Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment
Background: Exposure of Flinders Sensitive Line (FSL) rats to post-weaning social isolation rearing (SIR) causes depressive- and social anxiety-like symptoms resistant to, or worsened by, fluoxetine. SIR typically presents with psychotic-like symptoms, while the paradoxical response to fluoxetine su...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-12-01
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| Series: | IBRO Neuroscience Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667242122000616 |
| _version_ | 1811184427341971456 |
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| author | K. Mncube B.H. Harvey |
| author_facet | K. Mncube B.H. Harvey |
| author_sort | K. Mncube |
| collection | DOAJ |
| description | Background: Exposure of Flinders Sensitive Line (FSL) rats to post-weaning social isolation rearing (SIR) causes depressive- and social anxiety-like symptoms resistant to, or worsened by, fluoxetine. SIR typically presents with psychotic-like symptoms, while the paradoxical response to fluoxetine suggests unaddressed psychotic-like manifestations. Psychotic depression (MDpsy) is invariably treatment resistant. To further explore the mood-psychosis continuum in fluoxetine resistant FSL-SIR rats (Mncube et al., 2021), mood-, psychotic-, anxiety-, and social-related behaviour and biomarker response to antidepressant/antipsychotic treatment was studied in FSL-SIR rats. Methods: Sprague Dawley (SD) and FSL pups were subjected to social rearing or SIR from postnatal day (PND) 21. Thereafter FSL-SIR rats received olanzapine (5 mg/kg x 14 days) or olanzapine+fluoxetine (OLZ+FLX; 5 mg/kg + 10 mg/kg for 14 days) from PND 63. Psychotic-like, depressive, anxiety, and social behaviour were assessed from PND 72, versus saline-treated FSL-SIR rats, using the prepulse inhibition (PPI), forced swim, open field and social interaction tests. Post-mortem cortico-hippocampal norepinephrine (NE), serotonin (5-HT), and dopamine (DA), as well as plasma corticosterone and dopamine-beta-hydroxylase levels were evaluated. Results: SD-SIR and FSL-SIR rats present with significant depressive-like behaviour (p < 0.01) as well as significantly reduced sensorimotor gating (p < 0.01), although exacerbation versus SIR alone was not observed. Anxiety was significant in FSL-SIR (p < 0.01) but not SD-SIR rats. No deficit in social behaviour was evident. Cortico-hippocampal monoamines (NE, 5-HT, DA; p < .05) and dopamine beta hydroxylase (d = 1.13) were reduced in FSL-SIR rats, less so in SD-SIR rats. Except for dopamine-beta-hydroxylase, these deficits were reversed by both olanzapine and OLZ+FLX (p < 0.01). OLZ+FLX was superior to reverse hippocampal NE and DA changes (p < 0.01). However, OLZ (p < .05) and OLZ+FLX (p < .01) worsened depressive-like behaviour and failed to reverse PPI deficits in FSL-SIR rats. Conclusion: SIR-exposed FSL rats display worsened anxiety, as well as depressive and psychotic-like symptoms, variably responsive to olanzapine or OLZ+FLX. Depleted monoamines are reversed by OLZ+FLX, less so by olanzapine. FSL-SIR rats show promising face and construct but limited predictive validity for MDpsy, perhaps more relevant for bipolar disorder. |
| first_indexed | 2024-04-11T13:13:07Z |
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| institution | Directory Open Access Journal |
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| language | English |
| last_indexed | 2024-04-11T13:13:07Z |
| publishDate | 2022-12-01 |
| publisher | Elsevier |
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| series | IBRO Neuroscience Reports |
