Abstract
The forced swimming test (FST) predicts the efficacy of clinically effective antidepressants. In the present study, using the FST we examined the antidepressant potential of three novel tropane analogs: 8-methyl-2β-propanoyl-3β-(4-(1-methylethyl)- phenyl)-8-azabicyclo[3.2.1] (WF-31) and 2β-propanoyl-3β-(4(1-methylethyl)phenyl)-8-azabicyclo[3.2.1]octane (WF-50), selective inhibitors of serotonin uptake, and 8-methyl-2β-propanoyl-3β-(4-(1-methylphenyl)-8-azabicyclo[3.2.1] octane (PTT, WF-11), a selective inhibitor of dopamine uptake. Fluoxetine and GBR 12909 were used as controls for selective inhibitors of serotonin and dopamine, respectively. Drugs were administered three times in a 24-hr period between pretest and test sessions. Intraperitoneal administration of WF-31 (0.1–10.0 mg/kg), WF-50 (0.3–10.0 mg/kg) and fluoxetine (0.3–10.0 mg/kg) dose-dependently decreased immobility while increasing swimming. In contrast, WF-11 (0.3–3.0 mg/kg) dose-dependently decreased immobility and increased both swimming and climbing, whereas GBR 12909 (3.0–30.0 mg/kg) decreased immobility, increased climbing 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 swimming in the FST indicate that WF-11 produces antidepressant-like effects in addition to motor stimulation. These results confirm previous results that behavioral patterns manifested in the FST are characteristic of specific monoamine uptake inhibitors. In addition, these results demonstrate 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 with fluoxetine, the data suggest WF-31 and WF-50 may be therapeutically useful as potential antidepressant medications.
Footnotes
-
Send reprint requests to: Dr. Scott E. Hemby, Department of Pharmacology, 37 John Morgan Building, 36th and Hamilton Walk, University of Pennsylvania Medical Center, Philadelphia, PA 19104-2649. E-mail: hemby{at}pharm.med.upenn.edu
-
↵1 This research was supported in part by United States Public Health Service Research Grants DA-06634 (H.M.L.D., J.E.S., S.I.D.), DA-00114 (J.E.S.), DA-06301 (H.M.L.D.) and MH-36262 (I.L.).
-
↵2 Present address: Department of Pharmacology, 37 John Morgan Building, 36th and Hamilton Walk, University of Pennsylvania Medical Center, Philadelphia, PA 19104-2649.
-
↵3 S. R. Childers, unpublished observations.
-
↵4 S. I. Dworkin, unpublished observations.
-
↵5 J.-P. Reneric and I. Lucki, unpublished observations.
- Abbreviations:
- FST
- forced swimming test
- WF-11
- 8-methyl-2β-propanoyl-3β-(4-(1-methylphenyl)-8-azabicyclo[3.2.1]octane
- WF-31
- 8-methyl-2β-propanoyl-3β-(4-(1-methylethyl)phenyl)-8-azabicyclo[3.2.1]
- WF-50
- 2β-propanoyl-3β-(4-(1-methylethyl)phenyl)-8-azabicyclo[3.2.1]octane
- ANOVA
- analysis of variance
- Received September 24, 1996.
- Accepted April 28, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
