POTENTIAL ANTIDEPRESSANT - EFFECTS OF NOVEL TROPANE COMPOUNDS, SELECTIVE FOR SEROTONIN OR DOPAMINE TRANSPORTERS

The forced swimming test (FST) predicts the efficacy of clinically eff ective antidepressants. In the present study, using the FST we examine d the antidepressant potential of three novel tropane analogs: 8-methy l-2 beta-propanoyl-3 beta-(4-(1-methylethyl)phenyl)-8-azabicyclo[3.2.1 ] (WF-31) and 2 beta-propanoyl-3 4-(1-methylethyl)phenyl)-8-azabicyclo [3.2.1]octane (WF-50), selective inhibitors of serotonin uptake, and 8 -methyl-2 beta-propanoyl-3 beta-(4-(1-methylphenyl)-8-azabicyclo[3.2.1 ] octane (PTT, WF-50), a selective inhibitor of dopamine uptake. Fluox etine and GBR 12909 were used as controls for selective inhibitors of serotonin and dopamine, respectively. Drugs were administered three ti mes in a 24-hr period between pretest and test sessions. Intraperitone al administration of WF-31 (0.1-10.0 mg/kg), WF-50 (0.3-10.0 mg/kg) an d fluoxetine (0.3-10.0 mg/kg) dose-dependently decreased immobility wh ile increasing swimming. In contrast, WF-11 (0.3-3.0 mg/kg) dose-depen dently decreased immobility and increased both swimming and climbing, whereas GBR 12909 (3.0-30.0 mg/kg) decreased immobility, increased cli mbing but did not affect swimming. In a separate experiment, WF-11 (1. 0 mg/kg) increased locomotor activity, whereas a higher dose of WF-11 (3.0 mg/kg) and GBR-12909 (30.0 mg/kg) produced stereotypic behaviors, suggesting that the effects in the FST may have been attributable to increases in general activity. However, the effects of WF-11 on swimmi ng in the FST indicate that WF-11 produces antidepressant-like effects in addition to motor stimulation. These results confirm previous resu lts that behavioral patterns manifested in the FST are characteristic of specific monoamine uptake inhibitors. In addition, these results de monstrate that WF-31 and WF-50 produce behavioral patterns similar to fluoxetine in the FST without accompanying decreases in motor activity , suggesting a potential antidepressant action. Based on comparisons w ith fluoxetine, the data suggest WF-31 and WF-50 may be therapeuticall y useful as potential antidepressant medications.