, showing the variety of effects that these steroids exert on those systems, allowing the discussion of its mechanisms of action and its relevance to psychiatric disorders.     

Neuroendocrine control of maternal stress responses and fetal programming by stress in pregnancy

The major changes in highly dynamic neuroendocrine systems that are essential for establishing and maintaining pregnancy are outlined from studies on rodents. These changes optimise the internal environment to provide the life support system for the placenta, embryo and fetus. These include automatic prevention of further pregnancy, blood volume expansion, increased appetite and energy storage. The brain regulates these changes, in response to steroid (estrogens, progesterone) and peptide (lactogens, relaxin) hormone signals. Activation of inhibitory endogenous opioid mechanisms in the brain in late pregnancy restrains premature secretion of oxytocin, and attenuates hypothalamo-pituitary-adrenal (HPA) responses to stress. This opioid mechanism is activated by allopregnanolone, a neuroactive progesterone metabolite. The significance of reduced HPA axis responses in shifting maternal metabolic balance, and in protecting the fetuses from adverse programming of HPA axis stress responsiveness and anxious behaviour in later life is critically discussed. Experimental studies showing sex-dependent fetal programming by maternal stress or glucocorticoid exposure in late pregnancy are reviewed. The possibility of over-writing programming in offspring through neurosteroid administration is discussed. The impact of maternal stress on placental function is considered in the context of reconciling studies that show offspring programming by stress in very early or late pregnancy produce similar phenotypes in the offspring.     

Involvement of the endocannabinoid system in the neurobehavioural effects of stress and glucocorticoids

The endocannabinoid system is a neuroactive lipid signaling system that functions to gate synaptic transmitter release. Accumulating evidence has demonstrated that this system is responsive to modulation by both stress and glucocorticoids within the hypothalamus and limbic structures; however, the nature of this regulation is more complex than initially assumed. The aim of the current review is to summarize the research to date which examines the effects of acute stress and glucocorticoid administration on endocannabinoid signaling in limbic–hypothalamic–pituitary–adrenal (LHPA) axis, and in turn the role endocannabinoid signaling plays in the neurobehavioural responses to acute stress and glucocorticoid administration. The majority of research suggests that acute stress produces a mobilization of the endocannabinoid 2-arachidonoylglycerol (2-AG) while concurrently reducing the tissue content of the other endocannabinoid ligand anandamide. Genetic and pharmacological studies demonstrate that the reduction in anandamide signaling may be involved in the initiation of HPA axis activation and the generation of changes in emotional behaviour, while the increase in 2-AG signaling may be involved in terminating the stress response, limiting neuronal activation and contributing to changes in motivated behaviours. Collectively, these studies reveal a complex interplay between endocannabinoids and the HPA axis, and further identify endocannabinoid signaling as a critical regulator of the stress response.     

Ethyl-eicosapentaenoate (E-EPA) attenuates motor impairments and inflammation in the MPTP-probenecid mouse model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder, characterized by hypokinesia, but also mood and cognitive disorders. Neuropathologically, PD involves loss of nigrostriatal dopamine (DA) and secondary non-dopaminergic abnormalities. Inflammation may contribute to PD pathogenesis, evident by increased production of pro-inflammatory cytokines. PD onset has been positively associated with dietary intake of omega-(n)-6 polyunsaturated fatty acids (PUFA). On the other hand, omega-(n)-3 PUFA may benefit PD. One of these n-3 PUFA, eicosapentaenoic acid (EPA), is a neuroprotective lipid with anti-inflammatory properties, but its neuroprotective effects in PD are unknown. Thus, we presently tested the hypothesis that EPA can protect against behavioral impairments, neurodegeneration and inflammation in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-probenecid (MPTP-P) mouse model of PD. MPTP-P injections caused hypokinesia in the rotorod and pole test, hyperactivity in the open field, and impaired mice on the cued version (procedural memory) of the Morris water maze. MPTP-P caused a loss of nigrostriatal DA and altered neurochemistry in the frontal cortex and hippocampus. Furthermore, striatal levels of pro-inflammatory cytokines were increased, while the brain n-3/n-6 lipid profile remained unaltered. Feeding mice a 0.8% ethyl-eicosapentaenoate (E-EPA) diet prior to MPTP-P injections increased brain EPA and docosapentaenoic acid (DPA) but not docosahexaenoic acid (DHA) or n-6 PUFA. The diet attenuated the hypokinesia induced by MPTP-P and ameliorated the procedural memory deficit. E-EPA also suppressed the production of pro-inflammatory cytokines. However, E-EPA did not prevent nigrostriatal DA loss. Based on this partial protective effect of E-EPA, further testing may be warranted.     

