Cortisol’s effects on memory follow an inverted U-shaped function such that memory retrieval is impaired with very low concentrations, presumably due to insufficient activation of high-affine mineralocorticoid receptors (MR), or with very high concentrations, due to predominant low-affine glucocorticoid receptor (GR) activation. Through corresponding changes in re-encoding, the retrieval effect of cortisol might translate into a persistent change of the retrieved memory. We tested whether partial suppression of morning cortisol synthesis by metyrapone, leading to intermediate, circadian nadir-like levels with presumed predominant MR activation, improves retrieval, particularly of emotional memory, and persistently changes the memory. In a randomized, placebo-controlled, double-blind, within-subject cross-over design, 18 men were orally administered metyrapone (1 g) vs. placebo at 4:00 AM to suppress the morning cortisol rise. Retrieval of emotional and neutral texts and pictures (learned 3 days earlier) was assessed 4 h after substance administration and a second time one week later. Metyrapone suppressed endogenous cortisol release to circadian nadir-equivalent levels at the time of retrieval testing. Contrary to our expectations, metyrapone significantly impaired free recall of emotional texts (p < .05), whereas retrieval of neutral texts or pictures remained unaffected. One week later, participants still showed lower memory for emotional texts in the metyrapone than placebo condition (p < .05). Our finding that suppressing morning cortisol to nadir-like concentrations not only impairs acute retrieval, but also persistently weakens emotional memories corroborates the concept that retrieval effects of cortisol produce persistent memory changes, possibly by affecting re-encoding.
Cortisol is a potent modulator of memory, which differentially affects processes of encoding, consolidation, and retrieval (de Quervain et al., 2009, Kelemen et al., 2014 and Schwabe et al., 2011). Generally, it enhances encoding of information, but impairs memory retrieval, especially of negative material. Of note, memory retrieval is not only impaired at strongly elevated cortisol levels (de Quervain et al., 1998, de Quervain et al., 2000, Domes et al., 2005 and Kuhlmann et al., 2005), but also at minimum levels after suppression of cortisol synthesis by metyrapone (Marin et al., 2011 and Rimmele et al., 2010), suggesting an inverted U-shaped function that describes the relationship between memory retrieval and cortisol concentrations (Schilling, Kolsch, Larra, Zech, Blumenthal, Frings, & Schachinger, 2013). The inverted U-shaped response function has been linked to an imbalance in mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) activation with both enhanced GR activation at high cortisol levels and reduced MR activation at very low cortisol levels mediating impairing effects on retrieval. In line with this notion, administration of metyrapone at a dose of 3 g almost completely suppressed endogenous cortisol release, and this was accompanied by a significantly impaired free recall of texts and pictures, in particular when emotional (Rimmele et al., 2010). Thus, optimal memory retrieval is expected when MRs are occupied to a great extent, but not GRs, i.e. conditions presumably achieved during the circadian nadir of cortisol release (de Kloet et al., 1999 and Lupien et al., 2007).
Besides an acutely impairing effect on retrieval, there is first evidence that the impairing effect of metyrapone on memory retrieval persists beyond the acute period of cortisol suppression and is still present at a second retrieval test 4 days later (Marin et al., 2011). That study showed a persisting decrease of emotional, but not neutral memories for pictures with 1.5 g of metyrapone, but not with 0.75 g of metyrapone given before the first retrieval of the test materials. Salivary cortisol measures indicated that a significant suppression of cortisol was achieved only after the 1.5 g dosis.
Here, we tested the effect of metyrapone-induced cortisol inhibition during the morning hours on acute retrieval and the persistence of this effect over an even longer 1-week interval. Adopting the framework of an MR/GR activation balance that determines the direction of glucocorticoid effects, we chose a dose of 1 g metyrapone. Based on pilot studies and our previous work (Rimmele et al., 2010), this dose was expected to only partially block cortisol release and to induce cortisol levels comparable with those during the circadian nadir of pituitary-adrenal activity where MRs are estimated to be occupied by 50–70%, in the absence of substantial GR occupation (Reul and de Kloet, 1985, Spencer et al., 1993 and Kalman and Spencer, 2002). We expected that such predominance of MR over GR occupation would acutely enhance memory retrieval. Assuming that the effect on retrieval goes along with a parallel effect on re-encoding, we further expected that the acute enhancement in retrieval after metyrapone would persist during a second retrieval test 1 week later.
