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Objective: Older persons with human immunodeficiency virus (HIV) (PWH) are particularly susceptible to life-space restrictions. The aims of this study included: 1) using global positioning system (GPS) derived indicators as an assessment of time spent at home among older adults with and without HIV; 2) using ecological momentary assessment (EMA) to examine real-time relationships between life-space, mood (happiness, sadness, anxious), fatigue, and pain; and 3) determining if number of daily social interactions moderated the effect of life-space on mood., Methods: Eighty-eight older adults (PWH n = 54, HIV-negative n = 34) completed smartphone-based EMA surveys assessing mood, fatigue, pain, and social interactions four times per day for two weeks. Participants' smartphones were GPS enabled throughout the study. Mixed-effects regression models analyzed concurrent and lagged associations among life-space and behavioral indicators of health., Results: PWH spent more of their time at home (79% versus 70%, z = -2.08; p = 0.04) and reported lower mean happiness (3.2 versus 3.7; z = 2.63; p = 0.007) compared to HIV-negative participants. Controlling for covariates, more daily social interactions were associated with higher ratings of real-time happiness (b = 0.12; t = 5.61; df = 1087.9; p< 0.001). Similar findings were seen in lagged analyses: prior day social interactions (b = 0.15; t = 7.3; df = 1024.9; p < 0.0001) and HIV status (b = -0.48; t = -2.56; df = 1026.8; p = 0.01) attenuated the effect of prior day time spent at home on happiness., Conclusion: Accounting for engagement in social interactions reduced the significant effect of time spent at home and lower happiness. Interventions targeting social isolation within the context of constricted life-space may be beneficial for increasing positive mood in older adults, and especially relevant to older PWH., (Copyright © 2020 American Association for Geriatric Psychiatry. All rights reserved.)

The organophosphate insecticide tetrachlorvinphos (TCVP, Rabon) is the active ingredient in "feed-through" larvacides (e.g., Equitrol) for fly control around horse stables. As with other organophosphates, TCVP elicits toxicity by inhibiting acetylcholinesterase, leading to accumulation of the neurotransmitter acetylcholine and cholinergic signs. Relatively little is known, however, on the effects of TCVP-containing larvacides on acetylcholinesterase or other esterases in horses. Previous in vitro studies indicated that horse plasma cholinesterase activity was substantially (>10,000-fold) more sensitive than erythrocyte cholinesterase activity to inhibition by TCVP. In the current study, we examined the relative proportion of acetylcholinesterase and butyrylcholinesterase activities in horse plasma and muscle, and evaluated the in vivo effects of Equitrol on target and non-target esterases following oral feeding in horses. In vitro inhibition studies suggested that essentially all cholinesterase activity in horse plasma was butyrylcholinesterase, while muscle contained >90% acetylcholinesterase activity. For in vivo studies, adult, male horses (364-590kg; n=3/treatment group) were given either sweet feed alone or sweet feed supplemented with Equitrol daily for 21 consecutive days at the recommended rate. Clinical signs (vital signs, abdominal auscultation, ophthalmic exam, body temperature) were recorded on a daily basis. Heparinized blood samples were taken at days -1, 1, 3, 7, 21, 28, and 42 while muscle (semimembranosus) biopsies were taken under aseptic conditions on days -1 and 21. No signs of overt toxicity were noted at any time during the study. Plasma cholinesterase activity was significantly inhibited (33%) in larvacide-treated horses as early as one day after treatment and peak inhibition (69-71%) was noted at days 7 and 21. Following cessation of dosing, plasma cholinesterase activity recovered (46% and 83% of control on days 28 and 42, respectively). Neither erythrocyte cholinesterase activity nor plasma carboxylesterase activity was affected by larvacide treatment in vivo. Muscle cholinesterase activity was highly variable among individual horses (pre-treatment range: 0.50-4.92nmole/min/mg protein), but there was no suggestion of a treatment-related reduction in muscle cholinesterase activity. These in vivo results confirm our previous in vitro studies indicating marked differential sensitivity of horse plasma and erythrocyte cholinesterase to inhibition by TCVP. Furthermore, the results suggest that recommended dosing levels of the TCVP-containing larvacide in horses are unlikely to affect acetylcholinesterase activities or disrupt cholinergic neurotransmission in target tissues.

