ABSTRACT
Protein turnover is an important mechanism to maintain proteostasis. Long-lived proteins (LLPs) are vulnerable to lose their function due to time-accumulated damages. In this study we employed in vivo stable isotope labeling in mice from birth to postnatal day 89. Quantitative proteomics analysis of ten tissues and plasma identified 2113 LLPs, including widespread and tissue-specific ones. Interestingly, a significant percentage of LLPs was detected in plasma, implying a potential link to age-related cardiovascular diseases. LLPs identified in brains were related to neurodegenerative diseases. In addition, the relative quantification of DNA-derived deoxynucleosides from the same tissues provided information about cellular DNA renewal and showed good correlation with LLPs in the brain. The combined data reveal tissue-specific maps of mouse LLPs that may be involved in pathology due to a low renewal rate and an increased risk of damage. Tissue-derived peripheral LLPs hold promise as biomarkers for aging and age-related diseases.
ABSTRACT
BACKGROUND: Chemotherapy-induced neuropathic pain (CIPN) describes a pathological pain state that occurs dose-dependently as a side effect and can limit or even impede an effective cancer therapy. Unfortunately, current treatment possibilities for CIPN are remarkably confined and mostly inadequate as CIPN therapeutics themselves consist of low effectiveness and may induce severe side effects, pointing out CIPN as pathological entity with an emerging need for novel treatment targets. Here, we investigated whether the novel and highly specific FKBP51 inhibitor SAFit2 reduces paclitaxel-induced neuropathic pain. METHODS: In this study, we used a well-established multiple low-dose paclitaxel model to investigate analgesic and anti-inflammatory properties of SAFit2. For this purpose, the behavior of the mice was recorded over 14 days and the mouse tissue was then analyzed using biochemical methods. RESULTS: Here, we show that SAFit2 is capable to reduce paclitaxel-induced mechanical hypersensitivity in mice. In addition, we detected that SAFit2 shifts lipid levels in nervous tissue toward an anti-inflammatory and pro-resolving lipid profile that counteracts peripheral sensitization after paclitaxel treatment. Furthermore, SAFit2 reduced the activation of astrocytes and microglia in the spinal cord as well as the levels of pain-mediating chemokines. Its treatment also increased anti-inflammatory cytokines levels in neuronal tissues, ultimately leading to a resolution of neuroinflammation. CONCLUSIONS: In summary, SAFit2 shows antihyperalgesic properties as it ameliorates paclitaxel-induced neuropathic pain by reducing peripheral sensitization and resolving neuroinflammation. Therefore, we consider SAFit2 as a potential novel drug candidate for the treatment of paclitaxel-induced neuropathic pain.
Subject(s)
Neuralgia , Paclitaxel , Mice , Animals , Paclitaxel/toxicity , Neuroinflammatory Diseases , Gliosis/chemically induced , Gliosis/drug therapy , Neuralgia/chemically induced , Neuralgia/drug therapy , Neuralgia/prevention & control , Lipids/adverse effectsABSTRACT
Polymorphisms in the drug transporter gene ABCB1 predict the treatment response of selected antidepressants and limit anticonvulsive medication's effectiveness. The ABCB1 locus encodes the energy-dependent transporter P-glycoprotein (P-gp) of the blood brain barrier (BBB), which serves as an efflux pump of its substrates in the expressing tissues of vertebrates. One experimental setup to determine a posteriori the P-gp substrate status is the use of the double abcb1ab knock-out (KO) mice model. Since so far, P-gp substrate status of donepezil, a cholinesterase inhibitor wildly used in Alzheimer's disease therapy was inconclusive, we performed subcutanous (s.c.), continuous injections over 11 days in double abcb1ab KO and P-gp competent wildtype (WT) mice. Both in brain and in testis concentrations of donepezil were significantly higher in P-gp deficient mice compared to WT controls (2.39 and 2.24 times respectively). In conclusion, in mice donepezil's brain bioavailability depends on P-gp.
