Validation of chronic mild stress in the Wistar-Kyoto rat as an animal model of treatment-resistant depression

Willner, Paul; Gruca, Piotr; Łasoń, Magdalena; Tota-Glowczyk, Katarzyna; Litwa, Ewa; Niemczyk, Monika; Papp, Mariusz

doi:10.1097/fbp.0000000000000431

Cited by 66 publications

(58 citation statements)

References 71 publications

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“…fear conditioning tests) 49 . On note, in the literature addressing the performance of Kyoto rats in the EPM, Langen and Dost 50 , and Willner 51 reported an anxious profile for this strain, however other authors 15,16 showed no differences when comparing it with the Wistar rat. Taken together, these results suggest that the behavioural parameters measured in the EPM are not consistent when applied to characterize a rodent strain (trait), which is supposed to be stable over time, at least without treatment 52 .…”

Section: Discussionmentioning

confidence: 91%

Early-life stress affects drug abuse susceptibility in adolescent rat model independently of depression vulnerability

Alves

Oliveira

Lopes

et al. 2020

Sci Rep

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The development of substance abuse problems occurs due to a diverse combination of risk factors. Among these risks, studies have reported depression and early-life stress as of importance. These two factors often occur simultaneously, however, there is a lack of understanding of how their combined effect may impact vulnerability to drug abuse in adolescence. The present study used rats with different vulnerability to depression (Wistar and Wistar-Kyoto) to investigate the impact of maternal separation (MS) on emotional state and drug addiction vulnerability during the adolescence period. Mothers and their litters were subjected to MS (180 min/day) from postnatal day 2 to 14. The offspring emotional state was assessed by observing their exploratory behavior. Drug abuse vulnerability was assessed through conditioning to cocaine. MS impacted the emotional state in both strains. Wistar responded with increased exploration, while Wistar-Kyoto increased anxiety-like behaviours. Despite the different coping strategies displayed by the two strains when challenged with the behavioural tests, drug conditioning was equally impacted by MS in both strains. Early-life stress appears to affect drug abuse vulnerability in adolescence independently of a depression background, suggesting emotional state as the main driving risk factor. The development of substance abuse problems occurs due to an almost unpredictable combination of risk factors. Among the common risk factors, mental disorder and emotional stress are constantly cited as important 1,2. Among the main mental disorders, depression is one of the most common in adolescents, inspiring great concern due to its acute and long-lasting consequences 3. Depression in adolescence affects the physical, emotional and social development and can persist and recur into adulthood 4,5. Addiction and depression can be described as having a bidirectional relationship, in which individuals that use drugs for recreational purposes are more likely to develop depression, while individuals that suffer from depression are more likely to develop addiction due to the consumption of drugs (or alcohol) to cope with the depressive symptoms 6,7. Of note, depression and drug abuse comorbidity is highly prevalent in adolescence 8. Similarly to depression, emotional stress and its impact on one's physical and affective condition may lead to the development of addiction. Furthermore, it is known that early life stress, such as children carelessness and mistreatment, can also induce anxiety and depression in adulthood 9. This issue becomes especially relevant given the likelihood of the co-occurrence of these risk factors during early life. There is increased awareness about

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Section: Discussionmentioning

confidence: 91%

Early-life stress affects drug abuse susceptibility in adolescent rat model independently of depression vulnerability

Alves

Oliveira

Lopes

et al. 2020

Sci Rep

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“…Certainly, perseveration has been proved to be augmented by stress 67 . It has been repeatedly observed that CUS decreases the discrimination index either marginally 68 or significantly 69–74 , although others have reported that only a subset of CUS responders shows memory impairments in the ORT 75 . The lack of significant differences in the discrimination index may be related to the features of the objects used.…”

Section: Resultsmentioning

confidence: 99%

Behavioural characterisation of chronic unpredictable stress based on ethologically relevant paradigms in rats

