Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Recent clinical evidence supports the potential of neurokinin NK1 receptor antagonists as novel antidepressant drugs. A number of NK1 antagonists have reduced affinity for rat and mouse NK1 receptors compared to human, making it difficult to test for efficacy in traditional animal models. NK1 antagonists, in general, have similar affinity at gerbil and human NK1 receptors. The aims of these studies were, first to validate the gerbil tail suspension test, a test used frequently to demonstrate antidepressant drug efficacy in mice, and second, to determine whether the test could be used to demonstrate the antidepressant potential of NK1 antagonists. Immobility time was reduced by oral administration of the antidepressants imipramine (3-30 mg/kg), desipramine (1-30 mg/kg), amitriptyline (30 mg/kg), fluoxetine (1-30 mg/kg), paroxetine (3-10 mg/kg), citalopram (0.1-3 mg/kg), sertraline (1-30 mg/kg), venlafaxine (1-30 mg/kg) and nefazodone (100 mg/kg). Furthermore, oral administration of the NK1 antagonists M K-869 (10 mg/kg), L-742,694 (110 mg/kg), L-733,060 (10 mg/kg), CP-99,994 (30 mg/kg), and CP-122,721 (3-30 mg/kg) reduced immobility time. Diazepam (1-10 mg/kg), chlordiazepoxide (1-10 mg/kg), buspirone (3-30 mgAg), FG-7142 (1-30 mg/kg), and haloperidol (1-10 mg/kg) did not reduce immobility. Amphetamine (0.3-10 mg/kg) and atropine (0.3-10 mg/kg) reduced immobility, suggesting susceptibility to false positives, e.g. compounds that affect locomotion. Compounds were therefore tested in a gerbil locomotor activity (LMA) test to ensure that the antidepressant-like effects were not secondary to effects on activity. Antidepressant drugs and NK1 antagonists had no effect on LMA at doses that reduced immobility, whereas amphetamine and atropine induced marked hyperactivity. These studies support both the utility of gerbils in behavioral pharmacology and the antidepressant potential of selective NK1 antagonists

Activity. --- Amphetamine. --- Animal model. --- Animal-model. --- Animal-models. --- Animal. --- Antidepressant drugs. --- Antidepressant. --- Anxiolytic-like. --- Atropine. --- Behavior. --- Blockade. --- Citalopram. --- Depression. --- Diazepam. --- Drug. --- Drugs. --- Fluoxetine. --- Gerbil. --- Gerbils. --- Haloperidol. --- Human. --- Hyperactivity. --- Immobility. --- Inhibition. --- Locomotion. --- Locomotor activity. --- Locomotor-activity. --- Mice. --- Model. --- Models. --- Mouse. --- Neurokinin nk1 receptor antagonists. --- Neurokinin nk1 receptor. --- Nk1 receptor antagonists. --- Nonpeptide antagonist. --- Pharmacology. --- Rat. --- Receptor antagonist. --- Receptor. --- Receptors. --- Social-interaction. --- Substance p. --- Substance-p receptors. --- Susceptibility. --- Tail suspension test. --- Test. --- Time.

Choose an application

• Reference Manager
• EndNote
• RefWorks (Direct export to RefWorks)

Neurokinin NK1 receptor antagonists may have therapeutic potential in the treatment of anxiety and depression. Species variants in the NK1 receptor result in reduced affinity of NK1 receptor antagonists at rat and mouse NK1 receptors, making it difficult to test NK1 antagonists in traditional preclinical models of anxiety and depression. Gerbil NK1 receptors are similar in homology to the human NK1 receptor. In a companion article, we described the anxiety-like behavioral profile of gerbils on an adapted elevated plus-maze, and the ability of anxiolytic drugs to produce anti-anxiety effects in the gerbil elevated plus-maze. The aim of the present study was to determine whether oral (p.o.) administration of the NK1 receptor antagonists MK-869, L-742,694, L-733,060, CP-99,994, and CP-122,721 produced anxiolytic-like effects in the gerbil elevated plus-maze. Upon testing, all five NK1 antagonists produced anxiolytic-like effects. MK-869 (0.01-3 mg/kg) was the most potent NK1 antagonist, producing anxiolytic-like effects on percentage of open arm time, percentage of open arm entries, stretch-attend postures, and head dips at 0.03-0.3 mg/kg doses. L-742,694 (1-30 mg/ kg) and L-733,060 (1-10 mg/kg) produced anxiolytic-like effects on percentage of open arm time and stretch-attend postures at 3-10 mg/kg doses. CP-99,994 (3-30 mg/kg) only produced an anxiolytic-like effect on stretch-attend postures. CP-122,721 (3-30 mg/kg) produced an anxiolytic-like effect on percentage of open arm time at 30 mg/kg. The order of potency of the NK1 antagonists to increase percentage of open arm time was very similar to their potency to block NK1 agonist-induced foot-tapping. These studies demonstrate that neurokinin NK1 receptor antagonists produce anxiolytic-like effects in a novel gerbil elevated plus-maze, and suggest that this is an appropriate model to test NK1 antagonists for preclinical anxiolytic activity. (C) 2002 American College of Neuropsychopharmacology. Published by Elsevi

Ability. --- Activity. --- Agonists. --- Anxiety. --- Anxiolytic activity. --- Anxiolytic drugs. --- Anxiolytic-like. --- Behavior. --- Depression. --- Drug. --- Drugs. --- Elevated plus maze. --- Elevated plus-maze. --- Gerbil. --- Gerbils. --- Human. --- Increase. --- Inhibition. --- Model. --- Models. --- Mouse. --- Neurokinin nk1 receptor antagonists. --- Neurokinin nk1 receptor. --- Nk1 receptor antagonists. --- Nkp608. --- Nonpeptide antagonist. --- Pharmacology. --- Posture. --- Potency. --- Rat. --- Rats. --- Receptor antagonist. --- Receptor. --- Receptors. --- Social-interaction test. --- Substance-p receptors. --- Tachykinin. --- Test. --- Time. --- Treatment.