Biomedical subjects

Barbara K Lipska

Publications and source records attributed to Barbara K Lipska.

At least 19 recordsLinked to original sources

PubMed2007

Post-pubertal disruption of medial prefrontal cortical dopamine-glutamate interactions in a developmental animal model of schizophrenia.

BACKGROUND: A neonatal ventral hippocampal lesion (NVHL) induces behavioral and physiological anomalies mimicking pathophysiological changes of schizophrenia. Because prefrontal cortical (PFC) pyramidal neurons recorded from adult NVHL rats exhibit abnormal responses to activation of the mesocortical dopaminergic (DA) system, we explored whether these changes are due to an altered DA modulation of pyramidal neurons. METHODS: Whole-cell recordings were used to examine the effects of DA and glutamate agonists on cell excitability in brain slices obtained from pre- (postnatal day [PD] 28-35) and post-pubertal (PD > 61) sham and NVHL animals. RESULTS: N-methyl d-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA), and the D(1) agonist SKF38393 increased excitability of deep layer pyramidal neurons in a concentration-dependent manner. The opposite effect was observed with the D(2) agonist quinpirole. The effects of NMDA (but not AMPA) and SKF38393 on cell excitability were significantly higher in slices from NVHL animals, whereas quinpirole decrease of cell excitability was reduced. These differences were not observed in slices from pre-pubertal rats, suggesting that PFC DA and glutamatergic systems become altered after puberty in NVHL rats. CONCLUSIONS: A disruption of PFC dopamine-glutamate interactions might emerge after puberty in brains with an early postnatal deficit in hippocampal inputs, and this disruption could contribute to the manifestation of schizophrenia-like symptoms.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

PubMed2006

Critical factors in gene expression in postmortem human brain: Focus on studies in schizophrenia.

BACKGROUND: Studies of postmortem human brain are important for investigating underlying pathogenic molecular mechanisms of neuropsychiatric disorders. They are, however, confounded by pre- and postmortem factors. The purpose of this study was to identify sources of variation that will enable a better design of gene expression studies and higher reliability of gene expression data. METHODS: We assessed the contribution of multiple variables to messenger RNA (mRNA) expression of reference (housekeeping) genes measured by reverse transcriptase-polymerase chain reaction (RT-PCR) by multiple regression analysis in a large number (N = 143) of autopsy samples from the hippocampus and white and grey matter of the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia and normal control subjects. RESULTS: The strongest predictor of gene expression was total RNA quality. Other significant factors included pH, postmortem interval, age and the duration of the agonal state, but the importance of these factors depended on transcript measured, brain region analyzed, and diagnosis. The quality of RNA obtained from the DLPFC white matter was also adversely affected by smoking. CONCLUSIONS: Our results show that normalization of expression data of target genes with a geometric mean of multiple housekeeping genes should be used to control for differences in RNA quality between samples. The results also suggest that accurate assessment of other confounding factors and their inclusion as regressors in the analysis is critical for obtaining reliable and accurate quantification of mRNA expression.

Adult↗

PubMed2006

RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity.

Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia.

Alleles↗

PubMed2006

Genetic mouse models of schizophrenia: from hypothesis-based to susceptibility gene-based models.

Translation of human genetic mutations into genetic mouse models is an important strategy to study the pathogenesis of schizophrenia, identify potential drug targets, and test new drugs for new antipsychotic treatments. Although it is impossible to recapitulate the full spectrum of schizophrenia symptoms in animal models, hypothesis-driven genetic mouse models have been successful in reproducing several schizophrenia-like behaviors and uncovering the roles of specific genes in dopamine and glutamine neurotransmission systems in mediating schizophrenia-like behaviors. Recent discoveries of susceptibility genes for schizophrenia and recognition of cognitive dysfunction as a core feature of schizophrenia and a phenotype of susceptibility for schizophrenia offer opportunities to develop newer genetic mouse models based on susceptibility. This new generation of genetic mouse models could shed light on the etiology of schizophrenia and lead us to new hypotheses, novel diagnostic tools, and more effective therapy.

Animals↗

PubMed2006

Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5' SNPs associated with the disease.

Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5' upstream region of the gene for their effects on mRNA abundance of NRG1 types I-IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription factors, serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1. These data implicate variation in isoform expression as a molecular mechanism for the genetic association of NRG1 with schizophrenia.

Adult↗

PubMed2006

Expression of DISC1 binding partners is reduced in schizophrenia and associated with DISC1 SNPs.

DISC1 has been identified as a schizophrenia susceptibility gene based on linkage and SNP association studies and clinical data suggesting that risk SNPs impact on hippocampal structure and function. In cell and animal models, C-terminus-truncated DISC1 disrupts intracellular transport, neural architecture and migration, perhaps because it fails to interact with binding partners involved in neuronal differentiation such as fasciculation and elongation protein zeta-1 (FEZ1), platelet-activating factor acetylhydrolase, isoform Ib, PAFAH1B1 or lissencephaly 1 protein (LIS1) and nuclear distribution element-like (NUDEL). We hypothesized that altered expression of DISC1 and/or its molecular partners may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and these selected binding partners as well as reelin, a protein in a related signaling pathway, in the hippocampus and dorsolateral prefrontal cortex of postmortem human brain patients with schizophrenia and controls. We found no difference in the expression of DISC1 or reelin mRNA in schizophrenia and no association with previously identified risk DISC1 SNPs. However, the expression of NUDEL, FEZ1 and LIS1 was each significantly reduced in the brain tissue from patients with schizophrenia and expression of each showed association with high-risk DISC1 polymorphisms. Although, many other DISC1 binding partners still need to be investigated, these data implicate genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed2006

Alternative splicing of human metabotropic glutamate receptor 3.

The metabotropic glutamate receptor 3 (GRM3, mGluR3) is important in regulating synaptic glutamate. Here, we report the existence of three splice variants of GRM3 in human brain arising from exon skipping events. The transcripts are expressed in prefrontal cortex, hippocampus and cerebellum, and in B lymphoblasts. We found no evidence for alternative splicing of GRM2. The most abundant GRM3 variant lacks exon 4 (GRM3Delta4). In silico translation analysis of GRM3Delta4 predicts a truncated protein with a conserved extracellular ligand binding domain, absence of a seven-transmembrane domain, and a unique 96-amino acid C-terminus. When expressed in rat hippocampal neurons, GRM3Delta4 is translated into a 60 kDa protein. Immunostaining and cell fractionation data indicate that the truncated protein is primarily membrane-associated. An antibody developed against the GRM3Delta4 C-terminus detects a protein of approximately 60 kDa in human brain lysates and in B lymphoblasts, suggesting translation of GRM3Delta4 in vivo. The existence of the GRM3Delta4 isoform is relevant in the light of the reported association of non-coding single nucleotide polymorphisms (SNPs) in GRM3 with schizophrenia, and with the potential of GRM3 as a therapeutic target for several neuropsychiatric disorders.

Adult↗

PubMed2006

Neonatal ventral hippocampal lesions produce an elevation of DeltaFosB-like protein(s) in the rodent neocortex.

Rats that have sustained bilateral excitotoxic lesions of the ventral hippocampus (VH) as neonates develop behavioral abnormalities as adults (hyper-responsiveness to stress, diminished prepulse inhibition, and increased sensitivity to dopamine agonists), which resemble certain aspects of schizophrenia. Although this behavioral profile is thought to reflect dysregulation of the mesolimbic dopamine system, the precise neuroanatomical and neurochemical substrates that mediate the emergence of these abnormalities during brain maturation are unclear. In order to identify putative sites responsible for the development of behavioral abnormalities following neonatal lesions of the VH, we utilized the chronic neuronal activity marker DeltaFosB. By comparison to sham lesioned animals, bilateral destruction of the VH elevated DeltaFosB expression throughout the caudate putamen and neocortex of animals lesioned as neonates. These increases were not observed in rats lesioned as young-adults, suggesting that DeltaFosB induction in the cortex of neonatally lesioned rats may be related to altered cortical neurodevelopment. Accumulating evidence implicates DeltaFosB in mediation of the long-lasting effects of altered dopaminergic neurotransmission on behavior. The present findings are consistent with this proposal and suggest that elevated expression of DeltaFosB identifies overactive neurons that may contribute to the enhanced sensitivity to stress and dopaminergic agonists of rats that have sustained bilateral ventral hippocampal lesions as neonates.