| spelling | doaj.art-eb634e16536c453bb52dce7c054fc1522022-12-22T04:22:33ZengElsevierIBRO Neuroscience Reports2667-24212022-12-0113284298Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatmentK. Mncube0B.H. Harvey1Centre of Excellence for Pharmaceutical Sciences (PharmaCen), Division of Pharmacology, School of Pharmacy, North-West University (Potchefstroom Campus), South AfricaCentre of Excellence for Pharmaceutical Sciences (PharmaCen), Division of Pharmacology, School of Pharmacy, North-West University (Potchefstroom Campus), South Africa; MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Mental Health and Neuroscience Institute, University of Cape Town, South Africa; Corresponding author at: Centre of Excellence for Pharmaceutical Sciences (PharmaCen), Division of Pharmacology, School of Pharmacy, North-West University (Potchefstroom Campus), South Africa.Background: Exposure of Flinders Sensitive Line (FSL) rats to post-weaning social isolation rearing (SIR) causes depressive- and social anxiety-like symptoms resistant to, or worsened by, fluoxetine. SIR typically presents with psychotic-like symptoms, while the paradoxical response to fluoxetine suggests unaddressed psychotic-like manifestations. Psychotic depression (MDpsy) is invariably treatment resistant. To further explore the mood-psychosis continuum in fluoxetine resistant FSL-SIR rats (Mncube et al., 2021), mood-, psychotic-, anxiety-, and social-related behaviour and biomarker response to antidepressant/antipsychotic treatment was studied in FSL-SIR rats. Methods: Sprague Dawley (SD) and FSL pups were subjected to social rearing or SIR from postnatal day (PND) 21. Thereafter FSL-SIR rats received olanzapine (5 mg/kg x 14 days) or olanzapine+fluoxetine (OLZ+FLX; 5 mg/kg + 10 mg/kg for 14 days) from PND 63. Psychotic-like, depressive, anxiety, and social behaviour were assessed from PND 72, versus saline-treated FSL-SIR rats, using the prepulse inhibition (PPI), forced swim, open field and social interaction tests. Post-mortem cortico-hippocampal norepinephrine (NE), serotonin (5-HT), and dopamine (DA), as well as plasma corticosterone and dopamine-beta-hydroxylase levels were evaluated. Results: SD-SIR and FSL-SIR rats present with significant depressive-like behaviour (p < 0.01) as well as significantly reduced sensorimotor gating (p < 0.01), although exacerbation versus SIR alone was not observed. Anxiety was significant in FSL-SIR (p < 0.01) but not SD-SIR rats. No deficit in social behaviour was evident. Cortico-hippocampal monoamines (NE, 5-HT, DA; p < .05) and dopamine beta hydroxylase (d = 1.13) were reduced in FSL-SIR rats, less so in SD-SIR rats. Except for dopamine-beta-hydroxylase, these deficits were reversed by both olanzapine and OLZ+FLX (p < 0.01). OLZ+FLX was superior to reverse hippocampal NE and DA changes (p < 0.01). However, OLZ (p < .05) and OLZ+FLX (p < .01) worsened depressive-like behaviour and failed to reverse PPI deficits in FSL-SIR rats. Conclusion: SIR-exposed FSL rats display worsened anxiety, as well as depressive and psychotic-like symptoms, variably responsive to olanzapine or OLZ+FLX. Depleted monoamines are reversed by OLZ+FLX, less so by olanzapine. FSL-SIR rats show promising face and construct but limited predictive validity for MDpsy, perhaps more relevant for bipolar disorder.http://www.sciencedirect.com/science/article/pii/S2667242122000616InflammationFluoxetine plus olanzapineAnimal modelSocial anxietyPsychotic depressionBipolar disorder, dual hit |
| spellingShingle | K. Mncube B.H. Harvey Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment IBRO Neuroscience Reports Inflammation Fluoxetine plus olanzapine Animal model Social anxiety Psychotic depression Bipolar disorder, dual hit |
| title | Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment |
| title_full | Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment |
| title_fullStr | Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment |
| title_full_unstemmed | Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment |
| title_short | Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment |
| title_sort | bio behavioural changes in treatment resistant socially isolated fsl rats show variable or improved response to combined fluoxetine olanzapine versus olanzapine treatment |
| topic | Inflammation Fluoxetine plus olanzapine Animal model Social anxiety Psychotic depression Bipolar disorder, dual hit |
| url | http://www.sciencedirect.com/science/article/pii/S2667242122000616 |
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