Organophosphorus (OP) pesticides elicit acute toxicity by inhibiting acetylcholinesterase (AChE), the enzyme responsible for inactivating acetylcholine (ACh) at cholinergic synapses. A number of OP toxicants have also been reported to interact directly with muscarinic receptors, in particular the M(2) muscarinic subtype. Parasympathetic innervation to the heart primarily regulates cardiac function by activating M(2) receptors in the sinus node, atrial-ventricular node and conducting tissues. Thus, OP insecticides can potentially influence cardiac function in a receptor-mediated manner indirectly by inhibiting acetylcholinesterase and directly by binding to muscarinic M(2) receptors. Young animals are generally more sensitive than adults to the acute toxicity of OP insecticides and age-related differences in potency of direct binding to muscarinic receptors by some OP toxicants have been reported. We thus compared the effects of the common OP insecticide chlorpyrifos (CPF) on functional signs of toxicity and cardiac cholinesterase (ChE) activity and muscarinic receptor binding in neonatal and adult rats. Dosages were based on acute lethality (i.e., 0.5 and 1x LD(10): neonates, 7.5 and 15 mg/kg; adults, 68 and 136 mg/kg). Dose- and time-related changes in body weight and cholinergic signs of toxicity (involuntary movements) were noted in both age groups. With 1x LD(10), relatively similar maximal reductions in ChE activity (95%) and muscarinic receptor binding (approximately 30%) were noted, but receptor binding reductions appeared earlier in adults and were more prolonged in neonates. In vitro inhibition studies indicated that ChE in neonatal tissues was markedly more sensitive to inhibition by the active metabolite of chlorpyrifos (i.e., chlorpyrifos oxon, CPO) than enzyme in adult tissues (IC(50) values: neonates, 17 nM; adults, 200 nM). Chelation of free calcium with EDTA had relatively little effect on in vitro cholinesterase inhibition, suggesting that differential A-esterase activity was not responsible for the age-related difference in cholinesterase sensitivity between age groups. Pre-incubation of neonatal and adult tissues with selective inhibitors of AChE and butyrylcholinesterase (BChE) indicated that a majority (82-90%) of ChE activity in the heart of both neonates and adults was BChE. The rapid onset (by 4h after dosing) of changes in muscarinic receptor binding in adult heart may be a reflection of the more potent direct binding to muscarinic receptors by chlorpyrifos oxon previously reported in adult tissues. The results suggest that ChE activity (primarily BChE) in neonatal heart may be inherently more sensitive to inhibition by some anticholinesterases and that toxicologically significant binding to muscarinic receptors may be possible with acute chlorpyrifos intoxication, potentially contributing to age-related differences in sensitivity.

Maturational expression of carboxylesterase activity in laboratory animals has been correlated with age-related differences in sensitivity to many organophosphorus insecticides including chlorpyrifos. Little information is available, however, on the maturational expression of liver carboxylesterases in humans. Human liver carboxylesterase activity was compared in tissues from infants (2-24 months) and adults (20-36 years). There was no significant difference between mean infant and adult carboxylesterase activities. The carboxylesterase activity rank order was: 2 months<3 months<20 years<24 months<4 months<36 years<21 years<8 months<34 years<35 years. Proteins (3 microg) were separated and blotted using antibodies against rat hydrolase S (HS), human carboxylesterase (HCE) types 1 and 2, and CYP3A4. Again, there were no significant differences in staining density between infant and adult tissues with any isozyme. Aliquots of each sample were pre-incubated (30 min, 37 degrees C) with chlorpyrifos oxon to evaluate in vitro sensitivity. Based on 95% confidence intervals, no significant differences in IC50 values were obtained in 3-month to 36-year samples (range: 1.42-2.12 nM), while the IC50 was significantly lower in the 2-month sample (0.45 nM). Carboxylesterase activity across samples was correlated with cytochrome b5 content and HS immunosignal but not with other microsomal activities (total cyt P450 content, testosterone hydroxylation, coumarin hydroxylation, and EROD). The results suggest that, in contrast to rodents, human liver carboxylesterase expression changes relatively little during postnatal maturation.

Sulfotransferase (SULT) catalyzed sulfation is responsible for hormone regulation and xenobiotic detoxification. Induction of SULTs by various hormones has been reported. Stress regulation of SULTs has not been reported, however. Here we report that rat liver SULTs can be regulated by physical stress (forced running, EX) and chemical stress (the organophosphorus pesticide parathion, PS). Both EX and PS increased rat liver phenol-sulfating SULT1A1 and hydroxysteroid-sulfating SULT2A1 activities. The increase in SULT1A1 activity did not correlate with protein (Western blot) or mRNA (RT-PCR) results but correlated well with increased non-protein soluble thiols. This suggests a possible Cys modification mechanism for stress regulation of SULT1A1. In vitro studies on GSH/GSSG effects on SULT1A1 activity support this conclusion. In contrast, SULT2A1 activity following physical or chemical stress treatments correlated well with protein and mRNA levels. This suggests a stress regulation mechanism of SULT2A1 at the gene transcription level, possibly occurring via hormones., (Copyright 2004 Elsevier Inc.)

