Gene/Protein Disease Symptom Drug Enzyme Compound
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Differential display reverse transcription-polymerase chain reaction was used to identify mRNAs that are differentially expressed in the brain of rats treated chronically with the reference tricyclic antidepressant, imipramine, in comparison with control rats. The gene encoding for a mutation suppressor for Sec4-8 yeast (Mss4) transcript is overexpressed in the amygdala of treated rats after 3 weeks of daily administration. This overexpression is also found in the hippocampus of rats treated chronically with either tianeptine or fluoxetine. Mss4 protein has the properties of a guanine nucleotide exchange factor, interacting with several members of the Rab family implicated in Ca(2+)-dependent exocytosis of neurotransmitters. Mss4 was also overexpressed in other brain structures as judged by in situ hybridization. The kinetics of the up-regulation of Mss4 gene expression measured by Northern blot during the imipramine, tianeptine, or fluoxetine treatments are consistent with an antidepressant effect that occurs after 3 weeks. In rats in which anhedonia was induced by chronic mild stress during 3 weeks, Mss4 transcripts were specifically down-regulated in hippocampus and amygdala compared with control rats. It is proposed that Mss4 protein, which stimulates exocytosis in vivo, participates in the potentiation of the activity of neurotransmitter pathways implicated in the action of several antidepressants and constitutes one of the common functional molecules induced after chronic antidepressant treatment.
Mol Pharmacol 2002 Dec
PMID:Mss4 gene is up-regulated in rat brain after chronic treatment with antidepressant and down-regulated when rats are anhedonic. 1243

Major depression is a heterogeneous condition, and the search for neural correlates specific to clinically defined subtypes has been inconclusive. Theoretical considerations implicate frontostriatal, particularly subgenual prefrontal cortex (PFC), dysfunction in the pathophysiology of melancholia--a subtype of depression characterized by anhedonia--but no empirical evidence has been found yet for such a link. To test the hypothesis that melancholic, but not nonmelancholic depression, is associated with the subgenual PFC impairment, concurrent measurement of brain electrical (electroencephalogram, EEG) and metabolic (positron emission tomography, PET) activity were obtained in 38 unmedicated subjects with DSM-IV major depressive disorder (20 melancholic, 18 nonmelancholic subjects), and 18 comparison subjects. EEG data were analyzed with a tomographic source localization method that computed the cortical three-dimensional distribution of current density for standard frequency bands, allowing voxelwise correlations between the EEG and PET data. Voxel-based morphometry analyses of structural magnetic resonance imaging (MRI) data were performed to assess potential structural abnormalities in melancholia. Melancholia was associated with reduced activity in the subgenual PFC (Brodmann area 25), manifested by increased inhibitory delta activity (1.5-6.0 Hz) and decreased glucose metabolism, which themselves were inversely correlated. Following antidepressant treatment, depressed subjects with the largest reductions in depression severity showed the lowest post-treatment subgenual PFC delta activity. Analyses of structural MRI revealed no group differences in the subgenual PFC, but in melancholic subjects, a negative correlation between gray matter density and age emerged. Based on preclinical evidence, we suggest that subgenual PFC dysfunction in melancholia may be associated with blunted hedonic response and exaggerated stress responsiveness.
Mol Psychiatry 2004 Apr
PMID:Functional but not structural subgenual prefrontal cortex abnormalities in melancholia. 1469 31

The ability to modify mice genetically has been one of the major breakthroughs in modern medical science affecting every discipline including psychiatry. It is hoped that the application of such technologies will result in the identification of novel targets for the treatment of diseases such as depression and to gain a better understanding of the molecular pathophysiological mechanisms that are regulated by current clinically effective antidepressant medications. The advent of these tools has resulted in the need to adopt, refine and develop mouse-specific models for analyses of depression-like behavior or behavioral patterns modulated by antidepressants. In this review, we will focus on the utility of current models (eg forced swim test, tail suspension test, olfactory bulbectomy, learned helplessness, chronic mild stress, drug-withdrawal-induced anhedonia) and research strategies aimed at investigating novel targets relevant to depression in the mouse. We will focus on key questions that are considered relevant for examining the utility of such models. Further, we describe other avenues of research that may give clues as to whether indeed a genetically modified animal has alterations relevant to clinical depression. We suggest that it is prudent and most appropriate to use convergent tests that draw on different antidepressant-related endophenotypes, and complimentary physiological analyses in order to provide a program of information concerning whether a given phenotype is functionally relevant to depression-related pathology.
Mol Psychiatry 2004 Apr
PMID:In search of a depressed mouse: utility of models for studying depression-related behavior in genetically modified mice. 1474 84

