Acute and chronic effects of corticotropin-releasing factor on schedule-controlled responding and neurochemistry of pigeons.

Key pecking by pigeons was maintained under various schedules of food presentation. Acute i.c.v. administration of corticotropin-releasing factor (CRF) (3.0-30.0 micrograms/kg) decreased responding in both components of a multiple 3-min fixed-interval, 30-response fixed-ratio schedule and under a multiple fixed-ratio schedule in which responding during one component was punished by shock delivery. The rate-decreasing effects of intermediate doses of CRF were blocked by the CRF antagonist alpha-helical CRF9-41 under the multiple fixed-internal fixed-ratio schedule, with 10.0 micrograms/kg of the antagonist producing a more complete reversal than 30.0 micrograms/kg. The rate-reducing effects of 10.0 and 30.0 micrograms/kg of CRF disappeared rapidly when CRF was administered daily, with complete restoration of responding occurring by the 4th day of chronic administration. Acute effects were recovered when CRF administration was discontinued for 7 to 14 days. Analyses of cerebrospinal fluid revealed that behaviorally active doses of CRF produced large, dose-dependent increases in levels of the serotonin metabolite 5-hydroxyindoleacetic acid and in the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid; smaller increases also occurred in the levels of 3-methoxy-4-hydroxyphenylethylene glycol, the metabolite of norepinephrine. Chronic administration of 30 micrograms/kg of CRF for a 4-day period did not reveal any change in metabolite levels when compared to those obtained after acute administration, with the exception of 3-methoxy-4-hydroxyphenylethylene glycol which approached control levels after chronic CRF. These results indicate that, as is the case with mammals, CRF has potent behavioral and neurochemical activity in avian species and that tolerance occurs rapidly to the behavioral effects.