Pyridostigmine is a short-acting inhibitor of cholinesterase (ChE) used as a pretreatment against potential nerve agent exposure during the Persian Gulf War. As pyridostigmine contains a quaternary ammonium group, it is generally believed to elicit changes in the peripheral nervous system function only. It has been hypothesized, however, that the neurotoxicity of pyridostigmine may be altered by either stress or combined exposures to other toxicants. We evaluated the effects of forced running stress, exposure to the organophosphate anticholinesterase paraoxon, or a combination of both on the acute neurotoxicity of pyridostigmine. ChE (blood, diaphragm, and selected brain regions) and carboxylesterase (CE; liver, plasma) inhibition was also evaluated. Young adult male Sprague-Dawley rats were either given vehicle or paraoxon (0.1 mg/kg, i.m.) and subsets placed in their home cage or forced to run on a treadmill for 60 min. Pyridostigmine (0, 10 or 30 mg/kg, p.o.) was given 60 min after paraoxon dosing and rats were evaluated for cholinergic toxicity just prior to sacrifice 60 min later. No signs of toxicity were noted following paraoxon exposure while both dosages of pyridostigmine (10 and 30 mg/kg, p.o.) elicited signs of functional toxicity. Toxicity was not different with combined paraoxon-pyridostigmine exposures and forced running did not influence toxicity under any conditions. Paraoxon (0.1 mg/kg, i.m.) caused moderate (23-46%) ChE inhibition in blood, diaphragm and brain 2 h after exposure. Pyridostigmine (10 or 30 mg/kg, p.o.) caused extensive inhibition of blood (88-94%) and diaphragm (75-85%) ChE activity but no significant effect on brain regional ChE activity. Forced running stress did not influence the degree of tissue ChE inhibition following either paraoxon, pyridostigmine or paraoxon-pyridostigmine combined exposures. CE activities were inhibited (26-43%) in plasma and liver by paraoxon but inhibition was not influenced by either stress or combined paraoxon-pyridostigmine exposures. These results suggest that subclinical paraoxon exposure and forced running stress, by themselves or in combination, have little effect on acute pyridostigmine toxicity in rats.

Acetylcholine (ACh) release is modulated pre-synaptically by both muscarinic and nicotinic receptor-mediated processes. While muscarinic autoreceptors inhibit ACh release, nicotinic autoreceptors enhance ACh release and thus disruption of these processes could potentially affect cholinergic toxicity following exposure to anticholinesterases. Marked age-related differences in sensitivity to some organophosphorus (OP) anticholinesterases have been reported. We compared nicotinic autoreceptor function (NAF) during maturation and aging and evaluated its potential modulation by the common OP insecticide, chlorpyrifos (CPF). Cortical synaptosomes were pre-loaded with [3H]choline, superfused (0.6 ml/min) with physiological buffer and [3H]ACh release was evoked with potassium (KCl, 9 mM), with or without co-addition of exogenous ACh to stimulate nicotinic autoreceptors. Fractions of perfusate were subsequently collected and area under the curve (AUC) for [3H] was analyzed by scintillation counting. The difference in evoked release due to co-addition of exogenous ACh was defined as NAF. Under these conditions, atropine (ATR, 0.1 microM) appeared requisite for NAF; thus this muscarinic antagonist was subsequently added to all perfusion buffers. In synaptosomes from adult tissues, exogenous ACh (3-100 microM) significantly increased release in a concentration-dependent manner. The nicotinic antagonist mecamylamine (MEC, 100 microM) substantially reduced the potassium-evoked release elicited by co-addition of ACh (10 microM). Interestingly, the nicotinic agonists nicotine (NIC) and dimethylphenylpiperazinium (DMPP; 0.1-10 microM) had no effect on release. The active metabolite of CPF (i.e. chlorpyrifos oxon (CPO), 1-10 microM) inhibited NAF in vitro. Maturation-related expression of NAF was noted (AUC with co-addition of 10 microM ACh: 7-day rats, 7+/-6; 21-day rats, 44+/-6; 90-day rats, 196+/-37; 24-month rats, 173+/-52). NAF was substantially reduced (67-91%) 96 h after maximum tolerated dosages of CPF in adult and aged rats (279 mg/kg, sc) but not in juveniles (127 mg/kg, sc), even though AChE inhibition was similar among the age groups (>80%). Together these data suggest that NAF is differentially expressed during maturation and that this neuromodulatory process may be selectively altered by some OP insecticides, potentially contributing to age-related differences in response to AChE inhibitors. As NAF has been postulated to be activated under conditions of 'impaired' cholinergic function, selective alteration of this pre-synaptic process by OP anticholinesterases may be also important in age-related conditions associated with cholinergic hypofunction., (Copyright 2002 Elsevier Science Ireland Ltd.)

