Corticotropin-releasing factor (CRF) antagonist [D-Phe12,Nle21,38,C alpha MeLeu37]CRF attenuates the acute actions of the highly potent cannabinoid receptor agonist HU-210 on defensive-withdrawal behavior in rats.
The present study evaluated the modulatory role of central corticotropin-releasing factor (CRF) systems in the mediation of the effects of acute exposure to the brain cannabinoid receptor agonist HU-210 [3-(1,1-dimethylheptyl)-(-)-11-hydroxy-delta 8-tetrahydrocannabinol] on defensive withdrawal behavior in male rats. The apparatus used for the defensive withdrawal test consisted of a small chamber, set on one side of a one-square meter open field. The actions of the potent CRF antagonist [D-Phe12,Nle21,38,C alpha MeLeu37]CRF (D-Phe CRF12-41) were examined on defensive behavior under both novel and familiar conditions. The acute i.c.v. administration of D-Phe CRF12-41 (0.2-5 micrograms/injection) antagonized the defensive behavior response to stressing conditions such as novelty or swim stress in field-habituated animals. The acute i.p. administration of HU-210 (4, 20 and 100 micrograms/kg) produced a clear dose-dependent stress-like effects in field-habituated animals, as reflected in the HU-210-induced increase in both the emergence latency and the mean time spent in the small chamber. The i.c.v. administration of 5 micrograms of D-Phe CRF12-41, 5 min before the administration of the cannabinoid prevented the stressing actions of HU-210 (20 micrograms/kg, but not 100 micrograms/kg). Acute administration of HU-210 also induced a dose-dependent increase in plasma corticosterone levels which was not antagonized by pretreatment with 5 micrograms of D-Phe CRF12-41. The present study suggests a role of central CRF systems in the mediation of the anxiogenic effects of brain cannabinoid receptor agonists. This finding is consistent with a direct hypothalamic effect of cannabinoids on the activation of the pituitary-adrenal axis.
Rodríguez de Fonseca
F
F
Instituto Complutense de Drogodependencias, Universidad Complutense, Madrid, Spain.
Rubio
P
P
Menzaghi
F
F
Merlo-Pich
E
E
Rivier
J
J
Koob
G F
GF
Navarro
M
M
D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal / Q000187:drug effects*; D003345:Corticosterone / Q000097:blood; D003346:Corticotropin-Releasing Hormone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D003674:Defense Mechanisms; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D004357:Drug Synergism; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists*; D013312:Stress, Physiological / Q000503:physiopathology; D013550:Swimming
C083591:H-R corticotropin-releasing factor (12-41), Phe(12)-Nle(21,38), C(alpha-MeLeu(37))-; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C113202:phenylalanyl corticotropin-releasing factor (12-41); D013759:Dronabinol; D003346:Corticotropin-Releasing Hormone; C062018:HU 211; D003345:Corticosterone