Academic journal article Environmental Health Perspectives

Developmental Exposure of Rats to Chlorpyrifos Leads to Behavioral Alterations in Adulthood, Involving Serotonergic Mechanisms and Resembling Animal Models of Depression

Academic journal article Environmental Health Perspectives

Developmental Exposure of Rats to Chlorpyrifos Leads to Behavioral Alterations in Adulthood, Involving Serotonergic Mechanisms and Resembling Animal Models of Depression

Article excerpt

Developmental exposure to chlorpyrifos (CPF) causes persistent changes in serotonergic (5HT) systems. We administered 1 mg/kg/day CPF to rats on postnatal days 1-4, a regimen below the threshold for systemic toxicity. When tested in adulthood, CPF-exposed animals showed abnormalities in behavioral tests that involve 5HT mechanisms. In the elevated plus maze, males treated with CPF spent more time in the open arms, an effect seen with 5HT deficiencies in animal models of depression. Similarly, in an anhedonia test, the CPF-exposed group showed a decreased preference for chocolate milk versus water. Developmental CPF exposure also has lasting effects on cognitive function. We replicated our earlier finding that developmental CPF exposure ablates the normal sex differences in 16-arm radial maze learning and memory: during acquisition training, control male rats typically perform more accurately than do control females, but CPF treatment eliminated this normal sex difference. Females exposed to CPF showed a reduction in working and reference memory errors down to the rate of control males. Conversely, CPF-exposed males exhibited an increase in working and reference memory errors. After radial-arm acquisition training, we assessed the role of 5HT by challenging the animals with the 5H[T.sub.2] receptor antagonist ketanserin. Ketanserin did not affect performance in controls but elicited dose-dependent increases in working and reference memory errors in the CPF group, indicating an abnormal dependence on 5HT systems. Our results indicate that neonatal CPF exposures, classically thought to be subtoxic, produce lasting changes in 5HT-related behaviors that resemble animal models of depression. Key words: animal models, behavioral deficits, brain development, chlorpyrifos, depression, organophosphates, serotonin. doi:10.1289/ehp.7867 available via http://dx.doi.org/[Online 2 February 2005]

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Chlorpyrifos (CPF), one of the most widely used organophosphate pesticides, has undergone increased restriction of use in the United States because of developmental neurotoxicity [U.S. Environmental Protection Agency (EPA) 2000, 2002]. Many animal studies have focused on long-term cholinergic deficits and related behaviors, given the acknowledged role of cholinesterase inhibition and cholinergic hyperstimulation in the systemic toxicity of organophosphates (Barone et al. 2000; Clegg and van Gemert 1999a, 1999b; Mileson et al. 1998; Pope 1999; Slotkin 1999, 2004). However, in the developing brain, CPF affects many of the basic processes of neural cell development through mechanisms that are not reflective of cholinesterase inhibition or cholinergic mechanisms, eliciting widespread disruption of neural cell replication and differentiation, axonogenesis and synaptogenesis, and synaptic function (Barone et al. 2000; Casida and Quistad 2004; Gupta 2004; Pope 1999; Slotkin 1999, 2004). Importantly, most of these effects are seen at CPF exposures below the threshold for systemic toxicity and even below the threshold for cholinesterase inhibition (Barone et al. 2000; Casida and Quistad 2004; Gupta 2004; Pope 1999; Qiao et al. 2002, 2003; Schuh et al. 2002; Slotkin 1999, 2004) and are major contributors to persistent neurobehavioral defects (Icenogle et al. 2004; Levin et al. 2001, 2002).

In fact, long-term alterations after fetal or neonatal CPF exposure are not confined to cholinergic systems but rather involve a wide variety of neurotransmitters and, notably, serotonin (5HT) (Aldridge et al. 2003, 2004; Dam et al. 1999; Raines et al. 2001; Slotkin 1999, 2004; Slotkin et al. 2002). Deficiencies in 5HT systems are a hallmark of human depression, and the most effective therapies use drugs designed to restore 5HT synaptic function (Maes and Meltzer 1995). In the present study, we evaluated the effects of neonatal CPF exposure on behaviors in adulthood that are well established in animal models of depression to reflect 5HT synaptic dysfunction (Cairncross 1984; Cryan et al. …

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