Stress-induced change in the distribution of the drug pyridostigmine (PYR) has been proposed as a contributing factor to unexplained illnesses in Persian Gulf War veterans. We evaluated the effects of two stress models, forced running and forced swimming, on acute PYR (30 mg/kg, p.o.) toxicity and cholinesterase (ChE) inhibition in the blood and selected brain regions of young adult male Sprague-Dawley rats (6 weeks of age). Plasma corticosterone levels were measured at 0, 1 and 3 h after termination of forced swimming or forced running to confirm the induction of stress. PYR was given either immediately before stress (15 min swimming; 20 min running) or immediately after stress (15 min swimming; 90 min running) and cholinergic toxicity and ChE inhibition were evaluated at 1, 2 or 4 h after PYR exposure. Additionally, rats were subjected to either swimming (15 min) or running (90 min) stress, anesthetized, injected with horseradish peroxidase (HRP, 100 mg/kg, transcardial) and brain-regional HRP activity measured as an indicator of altered blood-brain barrier integrity. Both forced swimming and forced running resulted in significant elevations of plasma corticosterone levels. PYR caused cholinergic toxicity at all time-points evaluated. Swimming and running stress had little influence on expression of PYR-induced toxicity, however. Blood ChE activity was generally inhibited 77-91% at 1-4 h after PYR, but rats pretreated with PYR prior to forced swimming showed lesser inhibition (64%) 1 h after dosing, possibly because of swimming-induced hypothermia and delayed absorption of the drug. Minimal changes in ChE activity were noted in frontal cortex, cerebellum and hippocampus following PYR exposure (maximal inhibition 28%), and neither swimming nor running stress affected the degree of inhibition. Neither stress model increased HRP accumulation in any brain region. The results suggest that stress associated with forced running or forced swimming has little effect on acute PYR toxicity, entry of PYR into the brain or PYR-induced brain-regional ChE inhibition.

Organophosphorus insecticides elicit toxicity by inhibiting acetylcholinesterase. Young animals are generally more sensitive than adults to these toxicants. A number of studies reported that some organophosphorus agents also bind directly to muscarinic receptors, in particular the m(2) subtype, in tissues from adult rats. As both the density and agonist affinity states of cardiac muscarinic receptors (primarily m(2)) have been reported to change in an age-related manner, we evaluated the relative in vitro sensitivity of cardiac muscarinic receptors in tissues from neonatal (7-11 days of age) and adult (90 days of age) rats to selected organophosphorus compounds (chlorpyrifos, parathion, methyl parathion and their oxygen analogs or oxons). The effects of the cholinergic agonist carbachol (100 pM-5 microM) or an organophosphorus toxicant (50 pM-10 microM) on muscarinic receptor binding were determined using the nonselective muscarinic ligand [3H]quinuclidinyl benzilate or the m(2)-preferential ligand [3H]oxotremorine-M acetate. Carbachol displaced [3H]oxotremorine labeling in adult and neonatal membranes in a relatively similar manner (IC(50)=7-20 nM). The oxons all displaced [3H]oxotremorine binding in a concentration-dependent manner, with chlorpyrifos oxon being the most potent (IC(50): neonates, 15 nM; adults, 7 nM) and efficacious (maximum displacement: neonates, 42%; adults, 56%). Interestingly, methyl parathion was an extremely potent displacer of [3H]oxotremorine binding in adult tissues (IC(50)=0.5 nM, maximum displacement=37%) but had no effect in neonatal tissues. The displacement of [3H]oxotremorine binding by chlorpyrifos oxon (10 microM) was still apparent after washing the tissues, suggesting the oxon irreversibly blocked agonist binding to the receptor while interaction with MePS appeared reversible. As effective concentrations of the oxons were relatively similar to their anticholinesterase potencies, these findings suggest that direct interaction with cardiac muscarinic receptors by some organophosphorus agents may occur at relevant exposure levels and contribute to cardiac toxicity.