Effects of maternal L-tryptophan depletion and corticosterone administration on neurobehavioral adjustments in mouse dams and their adolescent and adult daughters

Major depressive disorder (MDD), a pathology characterized by mood and neurovegetative disturbances, depends on a multi-factorial contribution of individual predisposition (e.g., diminished serotonergic transmission) and environmental factors (e.g., neonatal abuse or neglect). Despite its female-biased prevalence, MDD basic research has mainly focused on male rodents. Most of present models of depression are also devalued due to the fact that they typically address only one of the aforementioned pathogenetic factors. In this paper we first describe the basic principles behind mouse model development and evaluation and then articulate that current models of depression are intrinsically devalued due to poor construct and/or external validity. We then report a first attempt to overcome this limitation through the design of a mouse model in which the genetic and the environmental components of early risk factors for depression are mimicked together. Environmental stress is mimicked through the supplementation of corticosterone in the maternal drinking water while biological predisposition is mimicked through maternal access to an l-tryptophan (the serotonin precursor) deficient diet during the first week of lactation. CD1 dams and their offspring exposed to the l-tryptophan deficient diet (T) and to corticosterone (80 mg/l; C) were compared to animal facility reared (AFR) subjects. T and C mice served as intermediate reference groups. Adolescent TC offspring, compared to AFR mice, showed decreased time spent floating in the forced-swim test and increased time spent in the open sectors of an elevated 0-maze. Adult TC offspring showed reduced preference for novelty, decreased breakpoints in the progressive ratio operant procedure and major alterations in central BDNF levels and altered HPA regulation.The route of administration and the possibility to control the independent variables predisposing to depressive-like symptoms disclose novel avenues towards the development of animal models with increased external and construct validity. Furthermore, the observation that, compared to adult subjects, adolescent mice display an opposite profile suggests that peri-pubertal developmental processes may interact with neonatal predispositions to calibrate the adult abnormal phenotype.     

Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice

Endocannabinoid analogues exhibit antidepressant and anti-compulsive like effects similar to that of serotonin selective reuptake inhibitors (SSRIs) indicating a parallelism between the effects of serotonin and endocannabinoids. Therefore, the present study was designed to investigate the role of endocannabinoids in the antidepressant and anti-compulsive like effect of fluoxetine using mice model of forced swim test (FST) and marble-burying behavior (MBB). The results revealed that intracerebroventricular injections of endocannabinoid analogues, anandamide, a CB₁ agonist (AEA: 1-20 μg/mouse); AM404, an anandamide transport inhibitor (0.1-10 μg/mouse); and URB597, a fatty acid amide hydrolase inhibitor (0.05-10 μg/mouse) produced antidepressant-like effect dose-dependently, whereas influenced the MBB in a biphasic manner (produced a U-shaped dose-response curve). Fluoxetine (2.5-20 mg/kg, i.p.) dose dependently decreased the immobility time as well as burying behavior. Co-administration of sub-effective dose of fluoxetine (2.5 mg/kg, i.p.) potentiated the effect of sub-effective dose of AEA (0.5 μg/mouse, i.c.v.), AM404 (0.05 μg/mouse, i.c.v) or URB597 (0.01 μg/mouse, i.c.v) in both the paradigms. Interestingly, pretreatment with AM251, a CB₁ antagonist, blocked the effect of fluoxetine in FST and MBB at a dose (1 μg/mouse, i.c.v) that per se had no effect on either parameter. Similar effects were obtained with endocannabinoid analogues in AM251 pretreated mice. However, AM251 increased the burying behavior in MBB at a highest dose tested (5 μg/mouse). None of the treatments had any influence on locomotor activity. Thus, the study indicates an interaction between endocannabinoid and serotonergic system in regulation of depressive and compulsive-like behavior.     

