Int J Neuropsychopharmacol. 2015 Mar 26;18(10):pyv038. doi: 10.1093/ijnp/pyv038.

Two Chronic Stress Models Based on Movement Restriction in Rats Respond Selectively to Antidepressant Drugs: Aldolase C As a Potential Biomarker.

Ampuero E1, Luarte A1, Santibañez M1, Varas-Godoy M1, Toledo J1, Diaz-Veliz G1, Cavada G1, Rubio FJ1, Wyneken U2.
  • 1Facultad de Medicina, Universidad de los Andes, Chile (Dr Ampuero, Mr Luarte, Dr Santibañez, Mr Toledo, Drs Varas-Godoy, Cavada, Rubio, and Wyneken); Laboratorio de Neurobiologia, Centro de Investigaciones Biomedicas, Universidad Andres Bello, Santiago, Chile (Dr Ampuero); Facultad de Medicina, Universidad de Chile (Dr Diaz-Veliz); Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (Dr Varas-Godoy).
  • 2Facultad de Medicina, Universidad de los Andes, Chile (Dr Ampuero, Mr Luarte, Dr Santibañez, Mr Toledo, Drs Varas-Godoy, Cavada, Rubio, and Wyneken); Laboratorio de Neurobiologia, Centro de Investigaciones Biomedicas, Universidad Andres Bello, Santiago, Chile (Dr Ampuero); Facultad de Medicina, Universidad de Chile (Dr Diaz-Veliz); Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden (Dr Varas-Godoy). uwyneken@uandes.cl.

 

Abstract

BACKGROUND: Clinically depressed individuals respond to different types of antidepressants, suggesting that different neurobiological mechanisms may be responsible for their depression. However, animal models to characterize this are not yet available.

METHODS: We induced depressive-like behaviors in rats using 2 different chronic stress models: restraint in small cages or immobilization in adaptable plastic cones. Both models increased anxiety responses evaluated by novelty-suppressed feeding and the elevated plus-maze; increased learned helplessness evaluated by the tail suspension and forced swimming tests; and increased anhedonia evaluated by the sucrose preference test.

RESULTS: We assessed the ability of 2 different types of antidepressants to ameliorate depressive-like behaviors. We administered the serotonin reuptake inhibitor fluoxetine or the noradrenaline reuptake inhibitor reboxetine once daily for 28 days to rats that received either chronic restraint or immobilization stress, or no stress. Behavioral analysis revealed that fluoxetine ameliorated depressive-like behaviors when induced by chronic restraint stress, whereas reboxetine ameliorated these behaviors when induced by chronic immobilization stress. To further test biological differences between both models, we evaluated the levels of Aldolase C, an enzyme expressed by forebrain astrocytes that is regulated by antidepressant treatment, in the cerebrospinal fluid: chronic restraint stress, but not immobilization stress, increased the levels of Aldolase C. Moreover, the presence of astrocyte-derived Aldolase C-GFP in the cerebrospinal fluid indicates its central origin.

CONCLUSIONS: Two stress paradigms induced depressive-like behaviors that were sensitive to different antidepressant treatments. Biomarkers such as Aldolase C could help determine optimal antidepressant treatments for clinically depressed patients.

KEYWORDS: Fluoxetine; chronic stress; immobilization; reboxetine; restraint

PMID: 25813018

 

Supplement:

Searching biomarkers of stress-induced disorders

Estíbaliz Ampuero and Ursula Wyneken

fig1Different types of stress precipitate mood disorders such as major depressive disorder and bipolar disorder. However, although mood disorders are highly heterogeneous both with respect to symptoms as well as probably to the underlying biological mechanisms, they are commonly treated with antidepressant drugs that act by increasing synaptic levels of the neurotransmitters serotonin and/or noradrenaline. The different antidepressant drug families, i.e. acting selectively on neurotransmitter systems, are prescribed mostly based on the clinical experience of psychiatrists. Although the heterogeneity of mood disorders are well accepted, a selectivity of drugs on potential disease subtypes have not been explored, and no animal models are available. Antidepressant drugs elevate neurotransmitter levels immediately after intake, however, patients have to wait weeks or months before achieving therapeutic remission. Moreover, many patients do not respond to the first treatment, and a second treatment with a different drug or a different dose, i.e. augmentation, has to be chosen. The correct election of an effective treatment at the beginning of the pharmacological treatment, able to shorten treatment periods and to alleviate the suffering of patients awaits for better diagnostic tools, such as biomarkers able to support psychiatrists in a non-biased manner. Additional difficulties come from the fact that the animal models for mood disorders are interesting attempts to reproduce depressive behaviors, but it is unknown whether the disease itself can be correctly modeled in rodents. In the paper: “Two chronic stress models based on movement restriction in rats respond selectively to antidepressant drugs: Aldolase C as a potential biomarker” by E. Ampuero, A. Luarte, M. Santibañez, M. Varas-Godoy, J. Toledo, G. Diaz-Veliz, G. Cavada, F.J. Rubio, and U. Wyneken, two fundamental findings have been done (Figure 1) (Ampuero et al., 2015):

 

1.- Rats were exposed to chronic stress by movement restriction (Buynitsky & Mostofsky, 2009). However, to attain restriction, two different “devices” were used that are commonly reported in the literature as very similar: small cages to reduce movement (stress by “restraint”) or plastic bags to impede movement (stress by “immobilization”). Both procedures induced depressive-like behaviors such as anhedonia, learned helplessness and anxiety. However, when these behaviors were induced by restraint, they were reverted by fluoxetine treatment (a drug that elevates the levels of the neurotransmitter serotonin) while after immobilization, the drug reboxetine (that elevates noradrenaline levels) reverted depressive behaviors effectively. Thus, we describe for the first time two animal models that are differentially affected by treatment with antidepressant drugs belonging to different drug families. The selective pharmacological responses suggests that differential underlying neurobiological mechanisms are in play. This could be reflected by the presence of biomarkers.

2.- In the search of biomarkers, it was found that a protein expressed by forebrain astrocytes is differentially present in the cerebrospinal fluid of rats exposed to stress,: this protein is the glycolitic enzyme Aldolase C (Sandoval et al., 2013). Aldolase C increases over 8 times after stress by restraint, but is not detectable after immobilization.

It is shown for the first time that the behavioral effects produced by different types of stress respond selectively to antidepressant drugs in two animal models, and this is characterized by a protein biomarker. The translation of these findings into the clinic needs further studies and the assessment molecular marker panels that would help to predict subtypes of diseases, preferential treatments or help to monitor treatment response. This study is a milestone in the search of biomarkers in animal models and the selective action of antidepressant therapy. Understanding the participation of forebrain astrocytes in the stress response will help to unravel underlying mechanisms and will hopefully booster the rational design of new antidepressant therapies.

 

 

 

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