Persistent alterations in seizure susceptibility, drug responsiveness and comorbidities associated with chemical kindling after neonatal exposure to an organophosphate

• Published in: Neurotoxicology (Park Forest South) 2019-07, Vol.73, p.92-99
• Main Authors: Alipour, Vida, Hoseinpour, Fahimeh, Vatanparast, Jafar
• Format: Article
• Language: English
• Subjects: Affect - drug effects; Animals; Animals, Newborn; Anticonvulsants - pharmacology; Antiepileptic agents; Behavior; Behavior, Animal - drug effects; Brain; Brain - drug effects; Brain - physiopathology; Chlorpyrifos; Chlorpyrifos - toxicity; Cholinergics; Cholinesterase Inhibitors - toxicity; Comorbidity; Convulsions; Convulsions & seizures; Dependence; Depression; Developmental neurotoxicology; Dimethyl sulfoxide; Dizocilpine; Drug dosages; Drug Resistance; Excitability; Exposure; Feeding Behavior - drug effects; Female; Fluoxetine; Glutamic acid receptors (ionotropic); Insecticide resistance; Insecticides; Kindling; Kindling, Neurologic - drug effects; Latency; Locomotion - drug effects; Male; Maze Learning - drug effects; Memory - drug effects; N-Methyl-D-aspartic acid receptors; Neonates; Neurotransmitters; Newborn babies; Organic chemistry; Organophosphate Poisoning - drug therapy; Organophosphate Poisoning - etiology; Organophosphate Poisoning - physiopathology; Organophosphate Poisoning - psychology; Organophosphates; Pentylenetetrazol kindling; Pentylenetetrazole; Pentylenetetrazole - toxicity; Pesticides; Phenobarbital; Rats, Wistar; Reaction Time - drug effects; Rodents; Scopolamine; Seizures; Seizures - chemically induced; Seizures - drug therapy; Seizures - physiopathology; Seizures - psychology; Serotonin; Sex Factors; Short term memory; Spatial memory; Subgroups; Sweet taste; Taste
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2019.03.002

•Neonatal rats were exposed to low dose of chlorpyrifos (CPF).•CPF sex-selectively reduced the efficacy of some drugs against PTZ-induced seizure.•PTZ-kindling was selectively retarded in female rats that neonatally exposed to CPF.•CPF exposure induced more working memory errors after kindling in male rats.•CPF increased depressive behavior in female rats, which was insensitive to fluoxetine. Developmental exposure to organophosphates (OPs), at doses that do not cause cholinergic crisis, induces profound and lasting alterations in different neurotransmitter systems, which contribute to several behavioral outcomes. The present work examines whether neonatal exposure to low dose of chlorpyrifos (CPF), a widely used OP insecticide, alters the general excitability of the adult brain, its responsiveness to drugs with antiepileptic properties, the process of chemical kindling and the kindling-induced behavioral outcomes. Neonatal rats were exposed to daily doses of CPF (1 mg/kg) or dimethyl sulfoxide (DMSO, vehicle) on postnatal days (PND) 1–4. On PND 60, a subgroup of animals from both CPF and DMSO groups were injected with additive doses of pentylenetetrazole (PTZ) to evaluate the latency time to the first seizure, the threshold of PTZ-induced convulsion, and to determine the anticonvulsive action of phenobarbital (20 mg/kg), ethosuximide (100 mg/kg) and scopolamine (0.6 mg/kg) when used as pretreatment. Rats in the other subgroups were kindled by repeated intraperitoneal injections of an initially subconvulsive dose of PTZ (37.5 mg/kg) at 48-h intervals for 4 weeks. Kindled rats were then subjected to radial arm maze, sweet taste preference and forced swim test. Neonatal exposure to CPF shortened the latency time to the first seizure after pretreatment with scopolamine in female rats and decreased the threshold for PTZ-induced clonic convulsions after phenobarbital pretreatment in male rats. Neonatal CPF exposure also decreased the rate of kindling progression in female rats during early stages of PTZ kindling. On the other hand, CPF exposure sex-selectively reduced the number of working memory errors after kindling only in male rats. Drug challenge with MK-801 induced more impairment in the working memory of female kindled rats, indicating more dependence of working memory on NMDA receptor activity in these animals. Female kindled rats from CPF exposed group also showed longer time of immobility in forced swim test, showing an increase in the depressive-like