Common Mechanisms Underlying the Proconflict Effects of Corticotropin-Releasing Factor, A Benzodiazepine Inverse Agonist and Electric Foot-Shock

摘要

The effects of corticotropin-releasing factor (CRF), a benzodiazepine inverse agonist (methyl-6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate; DMCM) and electric foot-shock on rat conflict behavior were characterized and compared. Rats were trained to lever press under a multiple fixed-ratio schedule (FR 20) of food reinforcement in which responses during the first component were not punished, and the first response of each FR during the second component produced electric shock of an intensity sufficient to suppress responding by 10% to 15%. Intracerebroventricular injection of CRF (0.1-5.6 µg) caused a dose-dependent decrease in the rate of responding in both components of the schedule. However, CRF was more potent in decreasing rates of punished responding (proconflict effect). DMCM (10-100 µg; i.c.v.) also decreased rates of punished and nonpunished responding and was more potent during the punishment component. The suppression of punished and nonpunished responding by CRF and DMCM was mimicked by increasing the shock intensity (Δ = 0.1 to 0.6 mA) during the punishment component. To determine whether CRF, DMCM and electric shock shared common mechanisms for these effects, rats were pretreated with i.c.v. injections of either a CRF antagonist (α helical CRF9-41, 50 µg), a benzodiazepine agonist (chlordiazepoxide, 10 µg) or a benzodiazepine antagonist (flumazenil, 10 µg) before the administration of equieffective doses of CRF or DMCM or an increase in shock intensity. Chlordiazepoxide attenuated the effects of all three stimuli. Flumazenil antagonized DMCM and CRF, but not shock, implicating a pharmacologic interaction between CRF and benzodiazepine systems. In contrast, α helical CRF9-41 antagonized CRF and shock, but not DMCM, suggesting that the effects of shock, but not of DMCM, may be due to endogeneous CRF release. Together, the present results indicate that the proconflict effects of CRF, DMCM and electric foot-shock share some common mechanisms and that the effects produced by CRF may require the release of an endogenous benzodiazepine inverse agonist.