Effect of short-term exposure to dichlorvos on synaptic plasticity of rat hippocampal slices: involvement of acylpeptide hydrolase and alpha(7) nicotinic receptors.
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 microM 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 alpha(7) 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 alpha(7) nicotinic receptors.
Olmos
Cristina
C
Laboratory of Environmental Neurotoxicology, Department of Biomedical Sciences, Faculty of Medicine, Universidad Católica del Norte, Larrondo 1281, 178-1421 Coquimbo, Chile.
Sandoval
Rodrigo
R
Rozas
Carlos
C
Navarro
Sebastián
S
Wyneken
Ursula
U
Zeise
Marc
M
Morales
Bernardo
B
Pancetti
Floria
F
D000818:Animals; D002800:Cholinesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D004006:Dichlorvos / Q000008:administration & dosage / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D009473:Neuronal Plasticity / Q000187:drug effects; D010447:Peptide Hydrolases / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002800:Cholinesterase Inhibitors; C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D004006:Dichlorvos; D010447:Peptide Hydrolases; C038220:acylaminoacyl-peptidase