Age Factors↗

PubMed2006

Functional genomics in postmortem human brain: abnormalities in a DISC1 molecular pathway in schizophrenia.

The disrupted in schizophrenia 1 (DISC1) gene has been identified as a schizophrenia susceptibility gene based on linkage and single nucleotide polymorphism (SNP) association studies and clinical data, suggesting that risk SNPs impact on hippocampal structure and function. We hypothesized that altered expression of DISC1 and/or its molecular partners (nuclear distribution element-like [NUDEL], fasciculation and elongation protein zeta-i [FEZ1], and lissencephaly 1 [LIS1]) may underlie its pathogenic role in schizophrenia and explain its genetic association. We examined the expression of DISC1 and its binding partners in the hippocampus and dorsolateral prefrontal cortex of postmortem human brains of schizophrenic patients and controls. We found no difference in the expression of DISC1 mRNA in schizophrenia, and no association with previously identified risk SNPs. However, the expression of NUDEL, FEZ1, and LIS1 was significantly reduced in tissue from schizophrenic subjects, and the expression of each showed association with high-risk DISC1 polymorphisms. These data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia.

Animals↗

PubMed2005

Cortical gene expression in the neonatal ventral-hippocampal lesion rat model.

Schizophrenia is a chronic, debilitating psychotic illness of unknown etiology that has been the subject of many genetic studies. We studied the neonatal ventral-hippocampal lesioned rat as an animal model of schizophrenia in order to identify novel candidate genes for schizophrenia. Temporal and frontal cortices were assessed using cDNA microarrays for differences in mRNA expression associated with the lesion, haloperidol treatment and in two rat strains with differential sensitivity to the behavioural effects of the lesion. Genes that had altered expression levels as a result of the lesion, that were normalized by haloperidol treatment, and that differed between rat strains were selected. The pattern of differential transcription was confirmed with quantitative PCR for all six candidate genes: large conductance calcium-activated potassium channel, subfamily M, beta member 1 (Kcnmb1); doublecortex (dcx); adenylyl cyclase-associated protein 1 (CAP1); adenosine monophosphate deaminase 2-isoform L (AMPD2); malic enzyme 3, NADP(+)-dependent, mitochondrial (Me3); and aspartylglucosaminidase (AGA). None of these genes has been extensively studied in schizophrenia, and further work with post-mortem tissue and genetic studies are ongoing.

Analysis of Variance↗

PubMed2005

A conserved mRNA expression profile of SREB2 (GPR85) in adult human, monkey, and rat forebrain.

SREB is a subfamily of G-protein-coupled receptors, which consists of SREB1 (GPR27), SREB2 (GPR85), and SREB3 (GPR173). Its high evolutionary conservation and predominant expression in the CNS suggest that SREB family members and their undiscovered ligand(s) may have significant functions in the nervous system. SREB2 is the most conserved receptor throughout vertebrate evolution. As a first step in understanding the function of the SREB family, we have determined the anatomical gene expression profile of SREB2 in adult human, monkey, and rat forebrain using in situ hybridization histochemistry. The expression pattern of SREB2 mRNA was well conserved across three mammalian species. SREB2 mRNA was expressed in neurons throughout the brain and the most abundant expression was detected in the hippocampal dentate gyrus in all species examined. The areas expressing high levels of SREB2 mRNA overlap with brain structures known to possess high levels of plasticity, namely, the hippocampal formation, olfactory system, and supraoptic and paraventricular nuclei. Further, the anatomical expression of SREB1 and SREB3 overlapped with that of SREB2 in the adult monkey brain. Together, these data suggest a possible link between SREB family and neural plasticity, which may explain its extremely high conservation throughout vertebrate evolution.

Animals↗

PubMed2004

A novel ELISA using PVDF microplates.