Sequeira‐Cordero

Salas-Bastos

Fornaguera

et al. 2019

Sci Rep

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The chronic unpredictable stress (CUS) paradigm is extensively used in preclinical research. However, CUS exhibits translational inconsistencies, some of them resulting from the use of adult rodents, despite the evidence that vulnerability for many psychiatric disorders accumulates during early life. Here, we assessed the validity of the CUS model by including ethologically-relevant paradigms in juvenile rats. Thus, socially-isolated (SI) rats were submitted to CUS and compared with SI (experiment 1) and group-housed controls (experiment 1 and 2). We found that lower body-weight gain and hyperlocomotion, instead of sucrose consumption and preference, were the best parameters to monitor the progression of CUS, which also affected gene expression and neurotransmitter contents associated with that CUS-related phenotype. The behavioural characterisation after CUS placed locomotion and exploratory activity as the best stress predictors. By employing the exploratory factor analysis, we reduced each behavioural paradigm to few latent variables which clustered into two general domains that strongly predicted the CUS condition: (1) hyper-responsivity to novelty and mild threats, and (2) anxiety/depressive-like response. Altogether, the analyses of observable and latent variables indicate that early-life stress impairs the arousal-inhibition system leading to augmented and persistent responses towards novel, rewarding, and mildly-threatening stimuli, accompanied by lower body-weight gain.

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“…CUS-exposed rodents that fail to respond to conventional antidepressants are considered non-responders 84 , 85 . Also, Wistar-Kyoto rats subjected to CUS have been recently validated as a model of TRD 86 , 87 . Notably, these models showed a good response to deep brain stimulation 84 – 87 ; however, the effects of rTMS in these treatment-resistant animals have not yet been studied.…”

Section: Discussionmentioning

confidence: 99%

Recovering from depression with repetitive transcranial magnetic stimulation (rTMS): a systematic review and meta-analysis of preclinical studies

Risio¹,

Borgi

Pettorruso

et al. 2020

Transl Psychiatry

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Repetitive transcranial magnetic stimulation (rTMS) has gained growing interest for the treatment of major depression (MDD) and treatment-resistant depression (TRD). Most knowledge on rTMS comes from human studies as preclinical application has been problematic. However, recent optimization of rTMS in animal models has laid the foundations for improved translational studies. Preclinical studies have the potential to help identify optimal stimulation protocols and shed light on new neurobiological-based rationales for rTMS use. To assess existing evidence regarding rTMS effects on depressive-like symptoms in rodent models, we conducted a comprehensive literature search in accordance with PRISMA guidelines (PROSPERO registration number: CRD42019157549). In addition, we conducted a meta-analysis to determine rTMS efficacy, performing subgroup analyses to examine the impact of different experimental models and neuromodulation parameters. Assessment of the depressive-like phenotype was quite homogeneous whilst rTMS parameters among the 23 included studies varied considerably. Most studies used a stress-induced model. Overall, results show a largely beneficial effect of active rTMS compared to sham stimulation, as reflected in the statistically significant recovery of both helplessness (SDM 1.34 [1.02;1.66]) and anhedonic (SDM 1.87 [1.02;2.72]) profiles. Improvement of the depressive-like phenotype was obtained in all included models and independently of rTMS frequency. Nonetheless, these results have limited predictive value for TRD patients as only antidepressant-sensitive models were used. Extending rTMS studies to other MDD models, corresponding to distinct endophenotypes, and to TRD models is therefore crucial to test rTMS efficacy and to develop cost-effective protocols, with the potential of yielding faster clinical responses in MDD and TRD.

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Validation of chronic mild stress in the Wistar-Kyoto rat as an animal model of treatment-resistant depression

Cited by 66 publications

References 71 publications

Early-life stress affects drug abuse susceptibility in adolescent rat model independently of depression vulnerability

Early-life stress affects drug abuse susceptibility in adolescent rat model independently of depression vulnerability

Behavioural characterisation of chronic unpredictable stress based on ethologically relevant paradigms in rats

Recovering from depression with repetitive transcranial magnetic stimulation (rTMS): a systematic review and meta-analysis of preclinical studies

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