Subject(s)
Alzheimer Disease , Cholinesterase Inhibitors , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Alzheimer Disease/drug therapy , Alzheimer Disease/genetics , Animals , Blood-Brain Barrier/metabolism , Brain/metabolism , Cholinesterase Inhibitors/pharmacology , Donepezil , Male , Mice , Mice, KnockoutABSTRACT
A clinically important and well-studied transporter of the blood-brain barrier (BBB) is P-glycoprotein (P-gp), the gene product of ABCB1. Animal studies have shown that brain concentrations of many antidepressants depend on P-gp. However, biochemical properties, which might allow the prediction of pharmacodynamical involvement of P-gp have not yet been identified, hence thorough experimental testing of each novel drug is needed to determine its P-gp substrate status. In the current study, we tested the P-gp substrate status for the antidepressant vortioxetine using double abcb1ab knock-out (KO) mice. Cerebral concentrations of vortioxetine were 2.3 times higher in P-gp deficient mice compared to wildtype (WT) controls. No significant difference was found regarding the concentration of the drug in the plasma and other organs (liver, kidney, spleen) between KO and WT mice. The results of our study provide conclusive in-vivo evidence that in mice vortioxetine's brain bioavailability is P-gp dependent, expanding previous findings on this topic.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Antidepressive Agents/pharmacokinetics , Blood-Brain Barrier/metabolism , Brain/drug effects , Brain/metabolism , Vortioxetine/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/deficiency , Animals , Male , Mice , Mice, Knockout , Models, AnimalABSTRACT
N6-methyladenosine (m6A) and N6,2'-O-dimethyladenosine (m6Am) are abundant mRNA modifications that regulate transcript processing and translation. The role of both, here termed m6A/m, in the stress response in the adult brain in vivo is currently unknown. Here, we provide a detailed analysis of the stress epitranscriptome using m6A/m-seq, global and gene-specific m6A/m measurements. We show that stress exposure and glucocorticoids region and time specifically alter m6A/m and its regulatory network. We demonstrate that deletion of the methyltransferase Mettl3 or the demethylase Fto in adult neurons alters the m6A/m epitranscriptome, increases fear memory, and changes the transcriptome response to fear and synaptic plasticity. Moreover, we report that regulation of m6A/m is impaired in major depressive disorder patients following glucocorticoid stimulation. Our findings indicate that brain m6A/m represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A/m response may contribute to the pathophysiology of stress-related psychiatric disorders.
Subject(s)
Adenosine/analogs & derivatives , RNA, Messenger/genetics , RNA, Messenger/metabolism , Stress, Psychological/genetics , Stress, Psychological/metabolism , Adenosine/genetics , Adenosine/metabolism , Adult , Animals , Cell Line, Transformed , Humans , Male , Methylation , Mice , Mice, Inbred C57BL , Mice, Knockout , Middle Aged , Stress, Psychological/psychologyABSTRACT
The co-chaperone FKBP5 is a stress-responsive protein-regulating stress reactivity, and its genetic variants are associated with T2D related traits and other stress-related disorders. Here we show that FKBP51 plays a role in energy and glucose homeostasis. Fkbp5 knockout (51KO) mice are protected from high-fat diet-induced weight gain, show improved glucose tolerance and increased insulin signaling in skeletal muscle. Chronic treatment with a novel FKBP51 antagonist, SAFit2, recapitulates the effects of FKBP51 deletion on both body weight regulation and glucose tolerance. Using shorter SAFit2 treatment, we show that glucose tolerance improvement precedes the reduction in body weight. Mechanistically, we identify a novel association between FKBP51 and AS160, a substrate of AKT2 that is involved in glucose uptake. FKBP51 antagonism increases the phosphorylation of AS160, increases glucose transporter 4 expression at the plasma membrane, and ultimately enhances glucose uptake in skeletal myotubes. We propose FKBP51 as a mediator between stress and T2D development, and potential target for therapeutic approaches.