Here we describe the development of a novel specific, rapid ELISA system, which is performed on modified microplates where polyvinylidine fluoride (PVDF) forms the base of each well. The use of microplates with PVDF membranes as the solid phase allows for a greater binding capacity of protein in comparison to the solid phases of traditional ELISAs. The increased binding capacity of the solid phase provides for the direct binding of antigens, which can subsequently be assayed using a single, specific and well-characterized antibody. This direct assay system eliminates the need for two distinct antibodies that are often necessary in conventional two site ELISA systems. The system is able to specifically detect purified proteins as well as antigens in crude preparations of tissue homogenates. The PVDF-based ELISA performs with similar sensitivity and reproducibility as conventional two site ELISAs in tissue homogenates. The intra- and inter-assay coefficients of variation for the measurement of actin in crude rat brain homogenate were 2.36 and 5.15%, respectively.

Actins↗

PubMed2004

Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain.

Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3' flanking region (rs165599)--both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val--had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3' SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.

Analysis of Variance↗

PubMed2004

Effects of chronic haloperidol and clozapine treatment on neurogenesis in the adult rat hippocampus.

It has been proposed that the therapeutic benefits of treatment with antidepressants and mood stabilizers may arise partially from their ability to stimulate neurogenesis. This study was designed to examine the effects of chronic antipsychotic treatment on cell proliferation and survival in the adult rat hippocampus. Haloperidol (0.05 and 2 mg/kg), clozapine (0.5 and 20 mg/kg), or vehicle were administered i.p. for 28 days, followed by bromodeoxyuridine (BrdU, 200 mg/kg, i.p.), a marker of DNA synthesis. One group of rats was killed 24 h following BrdU administration and BrdU-positive cells were quantified to assess the effects of drug treatment on cell proliferation. The remaining animals continued on antipsychotic medication for an additional 3 weeks following BrdU administration to assess the effects of antipsychotics on cell survival. Our results show that 24 h following BrdU, a low dose of clozapine (0.5 mg/kg) increased the number of BrdU-positive cells in the dentate gyrus (DG) by two-fold. Neither 20 mg/kg of clozapine nor haloperidol had any effect on cell proliferation in DG. Moreover, neither drug at either dose had an effect on the number of newly generated neurons surviving in the DG 3 weeks following BrdU administration. These preliminary findings suggest that clozapine may influence the number of cells which divide, but antipsychotics do not promote the survival of the newly generated neurons at 3 weeks after a BrdU injection.

Analysis of Variance↗

PubMed2004

Using animal models to test a neurodevelopmental hypothesis of schizophrenia.

A series of studies has shown that neonatal excitotoxic disconnection of the rat ventral hippocampus may serve as a heuristic model of schizophrenia. The model mimics a spectrum of neurobiologic and behavioural features of schizophrenia. It produces functional pathology in critical brain regions implicated in schizophrenia and connected with the hippocampal formation, namely, the striatum, nucleus accumbens and the prefrontal cortex. These brain regions are also targeted by antipsychotic drugs. Neonatal insult leads in young adulthood to the emergence of abnormalities in a number of dopamine-related behaviours. It also models some of the negative aspects of schizophrenia, such as social impairments and working memory deficits. Moreover, our data show that even transient inactivation of the ventral hippocampus during a critical period of development that produces subtle anatomical changes in the hippocampus may be sufficient to trigger behavioural changes similar to those observed in animals with the permanent excitotoxic lesion. The results of bromodeoxyuridine (BrdU) incorporation studies show that this transient disconnection in the CA1 and CA2 area of the hippocampus may have long-lasting consequences for neurogenesis in the dentate gyrus. Our data suggest that neonatal disconnection of the ventral hippocampus alters development and plasticity of prefrontal cortical circuitry and produces a constellation of behavioural and cellular changes that mimic many aspects of schizophrenia. The neonatal hippocampal disconnection model represents a potential new model of schizophrenia without a gross anatomical lesion.

Animals↗

PubMed2003

The anxiogenic beta-carboline FG-7142 inhibits locomotor exploration similarly in postweanling and adult rats.

