title: NK1 receptor antagonism lowers occupancy requirement for antidepressant-like effects of SSRIs in the gerbil forced swim test.
abstract: The known interactions between the serotonergic and neurokinin systems suggest that serotonin reuptake inhibitor (SSRIs) efficacy may be improved by neurokinin-1 receptor (NK1R) antagonism. In the current studies combination of a subeffective dose of an SSRI (0.3 mg/kg fluoxetine or 0.03 mg/kg citalopram) with a subeffective dose of an NK1R antagonist (0.3 mg/kg aprepitant or 1 mg/kg CP-122,721) produced efficacy in the gerbil forced swim test (FST). Serotonin transporter (SERT) occupancy produced by 1 mg/kg fluoxetine (lowest efficacious dose) was 52 ± 5% and was reduced to 29 ± 4% at 0.3 mg/kg, a dose that was efficacious in combination with 0.3 mg/kg aprepitant or 1 mg/kg CP-122,721; the corresponding NK1R occupancies were 79 ± 4% and 61 ± 4% for aprepitant and CP-122,721, respectively. For citalopram, SERT occupancy at the lowest efficacious dose (0.1 mg/kg) was 50 ± 4% and was reduced to 20 ± 5% at 0.03 mg/kg, a dose that was efficacious when combined with aprepitant (0.3 mg/kg). Aprepitant (10 mg/kg) augmented the serotonin elevation produced by fluoxetine (1 or 10 mg/kg) in the gerbil prefrontal cortex; i.e. NK1R antagonism can modulate serotonin responses. A novel orally-available dual-acting NK1R antagonist/SERT inhibitor BMS-795176 is described; gerbil Ki = 1.4 and 1 nM at NK1R and SERT, respectively. BMS-795176 was efficacious in the gerbil FST; efficacy was observed with 35 ± 3% SERT occupancy and 73 ± 3% NK1R occupancy. The interaction between NK1R antagonism and SERT inhibition to lower the SERT occupancy required for antidepressant-like efficacy suggests that BMS-795176 has the potential to improve efficacy with a reduction in SSRI-associated side effects.
authors.affiliation: Neuroscience Biology, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492-7660, USA.
authors.forename: Snjezana
authors.initials: S
authors.lastname: Lelas
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Wallace-Boone
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Taber
authors.forename: Amy E
authors.initials: AE
authors.lastname: Newton
authors.forename: Rick L
authors.initials: RL
authors.lastname: Pieschl
authors.forename: Carl D
authors.initials: CD
authors.lastname: Davis
authors.forename: Thaddeus F
authors.initials: TF
authors.lastname: Molski
authors.forename: Kimberly S
authors.initials: KS
authors.lastname: Newberry
authors.forename: Michael F
authors.initials: MF
authors.lastname: Parker
authors.forename: Kevin W
authors.initials: KW
authors.lastname: Gillman
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D000077608:Aprepitant; D015283:Citalopram / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005473:Fluoxetine / Q000494:pharmacology*; D005849:Gerbillinae; D057809:HEK293 Cells; D006801:Humans; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D018040:Receptors, Neurokinin-1 / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D000077608:Aprepitant; D015283:Citalopram; D005473:Fluoxetine; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018040:Receptors, Neurokinin-1; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C099414:(2S,3S)-2-phenyl-3-((5-trifluoromethoxy-2-methoxy)benzylamino)piperidine
keywords: BMS-795176; Depression; Gerbil; Neurokinin-1 receptor; Occupancy; Serotonin transporter