Role of metalloproteinase inhibitors in human aversive memory

Matrix metalloproteinase 9 (MMP9) signalling is thought to be required for synaptic consolidation in LTP models, and in some non-human models of hippocampus-dependent memory. This suggests clinical application potential for preventing stress-related disorders following psychological trauma. However, it remains unclear whether (a) MMP9 signalling is required for memory consolidation in humans, and (b) it plays a critical role in aversive memory paradigms, where rodent findings have been mixed. We addressed these questions in healthy humans, in four pre-registered, randomised, placebo-controlled trials (RCTs) using a single 200 mg dose of the MMP-inhibiting tetracycline antibiotics doxycycline and minocycline. In RCT1 (N = 76) the broadband MMP inhibitor doxycycline was tested in a delay cued fear conditioning task. In all studies, learning took place under the drug, and memory recall was tested 7 days later using fear-potentiated start.e. When learning took place under doxycycline, memory retention 7 days later was reduced. However, this effect did not replicate in two hippocampus-dependent conditioning paradigms. RCT2 (N = 97), using trace fear conditioning (15 s interval), yielded mixed evidence, while RCT3 (N = 100), using configural fear conditioning, showed no evidence of impaired consolidation. We therefore tested minocycline, which has greater MMP9 specificity and potentially a shorter time to reach maximum plasma concentration. In RCT4 (N = 105), using the same configural paradigm as RCT3, minocycline reduced fear retention at seven days compared with placebo and with the doxycycline group in RCT3. An ongoing clinical study is currently evaluating the therapeutic potential of minocycline.