Dichlorvos is the active molecule of the pro-drug metrifonate used to revert the cognitive deficits associated with Alzheimer's disease. A few years ago it was reported that dichlorvos inhibits the enzyme acylpeptide hydrolase at lower doses than those necessary to inhibit acetylcholinesterase to the same extent. Therefore, the aim of our investigation was to test the hypothesis that dichlorvos can enhance synaptic efficacy through a mechanism that involves acylpeptide hydrolase instead of acetylcholinesterase inhibition. We used long-term potentiation induced in rat hippocampal slices as a model of synaptic plasticity. Our results indicate that short-term exposures (20 min) to 50 μM dichlorvos enhance long-term potentiation in about 200% compared to the control condition. This effect is correlated with approximately 60% inhibition of acylpeptide hydrolase activity, whereas acetylcholinesterase activity remains unaffected. Paired-pulse facilitation and inhibition experiments indicate that dichlorvos does not have any presynaptic effect in the CA3 → CA1 pathway nor affect gabaergic interneurons. Interestingly, the application of 100 nM methyllicaconitine, an α7 nicotinic receptor antagonist, blocked the enhancing effect of dichlorvos on long-term potentiation. These results indicate that under the exposure conditions described above, dichlorvos enhances long-term potentiation through a postsynaptic mechanism that involves (a) the inhibition of the enzyme acylpeptide hydrolase and (b) the modulation of α7 nicotinic receptors.
Bibliographical noteFunding Information:
This work was supported by grants from Dirección General de Investigación y Postgrado (DGIP) from Universidad Católica del Norte to F.P., from Programa Bicentenario en Ciencia y Tecnología PSD-11 to F.P. and R.S. and from Fondecyt grant No. 1030220 to B.M. and F.P. We thank to Dr. Fernando Sáchez-Santed for his helpful reading of the manuscript, and to Dr. Luis G. Aguayo for providing us with the α 7 nAChR cDNA clone.
- Acylpeptide hydrolase
- Nicotinic receptors
- Synaptic plasticity