Subject(s)
GTPase-Activating Proteins/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Tacrolimus Binding Proteins/metabolism , Animals , Biological Transport, Active , Diet, High-Fat , Glucose/metabolism , Glucose Transporter Type 4/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Biological , Muscle Fibers, Skeletal/metabolism , Phosphorylation , Signal Transduction , Stress, Physiological , Tacrolimus Binding Proteins/deficiency , Tacrolimus Binding Proteins/genetics , Weight GainABSTRACT
Glucocorticoid challenge tests such as the dexamethasone suppression test (DST) and the combined dexamethasone/corticotropin-releasing hormone (dex-CRH) test are considered to be able to sensitively measure hypothalamic-pituitary-adrenal (HPA) axis activity in stress-related psychiatric and endocrine disorders. We used mass-spectrometry to assess the relationship of plasma dexamethasone concentrations and the outcome of these tests in two independent cohorts. Dexamethasone concentrations were measured after oral ingestion of 1.5mg dexamethasone in two cohorts that underwent a standard (dexamethasone at 23:00h) as well as modified (18:00h) DST and dex-CRH test. The first study population was a case/control cohort of 105 depressed patients and 133 controls in which peripheral blood mRNA expression was also measured. The second was a cohort of 261 depressed patients that underwent a standard dex-CRH test at baseline and after 12 weeks' treatment with cognitive-behavioral therapy or antidepressants. Dexamethasone concentrations explained significant proportions of the variance in the DST in both the first (24.6%) and the second (5.2%) cohort. Dexamethasone concentrations explained a higher proportion of the variance in the dex-CRH test readouts, with 41.9% of the cortisol area under the curve (AUC) in the first sample and 24.7% in the second sample. In contrast to these strong effects at later time points, dexamethasone concentrations did not impact cortisol or ACTH concentrations or mRNA expression 3hours after ingestion. In the second sample, dexamethasone concentrations at baseline and week 12 were highly correlated, independent of treatment type and response status. Importantly, a case/control effect in the Dex-CRH test was only apparent when controlling for dexamethasone concentrations. Our results suggest that the incorporation of plasma dexamethasone concentration or measures of earlier endocrine read-outs may help to improve the assessment of endocrine dysfunction in depression.
Subject(s)
Receptors, Glucocorticoid/drug effects , Receptors, Glucocorticoid/metabolism , Adrenocorticotropic Hormone/blood , Adult , Antidepressive Agents/therapeutic use , Case-Control Studies , Corticotropin-Releasing Hormone/metabolism , Depression/blood , Depression/metabolism , Depressive Disorder, Major/metabolism , Dexamethasone/analysis , Dexamethasone/blood , Dexamethasone/metabolism , Female , Gene Expression , Glucocorticoids/pharmacology , Humans , Hydrocortisone/analysis , Hydrocortisone/blood , Hypothalamo-Hypophyseal System/physiopathology , Male , Middle Aged , Pituitary-Adrenal System/physiopathology , Time FactorsABSTRACT
Manipulating the function of neurons and circuits that translate electrical and chemical signals into behavior represents a major challenges in neuroscience. In addition to optogenetic methods using light-activatable channels, pharmacogenetic methods with ligand induced modulation of cell signaling and excitability have been developed. However, they are largely based on ectopic expression of exogenous or chimera proteins. Now, we describe the remote and reversible expression of a Kir2.1 type potassium channel using the chemogenetic technique of small molecule induced protein stabilization. Based on shield1-mediated shedding of a destabilizing domain fused to a protein of interest and inhibition of protein degradation, this principle has been adopted for biomedicine, but not in neuroscience so far. Here, we apply this chemogenetic approach in brain research for the first time in order to control a potassium channel in a remote and reversible manner. We could show that shield1-mediated ectopic Kir2.1 stabilization induces neuronal silencing in vitro and in vivo in the mouse brain. We also validated this novel pharmacogenetic method in different neurobehavioral paradigms.The DD-Kir2.1 may complement the existing portfolio of pharmaco- and optogenetic techniques for specific neuron manipulation, but it may also provide an example for future applications of this principle in neuroscience research.
