Antidepressant-like effects of CP-154,526, a selective CRF1 receptor antagonist.
The effects of CP-154,526 (butyl-ethyl-[2,5-dimethyl-7-(2,4,6 -trimethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine), a selective corticotropin releasing factor (CRF1) receptor antagonist, were examined in the learned helplessness procedure, a putative model of depression with documented sensitivity to diverse classes of antidepressant drugs. Rats were exposed to a series of inescapable foot shocks on three consecutive days and tested in a shock-escape procedure on the fourth day. Animals exposed to 'helplessness' training performed poorly in the shock-escape test compared with control animals not receiving inescapable shocks. CP-154,526 (10-32 mg/kg, intraperitoneally) dose-dependently reversed the escape deficit when administered 60 min prior to the test session, but had no effect on the performance of control rats not receiving prior exposure to inescapable stress. In comparison, the tricyclic antidepressant imipramine (17.8 mg/kg) reversed the escape deficit after repeated, but not acute, administration. These data support evidence implicating stress systems in the pathophysiology of depression, and suggest potential efficacy of small-molecule CRF receptor antagonists in the treatment of affective disorders.
Mansbach
R S
RS
Department of Neuroscience, Pfizer Central Research, Groton, CT 06340, USA. mansbach@pfizer.com
Brooks
E N
EN
Chen
Y L
YL
D000704:Analysis of Variance; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003863:Depression / Q000188:drug therapy*; D004195:Disease Models, Animal; D006380:Helplessness, Learned; D007099:Imipramine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*
D000929:Antidepressive Agents, Tricyclic; C101628:CP 154526; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D007099:Imipramine