Behavioral and molecular methods were used to study and determine whether there is a link between depression that may be a factor in drug/alcohol addiction, and the endocannabinoid hypothesis of substance abuse. Depression is a lack of interest in the pleasurable things of life (termed anhedonia) and depressed mood. It is unknown whether CB2 cannabinoid receptors are expressed in the brain and whether they are involved in depression and substance abuse. Therefore, mice were subjected daily for 4 wk to chronic mild stress (CMS), and anhedonia was measured by the consumption of 2% sucrose solution. Behavioral and rewarding effects of abused substances were determined in the CMS and control animals. The expression of CB2 receptors and their gene transcripts was compared in the brains of CMS and control animals by Western blotting using CB2 receptor antibody and reverse transcriptase-polymerase chain reaction (RT-PCR). Furthermore, the expression and immunocytochemical identification of CB2 cannabinoid receptor in the rat brain were determined. CMS induced gender-specific aversions, which were blocked by WIN55,212-2, a nonspecific CB1 and CB2 cannabinoid receptor agonist. Direct CB2 antisense oligonucleotide microinjection into the mouse brain induced anxiolysis, indicating that CB2 or CB2-like receptors are present in the brain and may influence behavior. The major finding from these studies was the expression of CB2 receptor and its gene transcript in the mouse brain, which was enhanced by CMS. These preliminary results, if confirmed, suggest that the CB2 receptors are expressed in the mammalian brain and may be involved in depression and substance abuse.
Methods Mol Med 2006
PMID:Methods to study the behavioral effects and expression of CB2 cannabinoid receptor and its gene transcripts in the chronic mild stress model of depression. 1650 15

Vitamin D is a seco-steroid hormone with multiple actions in the brain, mediated through the nuclear vitamin D receptor (VDR). We have recently shown that mutant mice lacking functional VDR demonstrate altered emotional behavior and specific motor deficits. Here we further examine phenotype of these mice, testing their novelty responses, as well as cognitive and sensory (olfactory and gustatory) functions in the novel food, two-trial Y-maze and tastant consumption tests. In addition, we study depression-like behavior in these mice, using anhedonia-based sucrose preference test. Overall, VDR mutant mice showed neophobic response in several different tests, but displayed unimpaired olfactory and gustatory functions, spatial memory and baseline hedonic responses. Collectively, these data confirm that mutation of VDR in mice leads to altering emotional/anxiety states, but does not play a major role in depression, as well as in the regulation of some sensory and cognitive processes. These results support the role of the vitamin D/VDR neuroendocrine system in the regulation of behavior, and may have clinical relevance, enabling a better focus on psychiatric and behavioral disorders associated with dysfunctions in this neuroendocrine system.
J Steroid Biochem Mol Biol 2007 May
PMID:Neophobia, sensory and cognitive functions, and hedonic responses in vitamin D receptor mutant mice. 1748 6

Anhedonia, the reduced capacity to gain pleasure from pleasurable experiences, is a key symptom of major depression and schizophrenia. Reduced hedonic capacity can also be measured as an enduring trait in non-clinical subjects. Such altered hedonic capacity is likely the result of a basic neuropsychophysiological dysfunction and a vulnerability marker that potentially precedes and contributes to the liability of developing psychiatric disorders. The characterization of the structural and functional neural correlates of trait anhedonia in non-clinical individuals may provide new insights for the early detection of such psychiatric diseases. Twenty-nine non-clinical subjects were scanned at the Montreal Neurological Institute. Trait anhedonia was measured using the Chapman Revised Physical Anhedonia Scale. Semi-automated and automated structural MRI segmentation techniques were used to explore structural correlates of trait anhedonia. Seventeen of the 29 subjects also underwent a functional imaging task where responses to the viewing of affective stimuli were examined to identify the functional correlates of trait anhedonia. Trait anhedonia was inversely related to anterior caudate volume, but positively related to ventromedial prefrontal cortex activity during the processing of positive information. These findings may reflect a specific kind of vulnerability for the development of psychiatric affective disorders and suggest that trait anhedonia may be linked to a volumetric reduction in the basal ganglia and to a prefrontal functional abnormality during hedonic processing.
Mol Psychiatry 2007 Aug
PMID:Individual differences in trait anhedonia: a structural and functional magnetic resonance imaging study in non-clinical subjects. 1750 65