Subject(s)
Neurons/drug effects , Neurons/physiology , Potassium Channels/metabolism , Animals , Behavior, Animal/drug effects , Cell Line , Humans , Memory/drug effects , Mice , Morpholines/pharmacology , Potassium Channels/genetics , Potassium Channels, Inwardly Rectifying/genetics , Potassium Channels, Inwardly Rectifying/metabolism , Protein Interaction Domains and Motifs/genetics , Protein Stability/drug effects , Tacrolimus Binding Protein 1A/genetics , Tacrolimus Binding Protein 1A/metabolismABSTRACT
Although mental disorders as major depression are highly prevalent worldwide their underlying causes remain elusive. Despite the high heritability of depression and a clear genetic contribution to the disease, the identification of genetic risk factors for depression has been very difficult. The first published candidate to reach genome-wide significance in depression was SLC6A15, a neuronal amino acid transporter. With a reported 1,42 fold increased risk of suffering from depression associated with a single nucleotide polymorphism (SNP) in a regulatory region of SLC6A15, the polymorphism was also found to affect hippocampal morphology, integrity, and hippocampus-dependent memory. However, the function of SLC6A15 in the brain is so far largely unknown. To address this question, we investigated if alterations in SLC6A15 expression, either using a full knockout or a targeted hippocampal overexpression, affect hippocampal neurochemistry and consequently behavior. We could show that a lack of SLC6A15 reduced hippocampal tissue levels of proline and other neutral amino acids. In parallel, we observed a decreased overall availability of tissue glutamate and glutamine, while at the same time the basal tone of extracellular glutamate in the hippocampus was increased. By contrast, SLC6A15 overexpression increased glutamate/glutamine tissue concentrations. These neurochemical alterations could be linked to behavioral abnormalities in sensorimotor gating, a key translational endophenotype relevant for many psychiatric disorders. Overall, our data supports SLC6A15 as a crucial factor controlling amino acid content in the hippocampus, thereby likely interfering with glutamatergic transmission and behavior. These findings emphasize SLC6A15 as pivotal risk factor for vulnerability to psychiatric diseases.
Subject(s)
Amino Acid Transport Systems, Neutral/physiology , Behavior, Animal/physiology , Glutamic Acid/metabolism , Hippocampus/metabolism , Sensory Gating/physiology , Amino Acid Transport Systems, Neutral/genetics , Amino Acid Transport Systems, Neutral/metabolism , Animals , Hippocampus/anatomy & histology , Hippocampus/chemistry , Magnetic Resonance Spectroscopy , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Proline/metabolism , Real-Time Polymerase Chain Reaction , Signal TransductionABSTRACT
Anxiety-related psychiatric disorders represent one of the largest health burdens worldwide. Single nucleotide polymorphisms of the FK506 binding protein 51 (FKBP51) gene have been repeatedly associated with anxiety-related disorders and stress sensitivity. Given the intimate relationship of stress and anxiety, we hypothesized that amygdala FKBP51 may mediate anxiety-related behaviors. Mimicking the stress effect by specifically overexpressing FKBP51 in the basolateral amygdala (BLA) or central amygdala resulted in increased anxiety-related behavior, respectively. In contrast, application of a highly selective FKBP51 point mutant antagonist, following FKBP51(mut) BLA-overexpression, reduced the anxiogenic phenotype. We subsequently tested a novel FKBP51 antagonist, SAFit2, in wild-type mice via BLA microinjections, which reduced anxiety-related behavior. Remarkably, the same effect was observed following peripheral administration of SAFit2. To our knowledge, this is the first in vivo study using a specific FKBP51 antagonist, thereby unraveling the role of FKBP51 and its potential as a novel drug target for the improved treatment of anxiety-related disorders.
Subject(s)
Anti-Anxiety Agents/administration & dosage , Anxiety/metabolism , Tacrolimus Binding Proteins/antagonists & inhibitors , Tacrolimus Binding Proteins/biosynthesis , Amygdala/drug effects , Amygdala/metabolism , Animals , Anxiety/drug therapy , Anxiety/psychology , Ligands , Male , Mice , Mice, Inbred C57BL , Microinjections/methods , Risk FactorsABSTRACT
The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.
