title: Bacillus Calmette-Guérin vaccine induces a selective serotonin reuptake inhibitor (SSRI)-resistant depression like phenotype in mice.
abstract: Preclinical studies have shown that administration of Bacillus Calmette-Guérin (BCG) vaccine induces depression-like behaviors in mice; however, the effect of antidepressant drug treatment has not been reported earlier. In the present study, we induced depression-like behavior by administering BCG vaccine to BALB/c mice. BCG treatment produced robust serum sickness as shown by a decrease in body weight, reduced spontaneous locomotor activity and reduced voluntary wheel running activity. BCG treatment also elevated plasma IL6 and IFNγ levels and produced a marked activation of lung IDO activity. At a time point when serum sickness-related behaviors had fully recovered (i.e., day 14) BCG-treated mice showed a significant increase in immobility in the forced swim test (FST) and tail suspension test (TST) indicative of a pro-depressant phenotype. We observed significant increase in [(3)H]PK11195 binding in cortex and hippocampus regions of BGC-treated mice in comparison to saline-treated mice indicating prominent neuroinflammation. Pharmacological evaluation of FST behavior in BCG-treated mice demonstrated selective resistance to the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and escitalopram. In contrast the tricyclic antidepressant imipramine, the dual serotonin/norepinephrine reuptake inhibitor (SNRI) duloxetine, and the dual dopamine/norepinephrine reuptake inhibitor (DNRI) nomifensine retained antidepressant efficacy in these mice. The lack of efficacy with acute treatment with SSRIs could not be explained either by differences in drug exposure or serotonin transporter (SERT) occupancy. Our results demonstrate that BCG-vaccine induced depression like behavior is selectively resistant to SSRIs and could potentially be employed to evaluate novel therapeutic agents being developed to treat SSRI-resistance in humans.
authors.affiliation: Biology, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: K
authors.initials: K
authors.lastname: Vijaya Kumar
authors.affiliation: Biology, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Anjuman
authors.initials: A
authors.lastname: Rudra
authors.affiliation: Biology, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: M V
authors.initials: MV
authors.lastname: Sreedhara
authors.affiliation: Biology, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: T
authors.initials: T
authors.lastname: Siva Subramani
authors.affiliation: Biology, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Durga Shiva
authors.initials: DS
authors.lastname: Prasad
authors.affiliation: Biology, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Manish Lal
authors.initials: ML
authors.lastname: Das
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Senthil
authors.initials: S
authors.lastname: Murugesan
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Rajbharan
authors.initials: R
authors.lastname: Yadav
authors.affiliation: Pharmaceutical Candidate Optimization, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Ravi Kumar
authors.initials: RK
authors.lastname: Trivedi
authors.affiliation: Biology, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Justin V
authors.initials: JV
authors.lastname: Louis
authors.affiliation: Neuroscience Biology, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.affiliation: Neuroscience Biology, Research & Development, Bristol-Myers Squibb Company, Wallingford, CT, USA.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bristow
authors.affiliation: Biology, Biocon-Bristol Myers Squibb Research & Development Center, Syngene International Limited, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India.
authors.forename: Pattipati S
authors.initials: PS
authors.lastname: Naidu
authors.affiliation: Biology, Bristol-Myers Squibb India Pvt. Ltd., Biocon-Bristol Myers Squibb Research & Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore 560 099, India. Electronic address: reeba.vikramadithyan@bms.com.
authors.forename: Reeba Kannimel
authors.initials: RK
authors.lastname: Vikramadithyan
mesh_terms: D000818:Animals; D001500:BCG Vaccine; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D015283:Citalopram / Q000494:pharmacology / Q000627:therapeutic use*; D061218:Depressive Disorder, Treatment-Resistant / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009043:Motor Activity / Q000187:drug effects; D010641:Phenotype; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
chemical_list: D001500:BCG Vaccine; D015283:Citalopram; D005473:Fluoxetine; D007371:Interferon-gamma; D015850:Interleukin-6; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors
keywords: BCG vaccine; Forced swim test; Indoleamine-2,3-dioxygenase; Major depressive disorder; Neuroinflammation; SSRI resistance; Serum sickness; Tail suspension test