Effects of antipsychotics and reference monoaminergic ligands on marble burying behavior in mice

Antipsychotics constitute efficacious augmenting agents in the treatment of anxiety disorders, including refractory obsessive-compulsive disorder. We examined the effects of 36 compounds, including typical, atypical and novel antipsychotics with dual dopamine D2/5-hydroxytryptamine 1A (D2/5-HT1A) actions on marble burying behavior in mice, a putative preclinical test for anxiety disorders. One hour after drug administration, male NMRI mice were placed individually in cages containing 20 marbles, and the total number of marbles buried after 30 min was counted. The selective serotonin reuptake inhibitors, citalopram (2.5-40 mg/kg), fluoxetine (2.5-10 mg/kg) and the benzodiazepine diazepam (2.5-10 mg/kg), reduced the number of buried marbles. The atypical antipsychotic, clozapine (0.16-10 mg/kg), but not its congener olanzapine, was effective in this test. Haloperidol, a typical antipsychotic, also reduced the number of buried marbles, albeit not in a dose-dependent manner. The atypical risperidone was partially active (0.16-0.63 mg/kg), as was the benzamide derivative, amisulpride, albeit at high (10-40 mg/kg) doses. Among the 'third-generation' antipsychotics possessing combined D2/5-HT1A properties, bifeprunox was active at 0.0025 mg/kg, whereas SLV313 and aripiprazole were active only at the highest doses (2.5 and 10 mg/kg, respectively). SSR181507, F15063 and the antidyskinetic agent, sarizotan, were without any effect. Among a series of receptor subtype-selective ligands, only the 5-HT1A agonist, (+)-8-OH-DPAT (0.63-2.5 mg/kg) and the 5-HT2A/2B/2C antagonist, ritanserin (0.63-2.5 mg/kg) were active. Among novel antipsychotics with dual D2/5-HT1A properties, only bifeprunox was able to potently reduce the number of buried marbles. Inhibition of marble burying behavior may result from the interplay of several receptor systems, including 5-HT2 receptor blockade, dopamine D2 partial agonism and serotonin 5-HT1A agonism.