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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.

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Several neurokinin NK1 receptor antagonists currently being developed for anxiety and depression have reduced affinity for the rat and mouse NK1 receptor compared with human. Consequently, it has proven difficult to test these agents in traditional rat and mouse models of anxiety and depression. This issue has been overcome, in part, by using non-traditional lab species such as the guinea pig and gerbil, which have NK1 receptors closer in homology to human NK1 receptors. However, there are very few reports describing the behavior of gerbils in traditional models of anxiety. The aim of the present study was to determine if the elevated plus-maze, a commonly used anxiety model, could be adapted for the gerbil. Using a specially-designed elevated plus-maze, gerbils exhibited an 'anxious' behavioral profile similar to that observed in rats and mice, i.e., reduced entries into, and time spent exploring, an open, aversive arm. The anxiolytic drugs diazepam (0.03-3 mg/kg i.p.), chlordiazepoxide (0.3-10 mg/kg i.p.), and buspirone (0.3-30 mg/kg s.c.) increased open arm exploration and produced anxiolytic-like effects on risk-assessment behaviors (reduced stretch-attend postures and increased head dips). Of particular interest, the antidepressant drugs imipramine (1-30 mg/kg p.o.),fluoxetine (1-30 mg/kg, p.o.) and paroxetine (0.3-10 mg/kg p.o.) each produced some acute anxiolytic-like activity, without affecting locomotor activity. The antipsychotic, haloperidol, and the psychostimulant, amphetamine, did not produce any anxiolytic-like effects (1-10 mg/kg s.c). The anxiogenic beta-carboline, FG-7142, reduced time spent in the open arm and head dips, and increased stretch-attend postures (1-30 mg/kg, i.p.). These studies have demonstrated that gerbils exhibit an anxiety-like profile on an elevated plus-maze, and that the gerbil elevated plus-maze may have predictive validity for anxiolytics, and antidepressants with potential anxiolytic-like effects. (C) 2002 American Colle

5-ht1a agonist. --- Activity. --- Amphetamine. --- Antidepressant drugs. --- Antidepressant. --- Anxiety. --- Anxiolytic action. --- Anxiolytic drugs. --- Anxiolytic-like. --- Behavior. --- Benzodiazepines. --- Depression. --- Diazepam. --- Drug. --- Drugs. --- Elevated plus maze. --- Elevated plus-maze. --- Ethopharmacological analysis. --- Exploration. --- Fear. --- Gerbil. --- Gerbils. --- Guinea pig. --- Guinea-pig. --- Haloperidol. --- Human. --- Locomotor activity. --- Locomotor-activity. --- Mice. --- Model. --- Models. --- Mongolian gerbil. --- Mouse. --- Neurokinin nk1 receptor antagonists. --- Neurokinin nk1 receptor. --- Nk1 receptor antagonists. --- Pig. --- Posture. --- Rat. --- Rats. --- Receptor antagonist. --- Receptor. --- Receptors. --- Social-interaction test. --- Species-differences. --- Substance-p receptors. --- Tachykinin nk1 receptor. --- Test. --- Time. --- Validation.