Inhibition of cortisol production by metyrapone enhances trace, but not delay, eyeblink conditioning

Abstract

Hypercortisolism [ corrected] impairs trace classical conditioning of the eyeblink response to an air puff but does not affect delay conditioning. The opposite neurohormonal condition, hypocortisolism, may facilitate trace classical conditioning, which might be informative in understanding the role of classical conditioning in stress-sensitive syndromes such as fibromyalgia. Volunteers (n = 82) were randomized to receive either an inhibitor of cortisol production (metyrapone, 1500 mg) or placebo and to complete a delay or a trace eyeblink conditioning protocol (unconditioned stimulus: corneal air puff, 10 psi, 50 ms; conditioned stimulus: binaural pure tone, 75 dB, 1000 Hz, 400 ms; empty interval in trace conditioning: 600 ms), where conditioned eyeblink response probability was assessed electromyographically. Metyrapone induced hypocortisolism, reflected by a 30% decrease of salivary cortisol levels (p < 0.01), and facilitated trace eyeblink conditioning (p < 0.001), while delay eyeblink conditioning remained unaffected. Moreover, extinction of delay-conditioned eyeblink responses was impaired (p = 0.023), but extinction of trace-conditioned responses remained unaffected. We conclude that acute mild metyrapone-induced hypocortisolism facilitates hippocampus-mediated classical trace eyeblink conditioning but suppresses the extinction of cerebellum-based delay-conditioned responses. Both results may be of theoretical and clinical significance for the generation and persistence of psychosomatic symptoms in patient groups characterized by relative hypocortisolism (e.g., fibromyalgia and chronic fatigue).