Effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization anxiolytic test in rat pups.
CRF(1) receptor antagonists have been proposed as novel pharmacological treatments for depression, anxiety and stress disorders. The primary goal of the present study was to evaluate the effects of the CRF(1) receptor antagonist, CP 154,526, in the separation-induced vocalization (SIV) model of anxiety. Nine- to 11-day-old rat pups were separated from their litter and the effects of intraperitoneally administered test compounds on the elicited ultrasonic vocalizations were measured. Side-effect potential was assessed using a modified inclined plane test ('time on an inclined plane', or TIP), and using negative geotaxis. SIV was reduced by CP 154,526 at doses that did not affect TIP or negative geotaxis, a profile like that of the 5-HT(1A) partial agonist buspirone. The benzodiazepine anxiolytic, diazepam, decreased SIV but also produced significant side effects at one to three-fold higher doses. Additional pharmacological characterization of SIV demonstrated anxiolytic-like effects of the atypical antipsychotic, clozapine, but not the typical antipsychotic, haloperidol, and of the serotonin reuptake inhibitor, zimelidine, but not the norepinephrine reuptake inhibitor, desipramine. In summary, the data support the conclusion that selective CRF(1) receptor antagonists may have utility in anxiety and stress disorders. The data further support the use of separation-induced vocalizations for identifying mechanistically diverse compounds with anxiolytic actions in man.
Kehne
J H
JH
Neurogen Corporation, 35 Northeast Industrial Road, 06405, Branford, CT, USA. jkehne@nrgn.com
Coverdale
S
S
McCloskey
T C
TC
Hoffman
D C
DC
Cassella
J V
JV
D000704:Analysis of Variance; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000494:pharmacology; D001007:Anxiety / Q000517:prevention & control* / Q000523:psychology; D001522:Behavior, Animal / Q000187:drug effects; D002065:Buspirone / Q000494:pharmacology; D003024:Clozapine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008297:Male; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D012934:Social Isolation / Q000523:psychology*; D013315:Stress, Psychological; D014828:Vocalization, Animal / Q000187:drug effects*; D015031:Zimeldine / Q000494:pharmacology; D000099052:CRF Receptor, Type 1
D014151:Anti-Anxiety Agents; D014150:Antipsychotic Agents; C101628:CP 154526; D011743:Pyrimidines; D011758:Pyrroles; D018019:Receptors, Corticotropin-Releasing Hormone; D015031:Zimeldine; D000099052:CRF Receptor, Type 1; D003024:Clozapine; D006220:Haloperidol; D003975:Diazepam; D003891:Desipramine; D002065:Buspirone