Subject(s)
Tacrolimus Binding Proteins/antagonists & inhibitors , Adaptation, Psychological/drug effects , Animals , Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Binding Sites/drug effects , Cells, Cultured , Drug Discovery , Humans , Male , Mice , Mice, Inbred C57BL , Mutation/genetics , Neurites/drug effects , Protein Conformation , Tacrolimus Binding Proteins/chemistry , Tacrolimus Binding Proteins/drug effectsABSTRACT
Major depression (MD) is one of the most common psychiatric disorders, severely affecting the quality of life of millions of people worldwide. Despite the availability of several classes of antidepressants, treatment efficacy is still very variable and many patients do not respond to the treatment. Clomipramine (CMI), a classical and widely used antidepressant, shows widespread interindividual variability of efficacy, while the environmental factors contributing to such variability remain unclear. We investigated whether chronic stress modulates the bio-distribution of CMI, and as a result the behavioral response to CMI treatment in a mouse model of chronic social defeat stress (CSDS). Our results show that stress exposure increased anxiety-like and depressive-like behaviors and altered the stress response. Chronic defeat stress furthermore significantly altered CMI bio-distribution. Interestingly, CMI bio-distribution highly correlated with anxiety-like and depressive-like behaviors only under basal conditions. Taken together, we provide first evidence demonstrating that chronic stress exposure modulates CMI bio-distribution and behavioral responses. This may contribute to CMI's broad interindividual variability, and is especially relevant in clinical practice.
ABSTRACT
Increased vulnerability to aversive experiences is one of the main risk factors for stress-related psychiatric disorders as major depression. However, the molecular bases of vulnerability, on the one hand, and stress resilience, on the other hand, are still not understood. Increasing clinical and preclinical evidence suggests a central involvement of the glutamatergic system in the pathogenesis of major depression. Using a mouse paradigm, modeling increased stress vulnerability and depression-like symptoms in a genetically diverse outbred strain, and we tested the hypothesis that differences in AMPA receptor function may be linked to individual variations in stress vulnerability. Vulnerable and resilient animals differed significantly in their dorsal hippocampal AMPA receptor expression and AMPA receptor binding. Treatment with an AMPA receptor potentiator during the stress exposure prevented the lasting effects of chronic social stress exposure on physiological, neuroendocrine, and behavioral parameters. In addition, spatial short-term memory, an AMPA receptor-dependent behavior, was found to be predictive of individual stress vulnerability and response to AMPA potentiator treatment. Finally, we provide evidence that genetic variations in the AMPA receptor subunit GluR1 are linked to the vulnerable phenotype. Therefore, we propose genetic variations in the AMPA receptor system to shape individual stress vulnerability. Those individual differences can be predicted by the assessment of short-term memory, thereby opening up the possibility for a specific treatment by enhancing AMPA receptor function.
Subject(s)
Genetic Testing/methods , Hippocampus/metabolism , Individuality , Memory, Short-Term/drug effects , Receptors, AMPA/metabolism , Stress, Psychological/metabolism , Animals , Corticosterone/blood , Depressive Disorder, Major/etiology , Disease Models, Animal , Female , Gene Expression Regulation/drug effects , Hippocampus/drug effects , Male , Mice , Phenotype , Polymorphism, Single Nucleotide , Protein Array Analysis/methods , Receptors, AMPA/agonists , Receptors, AMPA/genetics , Resilience, Psychological/drug effects , Risk Factors , Stress, Psychological/blood , Stress, Psychological/genetics , Stress, Psychological/psychology , Sulfonamides/pharmacologyABSTRACT
BACKGROUND: P-glycoprotein (P-gp), an efflux transporter localized in the blood-brain barrier, limits the access of multiple xenobiotics to the central nervous system (CNS). For the new antipsychotic aripiprazole and its active metabolite dehydroaripiprazole differences in disposition in blood and brain were investigated after acute and sub-chronic administration in a P-gp knockout mouse model. METHODS: Serum and brain concentrations of both drugs were measured at several time points 1-24h after i.p. injection of 10mg/kg aripiprazole and after 11 days of sub-chronic administration in several tissues. Moreover, the expression of P-gp was determined by Western blot analysis after sub-chronic administration of the drug. RESULTS: In both wild type and abcb1ab (-/-) mice concentration of aripiprazole in brain were up to 9 fold higher than in serum. For dehydroaripiprazole the mean brain to serum ratios were below two. Brain to serum concentrations of both substances were significantly higher after acute and sub-chronic administration in connection to the expression of P-gp indicated by higher levels in abcb1ab (-/-) mice especially for dehydroaripiprazole. Sub-chronic aripiprazole treatment in WT animals had no effect on P-gp expression in the blood-brain barrier. CONCLUSIONS: Aripiprazole and, even more pronounced its active metabolite dehydroaripiprazole could be identified as substrates of P-gp. The efflux transporter P-gp must therefore be considered as a relevant factor that contributes to wanted or unwanted clinical effects in patients treated with aripiprazole.