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.
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.
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.