RESUMO
Corticotropin-releasing factor(1) (CRF(1)) antagonists may be effective in the treatment of anxiety disorders with fewer side effects compared with classic benzodiazepines. The behavioral effects of DMP904 [4-(3-pentylamino)-2,7-dimethyl-8-(2-methyl-4-methoxyphenyl)-pyrazolo-[1,5-a]-pyrimidine] and its effects on the hypothalamic-pituitary-adrenal (HPA) axis were related to its levels in plasma and estimated occupancy of central CRF(1) receptors. DMP904 (10-30 mg/kg, p.o.) and alprazolam (10 mg/kg, p.o.) increased time spent in open arms of an elevated-plus maze. In addition, acutely or chronically (14 days) administered DMP904 (1.0-30 mg/kg, p.o.) and acute alprazolam (1.0-3.0 mg/kg, p.o.) significantly reduced exit latency in the defensive withdrawal model of anxiety in rats, suggesting that tolerance may not develop to the anxiolytic-like effects of DMP904 in this model of anxiety. Acutely, DMP904 reversed the stress-induced increase in plasma corticosterone levels in defensive withdrawal at doses of 3.0 mg/kg and higher. These doses also resulted in levels of DMP904 in plasma similar to (for anxiolytic-like effects) or 4-fold higher (for effects on the HPA axis) than the in vitro IC(50) value for binding affinity at CRF(1) receptors and greater than 50% occupancy of CRF(1) receptors. Unlike alprazolam, DMP904 did not produce sedation, ataxia, or chlordiazepoxide-like subjective effects (as measured by locomotor activity, rotorod performance, and chlordiazepoxide discrimination assays, respectively) at doses at least 3-fold higher than anxiolytic-like doses. In conclusion, anxiolytic-like effects and effects on the stress-activated HPA axis of DMP904 in the defensive withdrawal model of anxiety required 50% or greater occupancy of central CRF(1) receptors. This level of CRF(1) receptor occupancy resulted in fewer motoric side effects compared with classic benzodiazepines.
