Selective and protracted effect of nifedipine on fear memory extinction correlates with induced stress response

Memory extinction, defined as a decrease of a conditioned response as a function of a non-reinforced conditioned stimulus presentation, has high biological and clinical relevance. Extinction is not a passive reversing or erasing of the plasticity associated with acquisition, but a novel, active learning process. Nifedipine blocks L-type voltage gated calcium channels (LVGCC) and has been shown previously to selectively interfere with the extinction, but not the acquisition, of fear memory. We studied here the effect of retrograde and anterograde shifts of nifedipine application, with respect to an extinction training, on the extinction of fear conditioning. Subcutaneous injection of 30 mg/kg nifedipine, at least up to 4 h before the extinction session, significantly impaired extinction, as did intraperitoneal injection of 15 mg/kg nifedipine, at least up to 2 h before extinction training. However, the injection of nifedipine also induced a strong and protracted stress response. The pharmacokinetics of nifedipine suggest that it was mainly this stress response that triggered the specific inhibition of extinction, not the blockade of LVGCC in the brain. Our results support recent findings that stress selectively interferes with the extinction, but not the acquisition, of fear memory. They also indicate that a pharmacological approach is not sufficient to study the role of brain LVGCC in learning and memory. Further research using specific genetically modified animals is necessary to delineate the role of LVGCC in fear memory extinction.