title: Role of glutamate and advantages of combining memantine with a 5HT6 ligand in a model of depression.
abstract: BACKGROUND
  It is a well-known fact that 5HT6 ligands increase glutamate levels. In the current study we investigated whether a 5HT6 antagonist, SB399885 would show antidepressant like property at a dose which would significantly increase the glutamate levels. Further we studied if the combination of a 5HT6 antagonist and N-methyl-D-aspartate (NMDA) antagonist, memantine would restore the antidepressant property. As dementia and depression are co-morbid, we evaluated if this combination would have an effect on cognition.
  
  
  METHODS
  The antidepressant like property of SB399885 alone and in combination with memantine was investigated using the forced swim test (FST). Object recognition task (ORT) was used to investigate the combination therapy on cognition. Additionally, glutamate levels in prefrontal cortex and corresponding brain concentration of SB399885 were determined.
  
  
  RESULTS
  Brain concentrations of SB399885 equal to or greater than 553 nM significantly increased brain glutamate levels and reduced immobility time in FST. When combined with memantine, glutamate levels and immobility time in FST was reduced. A dose dependent increase in the discriminative index was observed in ORT.
  
  
  CONCLUSIONS
  Loss of antidepressant like property seen at the highest tested dose of SB399885 could be due to increased glutamate levels which was reversed by memantine. Combining memantine and SB399885 offers the advantage of extending the therapeutic window of antidepressant like property of SB399885 as well as having procognitive effect. The combination therapy holds promise in treatment of dementia associated with depression.
authors.affiliation: Discovery Research, Suven Life Sciences Ltd, Hyderabad, India; Department of Pharmaceutical Sciences, Jawaharlal Nehru Technical University, Hyderabad, India.
authors.forename: Renny
authors.initials: R
authors.lastname: Abraham
authors.affiliation: Discovery Research, Suven Life Sciences Ltd, Hyderabad, India. Electronic address: nvsrk@suven.com.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Nirogi
authors.affiliation: Discovery Research, Suven Life Sciences Ltd, Hyderabad, India.
authors.forename: Anil
authors.initials: A
authors.lastname: Shinde
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism*; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013550:Swimming / Q000502:physiology
chemical_list: D000928:Antidepressive Agents; D008024:Ligands; D010879:Piperazines; C503990:SB 399885; D012702:Serotonin Antagonists; D013449:Sulfonamides; D012701:Serotonin; D018698:Glutamic Acid; D016202:N-Methylaspartate; D008559:Memantine
keywords: 5-HT(6) receptor; Depression; Glutamate; NMDA receptor; SB399885