1. Diminished responses to monoaminergic antidepressants but not ketamine in a mouse model for neuropsychiatric lupus
- Author
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Durga Shiva Prasad, Rick L. Pieschl, Yu-Wen Li, Siva Subramani, Muppana V. Sreedhara, Shailesh Dudhgaonkar, B.N. Srikumar, Reeba K. Vikramadithyan, Ratika Srivastava, Manish Lal Das, Justin Vijay Louis, Narasimharaju Kalidindi, Mahesh Paschapur, Bharath Adepu, Manjunath Ramarao, Pattipati S. Naidu, Linda J. Bristow, Vijaya K. Kuchibhotla, and Jignesh Nagar
- Subjects
Male ,Mice, Inbred MRL lpr ,medicine.medical_treatment ,Pharmacology ,03 medical and health sciences ,Depressive Disorder, Treatment-Resistant ,Mice ,0302 clinical medicine ,immune system diseases ,Monoaminergic ,medicine ,Animals ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Lupus Erythematosus, Systemic ,Pharmacology (medical) ,Ketamine ,Receptor, Serotonin, 5-HT2A ,skin and connective tissue diseases ,Antipsychotic ,Depression (differential diagnoses) ,Systemic lupus erythematosus ,business.industry ,medicine.disease ,Antidepressive Agents ,030227 psychiatry ,Psychiatry and Mental health ,Disease Models, Animal ,Antidepressant ,business ,Corticosterone ,Treatment-resistant depression ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Background: A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression–like behavior. Aims: We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice. Methods and results: MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30 mg/kg, intraperitoneally (i.p.)), imipramine (10 mg/kg, i.p.) or duloxetine (10 mg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03 mg/kg, subcutaneously)+fluoxetine (30 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.)+fluoxetine (30 mg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10 mg/kg, i.p.) or escitalopram (5 mg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies’ titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HT2aR expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity. Conclusion: In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery.
- Published
- 2018