Organophosphates (OPs) are important toxic compounds commonly used for a variety of purposes in agriculture, industry, and household settings (Maroni et al., 2000; Pope, 1999). These compounds affect a variety of central nervous system (CNS) functions (Pope et al., 2005). The relation between cognitive and behavioral effects following OPs intoxication has been well studied, and short-term neurobehavioral and emotional deficit in response to chlorpyrifos (CPF) exposure have been reported (Bushnell et al., 2001; Lopez-Crespo et al., 2009). Other studies have also reported neurobehavioral effects in humans after acute OP poisoning (Rohlman et al., 2011). In recent years, new evidence has pointed to the propensity of some OPs to cause neurotoxicity, neuroinflammation, and/or neurodegeneration (Ruiz-Munoz et al., 2011; Tansey et al., 2007), most likely via oxidative injury. It has also been demonstrated that acute administration of diisopropylphosphorofluoridate (DFP) to rats is associated with a significant increase in biomarkers of reactive oxygen species (ROS) (F2-isoprostanes [F2-IsoPs] and F4-neuroprostanes [F4-NeuroPs]) (Zaja-Milatovic et al., 2009). Other reports have demonstrated CPF-induced ROS generation (Gupta et al., 2010). In addition, acute CPF exposure in Wistar rats has been shown to cause short-term impairment in sensorimotor and cognitive functions, partly due to changes in brain lipoperoxidation (Ambali et al., 2010). Only a few studies have addressed the ability of acute parathion (PTN) exposure to elicit oxidative stress (Ojha and Srivastava, 2012). Given these observations and existing gaps in the literature, the major goal of this study was to investigate and compare the effects of CPF, DFP, and PTN on short-term cognitive and behavioral consequences, relating these effects to the respective efficacy of these OPs to generate oxidative stress. Acetylcholinesterase (AChE) inhibition and accumulation of acetylcholine at cholinergic synapses is evident within minutes to hours following exposure to OPs (Ecobichon, 1997; Lotti, 2001). However, the sensitivity of various AChE forms to OPs has yet to be determined. Within the brain, AChE exists in different molecular forms, mainly soluble (salt-soluble): monomeric, dimeric, and tetrameric forms, and particulate membrane-bound oligomeric (detergent-soluble). The tetrameric is the most abundant AChE form in the mammalian brain (Saez-Valero et al., 2003). Although the catalytic activity for both forms is analogous, it has been noted that they differ in mediating biological functions, such as plasticity (Kim et al., 2011) and cell adhesion properties (Ray et al., 2010); the latter are functions mediated by the AChE particulate form. Several studies have reported that in neurodegenerative disorders, such as Alzheimer’s disease (AD), the tetrameric form is selectively lost with a relatively small increase in AChE soluble monomers (Saez-Valero et al., 1999). Accordingly, the cholinergic system, and most specifically the AChE particulate form, plays an essential role in modulating cognitive performance in humans, vertebrates, and invertebrates. Therefore, emphasis should be placed on investigating the role of each of the AChE forms in relation to behavioral performance and other parameters. In addition, the recovery of AChE activity following OP exposure may result from increased expression of AChE causing variations in protein levels of each of the AChE forms providing additional rationale for studies aimed at deciphering their relative role in mediating various aspects of OP poisoning. Accordingly, we considered it timely to study the possible differences in OP-induced inhibition of these molecular forms. These observations led us to the second objective of this work, which is closely related to the first one, namely, is there a relationship between the inhibition of the soluble and particulate forms of AChE and oxidative stress? Furthermore, by inference, we questioned if CPF, DFP, and PTN mediate their effect by an analogous mechanism and similar time course? Therefore, a second experiment was designed to determine the degree of inhibition of AChE activity by separating the soluble and particulate forms of the enzyme. Several studies have suggested that protein product multimerization and membrane-bound properties of AChE (Meshorer and Soreq, 2006; Nijholt et al., 2004) as well as the recovery of AChE can be attributable to the alternative splicing of the AChE gene (Soreq and Seidman, 2001). In the CNS, Synaptic AChE-S mRNA is the main transcript expressed. Its product may be in the soluble form or it may be membrane-bound. However, under stress conditions, such as OPs exposure (Evron et al., 2007; Perrier et al., 2005), the transcription of the read-through splice variant, AChE-R mRNA increases (Adamec et al., 2008; Farchi et al., 2007). The AChE-R variant remains as a soluble monomer (Soreq and Seidman, 2001), and its overexpression may change the balance between the soluble and membrane-bound forms (Saez-Valero et al., 2003) and consequently their functions, affecting the restoration of cholinergic function. Finally, acylpeptide hydrolase (APH) has been considered a second target of OPs (Quistad et al., 2005; Rosenblum and Kozarich, 2003). The role of APH in the CNS is unknown. Notably, APH is significantly more sensitive to inhibition by diclorvos (DDVP) and DFP than AChE (Richards et al., 2000; Pancetti et al., 2007). APH participates in the degradation of oligomeric amyloid-beta, potentially representing a new therapy aimed at reducing neurodegeneration in the AD brain (Yamin et al., 2009). Conversely, inhibition of APH may induce neurodegeneration by increasing brain amyloid levels (Salazar et al., 2011). Accordingly, APH activity studies were incorporated into the study design to allow for comparison on the temporal dynamics of its inhibition by the three OPs with that of AChE.