oai:pubmedcentral.nih.gov:9529...
Elsevier
IBRO Neuroscience Reports
2022
12/12/2022
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.
Mncube, K.,Harvey, B.H., 2022, Bio-behavioural changes in treatment-resistant socially isolated FSL rats show variable or improved response to combined fluoxetine-olanzapine versus olanzapine treatment, Elsevier