The development of depression as well as recovery from depression is most likely accompanied by a change in protein expression profiles. The purpose of the present study was to quantitatively investigate global protein expression differences independent of any hypothesis describing depression etiology and recovery. Thus two-dimensional differential in-gel electrophoresis was employed to compare the ventral hippocampal proteomes between different treatment groups in the chronic mild stress (CMS) model of depression. The CMS paradigm induces anhedonic behaviour, which is a major symptom of depression, by exposing rats to a series of mild stressors for 7 weeks, with antidepressant treatment during the last 4 weeks. In the CMS model, animals were split into six different groups at the end of treatment; unchallenged control escitalopram (n = 12), unchallenged control vehicle (n = 12), CMS vehicle (n = 12), CMS escitalopram responders (n = 11), CMS escitalopram non-responders (n = 13) and CMS resilient (stress resistant) (n = 12). Protein levels in the ventral rat hippocampus were compared between the groups to provide putative markers of anhedonia, escitalopram resistance, and stress resilience. Twenty-eight candidate protein spots were selected, of which 13 were successfully identified using tandem mass spectrometry. DRP-2 (dihydropyrimidinase-related protein-2) was a potential marker for escitalopram resistance, whereas alpha-SNAP and beta-SNAP were associated with stress resilience. Furthermore, several molecular chaperones and cytoskeleton organisers were identified as being differentially expressed. Our data indicate that neuronal adaptation is an essential element of depression etiology and recovery, suggesting the involvement of cellular plasticity in the underlying molecular mechanism.
J Mol Neurosci 2007
PMID:Proteomic investigation of the ventral rat hippocampus links DRP-2 to escitalopram treatment resistance and SNAP to stress resilience in the chronic mild stress model of depression. 1787 97

The current antidepressant drugs are ineffective in 30 to 40% of the treated patients; hence, the pathophysiology of the disease needs to be further elucidated. We used the chronic mild stress (CMS) paradigm to induce anhedonia, a core symptom of major depression, in rats. A fraction of the animals exposed to CMS is resistant to the development of anhedonia; they are CMS resilient. In the CMS-sensitive animals, the induced anhedonic state is reversed in 50% of the animals when treating with escitalopram, whereas the remaining animals are treatment resistant. We used the microarray and the real-time quantitative reverse transcription polymerase chain reaction technique, as well as the ingenuity pathway analysis software to identify the differential gene expression pathways, which are associated with the occurrence of the treatment resistance and the stress-resilient rats. In the hippocampus, we found a significant upregulation of apoptotic pathways in the treatment-resistant animals and significantly increased expression levels of genes involved in hippocampal signaling in the CMS-resilient rats. We hypothesize that sensitivity to the stress-induced anhedonia in rats is correlated with the impairment of hippocampal neurogenesis.
J Mol Neurosci 2007
PMID:Molecular pathways associated with stress resilience and drug resistance in the chronic mild stress rat model of depression: a gene expression study. 1791 79

Schizophrenia is a serious and disabling mental disorder with symptoms such as auditory hallucinations, disordered thinking and delusions, avolition, anhedonia, blunted affect and apathy. In this review article we seek to present the current scientific findings from linkage studies and susceptible genes and the pathophysiology of white matter in schizophrenia. The article has been reviewed in two parts. The first part deals with the linkage studies and susceptible genes in schizophrenia in order to have a clear-cut picture of the involvement of chromosomes and their genes in schizophrenia. The genetic linkage results seem to be replicated in some cases but in others are not. From these results, we cannot draw a fine map to a single locus or gene, leading to the conclusion that schizophrenia is not caused by a single factor/gene. In the second part of the article we present the oligodendrocyte-related genes that are associated with schizophrenia, as we hypothesize a potential role of oligodendrocyte-related genes in the pathology of the disorder.
Mol Psychiatry 2008 Mar
PMID:The myelin-pathogenesis puzzle in schizophrenia: a literature review. 1792 96

Growing evidence indicates that glia pathology and amino-acid neurotransmitter system abnormalities contribute to the pathophysiology and possibly the pathogenesis of major depressive disorder. This study investigates changes in glial function occurring in the rat prefrontal cortex (PFC) after chronic unpredictable stress (CUS), a rodent model of depression. Furthermore, we analyzed the effects of riluzole, a Food and Drug Administration-approved drug for the treatment of amyotrophic laterosclerosis, known to modulate glutamate release and facilate glutamate uptake, on CUS-induced glial dysfunction and depressive-like behaviors. We provide the first experimental evidence that chronic stress impairs cortical glial function. Animals exposed to CUS and showing behavioral deficits in sucrose preference and active avoidance exhibited significant decreases in 13C-acetate metabolism reflecting glial cell metabolism, and glial fibrillary associated protein (GFAP) mRNA expression in the PFC. The cellular, metabolic and behavioral alterations induced by CUS were reversed and/or blocked by chronic treatment with the glutamate-modulating drug riluzole. The beneficial effects of riluzole on CUS-induced anhedonia and helplessness demonstrate the antidepressant action of riluzole in rodents. Riluzole treatment also reversed CUS-induced reductions in glial metabolism and GFAP mRNA expression. Our results are consistent with recent open-label clinical trials showing the drug's effect in mood and anxiety disorders. This study provides further validation of hypothesis that glial dysfunction and disrupted amino-acid neurotransmission contribute to the pathophysiology of depression and that modulation of glutamate metabolism, uptake and/or release represent viable targets for antidepressant drug development.
Mol Psychiatry 2010 May
PMID:Glial pathology in an animal model of depression: reversal of stress-induced cellular, metabolic and behavioral deficits by the glutamate-modulating drug riluzole. 1882 47


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