The beta-carboline FG-7142 exerts many stress-like effects in the adult rat, including the inhibition of locomotor exploration. However, comparable effects in immature animals have not been reported. Stress-like effects of FG-7142 are mediated via its inverse agonist actions on gamma-aminobutyric acid (GABA) receptors. GABA systems change considerably with development and GABA agonists such as diazepam have opposite behavioral actions in immature and adult rats. Accordingly, we compared FG-7142 effects on locomotor exploration in postweanling and adult rats. Postweanling male rats (24 days) and adult rats (90 days) received a single injection of vehicle or FG-7142 (15 mg/kg i.p.) and 15 min later were placed in photocell monitors for 1 h. Although postweanling animals traveled a smaller distance overall than adults, FG-7142 inhibited locomotor exploration to a similar degree in both groups. We conclude that FG-7142 exerts stress-like effects in postweanling rats and may be considered for use as a model of childhood stress.

Age Factors↗

PubMed2003

Behavioral effects of neonatal and adult excitotoxic lesions of the mediodorsal thalamus in the adult rat.

We examined in the rat, the effects of neonatal (postnatal Day 7) and adult excitotoxic lesions of the mediodorsal thalamus (MDT), a brain area innervating the prefrontal cortex and implicated as a site of neuropathology in schizophrenia. Previous studies showed that rats with neonatal excitotoxic damage of the ventral hippocampus (VH), used as an animal model of this disorder, display in young adulthood a variety of abnormalities reminiscent of schizophrenia, including hyperactivity to stressful stimuli and amphetamine. It has been speculated that behavioral abnormalities of the neonatally VH lesioned animals are mediated through MDT projections to the prefrontal cortex. We tested if rats with ibotenic acid (1.5 microg per hemisphere in neonates, 2 microg in adults) lesions of MDT exhibited motor hyperactivity in the same experimental conditions (i.e. in response to novelty, saline injections and amphetamine administration) as rats with the VH lesions. We found that, in contrast to rats with VH lesions, neonatally lesioned MDT rats showed reduced vertical activity in response to amphetamine and no changes in locomotor activity to novelty, saline or amphetamine injections 7 weeks postlesion. Adult lesioned MDT rats exhibited no changes in motor activity as compared to controls at 7 weeks postlesion. These results indicate that neonatal or adult excitotoxic lesions of MDT do not produce behavioral changes analogous to those seen after neonatal VH lesions and do not appear to reproduce animal model-like features of schizophrenia.

Aging↗

PubMed2003

Neonatal ventral hippocampal damage modifies serum corticosterone and dopamine release responses to acute footshock in adult Sprague-Dawley rats.

Rats with excitotoxic neonatal ventral hippocampal lesions (NVHL) manifest in early adulthood a variety of behavioral and neurochemical abnormalities mimicking those seen in patients with schizophrenia. Some of these aberrations implicate malfunction of the midbrain dopamine systems. We studied NVHL effects on dopamine release in the rat frontal cortex, nucleus accumbens, and striatum during acute stress caused by inescapable continuous footshock (0.45 mA). Serum total corticosterone and prolactin levels were used as peripheral indices of stress. As an indirect index of dopamine release, tissue 3-methoxytyramine levels attained in vivo 10 min after monoamine oxidase inhibition was assayed in rats sacrificed by instantaneous microwave fixation of the brain tissue. Nonshocked NVHL rats showed significantly less nucleus accumbens' 3-methoxytyramine accumulation than their sham counterparts. Frontal cortical 3-methoxytyramine levels rose similarly after 20-min footshock in both groups of rats, but while it normalized after 60-min footshock in the sham rats, it did not decrease in the NVHL rats. Nucleus accumbens' 3-methoxytyramine was significantly elevated after either 20-min or 60-min footshock in both groups, whereas striatal 3-methoxytyramine was significantly elevated in the NVHL rats only. Serum corticosterone showed similar elevations in the sham and NVHL rats, but the patterns differed in that there was no attenuation after 60-min footshock in the latter. The lesion did not affect serum prolactin response. These data indicate that neonatal ventral hippocampal damage enhances and prolongs certain neural and neuroendocrine responses to acute physical stressor(s), and thus may affect adaptation and enhance detrimental effects of stress.

Animals↗