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Blood-Brain Barrier/metabolism , Brain/metabolism , Piperazines/pharmacokinetics , Quinolones/pharmacokinetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Analysis of Variance , Animals , Antipsychotic Agents/pharmacokinetics , Aripiprazole , Biological Transport , Blotting, Western , Chromatography, High Pressure Liquid , Mass Spectrometry , Mice , Mice, KnockoutABSTRACT
The clinical efficacy of a systemically administered drug acting on the central nervous system depends on its ability to pass the blood-brain barrier, which is regulated by transporter molecules such as ABCB1 (MDR1). Here we report that polymorphisms in the ABCB1 gene predict the response to antidepressant treatment in those depressed patients receiving drugs that have been identified as substrates of ABCB1 using abcb1ab double-knockout mice. Our results indicate that the combined consideration of both the medication's capacity to act as an ABCB1-transporter substrate and the patient's ABCB1 genotype are strong predictors for achieving a remission. This finding can be viewed as a further step into personalized antidepressant treatment.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , Depression/genetics , Genetic Predisposition to Disease , Pharmacogenetics , Polymorphism, Single Nucleotide/genetics , ATP Binding Cassette Transporter, Subfamily B , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/genetics , Animals , Antidepressive Agents/therapeutic use , Depression/drug therapy , Female , Gene Frequency , Genotype , Humans , Male , Mice , Mice, Knockout , Middle Aged , Predictive Value of Tests , Statistics, NonparametricABSTRACT
In this study, the role of P-glycoprotein (P-gp) for the pharmacokinetics of dextromethorphan, a CYP2D6 substrate, and of melperone, a CYP2D6 inhibitor, was investigated. The substances were administered subcutaneously near the nape of the neck of wild-type mice and of abcb1ab (-/-) mice. One hour after injection, concentrations of the two drugs in cerebrum, plasma and in different organs were measured by high-performance liquid chromatography. No significant differences between wild-type mice and abcb1ab (-/-) mice were observed for melperone, suggesting that P-gp is not involved in the uptake of melperone into the brain or other organs of mice. The concentration of dextromethorphan in the brain was more than twice as high in abcb1ab (-/-) mice compared to wild-type mice. Therefore, P-gp appears to be a factor in the uptake of dextromethorphan into the mouse brain, and abcb1-polymorphisms need to be considered for CYP2D6 phenotyping experiments with this drug. There is an overlap in substrate specificity between P-gp and CYP2D6. P-gp is a factor in the uptake of dextromethorphan, but not of melperone.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/physiology , Brain/metabolism , Butyrophenones/metabolism , Cytochrome P-450 CYP2D6/metabolism , Dextromethorphan/metabolism , Animals , Brain/enzymology , Cytochrome P-450 CYP2D6/genetics , Kidney/enzymology , Kidney/metabolism , Mice , Mice, Knockout , Spleen/enzymology , Spleen/metabolism , Substrate Specificity , Tissue DistributionABSTRACT
Increased plasma arginine vasopressin (AVP) concentrations have been reported in depressed suicide attempters. Plasma AVP is primarily produced by the magnocellular system in response to increased plasma osmolality, and central AVP may be independently regulated. In the present study we investigated cerebrospinal fluid (CSF) and plasma AVP concentrations in depressed patients and controls. Nineteen drug-free depressed psychiatric inpatients (nine suicide attempters) and nine neurological control subjects underwent lumbar puncture and psychiatric evaluation. CSF and plasma concentrations of AVP, serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and cortisol were assayed. In 15 depressed patients (eight suicide attempters), the combined dexamethasone/corticotropin-releasing hormone (Dex/CRH) test was performed to examine the hypothalamic-pituitary-adrenocortical (HPA) system. There were no differences between depressed subjects and controls in all parameters measured. Suicide attempters did not differ from nonattempters. In depressed patients, plasma AVP correlated positively with cortisol. There was no relationship between CSF AVP and monoamine metabolites in CSF.