The WAG/Rij strain: a genetic animal model of absence epilepsy with comorbidity of depression [corrected

A great number of clinical observations show a relationship between epilepsy and depression. Idiopathic generalized epilepsy, including absence epilepsy, has a genetic basis. The review provides evidence that WAG/Rij rats can be regarded as a valid genetic animal model of absence epilepsy with comorbidity of depression. WAG/Rij rats, originally developed as an animal model of human absence epilepsy, share many EEG and behavioral characteristics resembling absence epilepsy in humans, including the similarity of action of various antiepileptic drugs. Behavioral studies indicate that WAG/Rij rats exhibit depression-like symptoms: decreased investigative activity in the open field test, increased immobility in the forced swimming test, and decreased sucrose consumption and preference (anhedonia). In addition, WAG/Rij rats adopt passive strategies in stressful situations, express some cognitive disturbances (reduced long-term memory), helplessness, and submissiveness, inability to make choice and overcome obstacles, which are typical for depressed patients. Elevated anxiety is not a characteristic (specific) feature of WAG/Rij rats; it is a characteristic for only a sub-strain of WAG/Rij rats susceptible to audiogenic seizures. Interestingly, WAG/Rij rats display a hyper-response to amphetamine similar to anhedonic depressed patients. WAG/Rij rats are sensitive only to chronic, but not acute, antidepressant treatments, suggesting that WAG/Rij rats fulfill a criterion of predictive validity for a putative animal model of depression. However, more and different antidepressant drugs still await evaluation. Depression-like behavioral symptoms in WAG/Rij rats are evident at baseline conditions, not exclusively after stress. Experiments with foot-shock stress do not point towards higher stress sensitivity at both behavioral and hormonal levels. However, freezing behavior (coping deficits) and blunted response of 5HT in the frontal cortex to uncontrollable sound stress, increased c-fos expression in the terminal regions of the meso-cortico-limbic brain systems and greater DA response of the mesolimbic system to forced swim stress suggest that WAG/Rij rats are vulnerable to some, but not to all types of stressors. We propose that genetic absence epileptic WAG/Rij rats have behavioral depression-like symptoms, are vulnerable to stress and might represent a model of chronic low-grade depression (dysthymia). Both 5HT and DAergic abnormalities detected in the brain of WAG/Rij rats are involved in modulation of vulnerability to stress and provocation of behavioral depression-like symptoms. The same neurotransmitter systems modulate SWDs as well. Recent studies suggest that the occurrence and repetition of absence seizures are a precipitant of depression-like behavior. Whether the neurochemical changes are primary to depression-like behavioral alterations remains to be determined. In conclusion, the WAG/Rij rats can be considered as a genetic animal model for absence epilepsy with comorbidity of dysthymia. This model can be used to investigate etiology, pathogenic mechanisms and treatment of a psychiatric comorbidity, such as depression in absence epilepsy, to reveal putative genes contributing to comorbid depressive disorder, and to screen novel psychotropic drugs with a selective and/or complex (dual) action on both pathologies.     

Decreased kainate receptors in the hippocampus of apolipoprotein D knockout mice

Apolipoprotein D (ApoD) has many actions critical to maintaining mammalian CNS function. It is therefore significant that levels of ApoD have been shown to be altered in the CNS of subjects with schizophrenia, suggesting a role for ApoD in the pathophysiology of the disorder. There is also a large body of evidence that cortical and hippocampal glutamatergic, serotonergic and cholinergic systems are affected by the pathophysiology of schizophrenia. Thus, we decided to use in vitro radioligand binding and autoradiography to measure levels of ionotropic glutamate, some muscarinic and serotonin 2A receptors in the CNS of ApoD^-/- and isogenic wild-type mice. These studies revealed a 20% decrease (mean ± SEM: 104 ± 10.2 vs. 130 ± 10.4 fmol/mg ETE) in the density of kainate receptors in the CA 2–3 of the ApoD^-/- mice. In addition there was a global decrease in AMPA receptors (F_1,214 = 4.67, p < 0.05) and a global increase in muscarinic M2/M4 receptors (F_1,208 = 22.77, p < 0.0001) in the ApoD^-/- mice that did not reach significance in any single cytoarchitectural region. We conclude that glutamatergic pathways seem to be particularly affected in ApoD^-/- mice and this may contribute to the changes in learning and memory, motor tasks and orientation-based tasks observed in these animals, all of which involve glutamatergic neurotransmission.