Acute exposure to the organophosphate pesticide chlorpyrifos (CPF) on gestation day 12 (GD12, 200 mg/kg/ml, SC) causes extensive neurochemical changes in maternal brain but lesser changes in fetal brain. In the present study, we examined the relative neurotoxicity of repeated, lower-level CPF exposures during gestation in rats. Pregnant Sprague-Dawley rats were exposed to CPF (6.25, 12.5, or 25 mg/kg per day, SC) from GD12-19 and sampled at either GD16, GD20, or postnatal day 3 (PND3) for measurement of various maternal and developmental neurochemical markers. In contrast to the high acute dose exposure, no maternal toxicity was noted with repeated lower-level dosing. Extensive acetylcholinesterase (AChE) inhibition (83-90%) was noted in maternal brain at all three time points following repeated exposures (25 mg/kg). Higher AChE inhibition (58%) was noted in fetal brain at GD20 compared to 19-25% on PND3 in treated pups cross-fostered to control dams and in control pups cross-fostered to treated dams following repeated exposures (25 mg/kg per day). Whereas similar reductions in brain muscarinic receptor binding were noted at GD20 and PND3 in dams and developing brain between acute and repeated dosing regimens, greater changes in [3H]CD and [3H]cytisine binding were evident following repeated exposures. Righting reflex and cliff avoidance tests were markedly altered following repeated exposures. The results suggest that lower-level repeated exposures to CPF cause extensive neurochemical and neurobehavioral changes in developing rats in the absence of maternal toxicity.

Neonatal (7 days old) rats are markedly more sensitive than adults (3 months old) to the acute toxic effects of the insecticide, chlorpyrifos (CPF). In the present study, we have compared the effects of subacute CPF exposures in these same age groups. Repeated doses of CPF (40 mg/kg, SC, every 4 days, total of 4 doses) caused extensive inhibition of cortical, hippocampal, and striatal cholinesterase (ChE) activity in adult rats at 4 (90-92%) and 14 (71-78%) days after the last treatment. Rats treated similarly during postnatal maturation (beginning on day 7) showed a much lower degree of ChE inhibition (21-60%) at these time points. Muscarinic ([3H]quinuclidinyl benzilate, QNB) receptor binding in cortex, hippocampus, and striatum was reduced in adult brain at 4 (30-43%) and 14 (22-32%) days after the final treatment, whereas receptor densities were only marginally affected (5-11% reduction) in young rats. Basal motor activity levels were not affected in either young or adult rats as a function of CPF exposure. CPF-treated adult rats exhibited higher activity levels after challenge with scopolamine (1 mg/kg, IP) at 2, 4, 6, and 8 weeks after treatment, whereas CPF exposure did not affect the motoric response to scopolamine in rats treated during postnatal maturation. These data suggest that although neonatal rats are more sensitive to acute lethal effects from high doses of CPF, adult rats exhibit more persistent neurochemical and neurobehavioral alterations following repeated, lower-level exposures.

The first step in the initiation of organophosphorus-induced delayed neuropathy (OPIDN) is proposed to be the phosphorylation of an enzyme found in the nervous system called neurotoxic esterase (neuropathy target esterase, NTE). It has been known for over twenty years that non-neuropathic inhibitors of NTE exist and can actually prevent OPIDN when given before a neuropathic organophosphate (OP). Within the last three years it has become evident that another outcome is possible following in vivo interaction between neuropathic and nonneuropathic NTE inhibitors. When administered after OP exposure, nonneuropathic inhibitors can intensify or potentiate signs of OPIDN in adult chickens. Additionally, whereas developing chickens are typically resistant to the effects of neuropathic OPs, resistant age groups will develop OPIDN when exposure to a neuropathic OP is followed by the non-neuropathic NTE inhibitor phenylmethylsulfonyl fluoride. As in the case of prevention, studies of the potentiation of OPIDN may yield insight into mechanisms involved in the pathogenesis of delayed neurotoxicity. A brief review of current knowledge regarding the role of NTE in both the prevention and potentiation of OPIDN is presented.

