CRF and urocortin decreased brain stimulation reward in the rat: reversal by a CRF receptor antagonist.
The present studies were designed to investigate the effects of corticotropin-releasing factor (CRF) receptor activation and antagonism on intracranial self-stimulation (ICSS) reward using a discrete-trial current-intensity threshold procedure. Bipolar electrodes were implanted in the lateral hypothalamus, and cannula guides were implanted above the lateral ventricle of male Wistar rats. Dose-effect functions were established for the effects on ICSS of the competitive CRF receptor agonist h/rCRF (0-5.0 microg, i.c.v. ), the CRF receptor agonist urocortin (0-5.0 microg, i.c.v.), and the CRF receptor antagonist [D-Phe(12), Nle(21,38), C(alpha) MeLeu(37)] h/rCRF(12-41) (0-5.0 microg, i.c.v.). Administration of h/rCRF or urocortin dose-dependently elevated ICSS thresholds without altering performance measures (latencies to respond to stimulation, extra and time-out responses). CRF was more potent than urocortin in terms of threshold dose-effects on ICSS thresholds compared to vehicle. Despite these apparent potency differences, percent effect sizes on ICSS thresholds were comparable at the highest doses of both peptides. In contrast to the significant threshold elevation effects of CRF and urocortin, the competitive CRF antagonist D-Phe CRF(12-41) had no effect on ICSS thresholds or performance measures. To determine the neuropharmacological specificity of the effect of CRF on brain stimulation reward, D-Phe CRF(12-41) was used to antagonize CRF-induced threshold elevations. Pretreatment with either the 5.0- or 10.0-microg doses of D-Phe CRF(12-41) effectively blocked CRF-induced reward threshold elevations (3.0 microg) without affecting other ICSS performance measures. These results indicate that CRF neurotransmission can modulate ICSS reward processes.
Macey
D J
DJ
Department of Neuropharmacology, CVN-7, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. dmacey@scripps.edu
Koob
G F
GF
Markou
A
A
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003346:Corticotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D012201:Reward; D012653:Self Stimulation / Q000187:drug effects* / Q000502:physiology; D054832:Urocortins
D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins; C113202:phenylalanyl corticotropin-releasing factor (12-41); D003346:Corticotropin-Releasing Hormone