title: Effect of NMDAR antagonists in the tetrabenazine test for antidepressants: comparison with the tail suspension test.
abstract: OBJECTIVE
  The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine, produces rapid and enduring antidepressant effect in patients with treatment-resistant depression. Similar dramatic effects have not been observed in clinical trials with other NMDAR antagonists indicating ketamine may possess unique pharmacological properties. Tetrabenazine induces ptosis (a drooping of the eyelids), and the reversal of this effect, attributed to a sympathomimetic action, has been used to detect first-generation antidepressants, as well as ketamine. Because the actions of other NMDAR antagonists have not been reported in this measure, we examined whether reversal of tetrabenazine-induced ptosis was unique to ketamine, or a class effect of NMDAR antagonists.
  
  
  METHODS
  The effects of ketamine and other NMDAR antagonists to reverse tetrabenazine-induced ptosis were examined and compared with their antidepressant-like effects in the tail suspension test (TST) in mice.
  
  
  RESULTS
  All the NMDAR antagonists tested produced a partial reversal of tetrabenazine-induced ptosis and, as expected, reduced immobility in the TST. Ketamine, memantine, MK-801 and AZD6765 were all about half as potent in reversing tetrabenazine-induced ptosis compared to reducing immobility in the TST, while an NR2B antagonist (Ro 25-6981) and a glycine partial agonist (ACPC) were equipotent in both tests.
  
  
  CONCLUSIONS
  The ability to reverse tetrabenazine-induced ptosis is a class effect of NMDAR antagonists. These findings are consistent with the hypothesis that the inability of memantine, AZD6765 (lanicemine) and MK-0657 to reproduce the rapid and robust antidepressant effects of ketamine in the clinic result from insufficient dosing rather than a difference in mechanism of action among these NMDAR antagonists.
authors: 1Division of Pharmacotherapies & Medical Consequences of Drug Abuse,NIDA,NIH,Bethesda,MD,USA.
authors: Phil
authors: P
authors: Skolnick
authors: 2Behavioral Neuroscience and Drug Development Institute of Pharmacology,Polish Academy of Sciences,Kraków,Poland.
authors: Tomasz
authors: T
authors: Kos
authors: 3Faculty of Health Sciences,Collegium Medicum,Jagiellonian University,Kraków,Poland.
authors: Janusz
authors: J
authors: Czekaj
authors: 2Behavioral Neuroscience and Drug Development Institute of Pharmacology,Polish Academy of Sciences,Kraków,Poland.
authors: Piotr
authors: P
authors: Popik
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001763:Blepharoptosis / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D019417:Hindlimb Suspension / Q000379:methods; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D010627:Phenethylamines / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013747:Tetrabenazine / Q000494:pharmacology*
chemical_list: C576352:4-methylbenzyl 3-fluoro-4-((pyrimidin-2-ylamino)methyl)piperidine-1-carboxylate; C585977:AZD6765; D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D010627:Phenethylamines; D010636:Phenols; D010880:Piperidines; D011725:Pyridines; D011743:Pyrimidines; D016194:Receptors, N-Methyl-D-Aspartate; C109643:Ro 25-6981; D007649:Ketamine; D013747:Tetrabenazine
keywords: NMDAR antagonist; antidepressant; ptosis; tail suspension test; tetrabenazine