Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline
Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline
05 January 2017
Revised:
21 February 2017
Accepted:
22 February 2017
Published online:
04 April 2017
Abstract
Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood–brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.
Blocking human fear memory with the matrix metalloproteinase inhibitor doxycycline
- Molecular Psychiatry
- doi:10.1038/mp.2017.65
- Download Citation
05 January 2017
Revised:
21 February 2017
Accepted:
22 February 2017
Published online:
04 April 2017
Abstract
Learning to predict threat is a fundamental ability of many biological organisms, and a laboratory model for anxiety disorders. Interfering with such memories in humans would be of high clinical relevance. On the basis of studies in cell cultures and slice preparations, it is hypothesised that synaptic remodelling required for threat learning involves the extracellular enzyme matrix metalloproteinase (MMP) 9. However, in vivo evidence for this proposal is lacking. Here we investigate human Pavlovian fear conditioning under the blood–brain barrier crossing MMP inhibitor doxycyline in a pre-registered, randomised, double-blind, placebo-controlled trial. We find that recall of threat memory, measured with fear-potentiated startle 7 days after acquisition, is attenuated by ~60% in individuals who were under doxycycline during acquisition. This threat memory impairment is also reflected in increased behavioural surprise signals to the conditioned stimulus during subsequent re-learning, and already late during initial acquisition. Our findings support an emerging view that extracellular signalling pathways are crucially required for threat memory formation. Furthermore, they suggest novel pharmacological methods for primary prevention and treatment of posttraumatic stress disorder.
The study medication was doxycycline, brand name Vibramycin (Pfizer, Zurich, Switzerland). The study dose of 200 mg was based on the smallest antibiotic dose recommended by the manufacturer, in order to reduce side effects. Peak cerebrospinal fluid concentrations are reached at approximately 180 min after oral administration.19 The drug's half-life is ~16 h according to manufacturer's information; such the drug was cleared by more than 99.9% at the retention test 7 days after ingestion.