Human exposure to organic solvents is often complicated by ethanol ingestion and the literature is replete with demonstrations of metabolic interactions between ethanol and organic solvents at a pharmacokinetic level. Because of the possible modulation of xylene toxicity by ethanol consumption, the present group of studies characterizes the effect of ethanol on the p-xylene-induced decrease in axonal transport in the rat optic system previously reported by our laboratory. Long-Evans, hooded, male rats were divided randomly into two groups: those receiving 10% ethanol in their drinking water and those receiving water only. These two groups were further subdivided into two groups which were either exposed by inhalation to 1600 ppm p-xylene for 6 h/day, 5 days/week for 8 exposure-days or were treated identically except that they were exposed to air while in the inhalation chambers. The ethanol-drinking rats were given ethanol 6 days prior to and on the days of the inhalation exposure. Immediately after removal from the inhalation chambers on the last exposure day, the animals were injected intraocularly with [35S]methionine and [3H]fucose to measure the synthesis and rapid axonal transport of proteins and glycoproteins, respectively, in the retinal ganglion cells. The animals were sacrificed 20 h later, and the amount of radioactivity in different areas of the retinal ganglion cells was determined by liquid scintillation counting. As in previous experiments, the xylene exposure group showed a significant reduction in axonal transport of proteins and glycoproteins, whereas the ethanol exposure alone produced no significant reductions in the transport of either proteins or glycoproteins. In the animals receiving both ethanol and xylene, however, the ethanol treatment prevented the decreased transport characteristic of the xylene only animals, i.e. in all areas of the optic projections the level of transport were similar to the level present in the control groups. These data suggest that the xylene-induced reduction in rapid axonal transport was reversed (or prevented) by subacute ethanol consumption.

A single dose of the organophosphate insecticide O,O'-diethyl-O-3,5,6- trichloro-2-pyridylphosphorothioate [chlorpyrifos (CPF), 279 mg/kg, SC] caused extensive inhibition of cortical and striatal cholinesterase (ChE) activity in adult rats at 2 (94-96%), 4 (82-83%), and 6 (58-60%) weeks after treatment. These persistent changes in ChE activity were concomitant with reductions in muscarinic receptor binding sites in cortex (34, 33, and 18% reduction in Bmax) and striatum (48, 40, and 23% reduction in Bmax) at 2, 4, and 6 weeks after exposure. Neither ChE activities nor muscarinic receptor densities were different from control levels at 12 weeks after exposure. CPF treatment caused a reduction in locomotor activity for the first 2 days after treatment, after which basal activity levels were not different from controls. CPF-treated rats showed higher activity relative to controls, however, following challenge with scopolamine (1 mg/kg, IP) at 2, 4, 6, 8, and 12 weeks after treatment. These data indicate that acute exposure to CPF in adult rats can cause long-term neurobehavioral changes that may persist following the recovery of neurochemical parameters associated with exposure and tolerance to cholinesterase inhibitors.

Developing mammals are markedly more sensitive to acute toxicity from exposure to a variety of organophosphorus (OP) pesticides. The present study examined dose-related inhibition of both brain and plasma cholinesterase activity in neonatal and adult rats exposed to sublethal doses of one of three common OP pesticides, methyl parathion, parathion and chlorpyrifos. Effective dose 50 (i.e., ED50 or dose which would inhibit 50% of the cholinesterase activity) values were determined and then correlated with an indicator of acute toxicity, the maximal tolerated dose (MTD). It was found that ED50 estimates for both brain and plasma cholinesterase correlated highly (r = 0.932-0.992) with previously derived MTD values. In no case was there a significant difference between in vivo brain and plasma cholinesterase inhibition across doses in neonatal rats was high (r = 0.962-0.975) but lower in adults (r = 0.700-0.943). The results suggest that in vivo inhibitory potency of the three OPs towards either brain or plasma ChE activity is highly correlated with sensitivity to acute toxicity in both neonatal and adult rats. Additionally, under defined experimental conditions, plasma ChE inhibition may be a useful quantitative index for the degree of brain cholinesterase inhibition following OP exposures.

Developing mammals are more sensitive than adults to a variety of organophosphorothioate insecticides (OPs), compounds which act in vivo by inhibition of cholinesterase (ChE). Little is known, however, regarding age-related differences in biochemical responses to these toxicants. The time course of ChE inhibition and recovery in whole brain was compared in neonatal (7 days of age) and adult (80-100 days of age) rats after treatment with maximal tolerated doses (MTDs) of either methyl parathion (MPS), parathion (PS) or chlorpyrifos (CPF). Neonatal rats were more sensitive than adults in all cases (MTDs for MPS, PS and CPF; neonates = 7.8, 2.1 and 45 mg/kg, s.c.; adults = 18, 18, and 279 mg/kg, s.c., respectively). In general, maximal brain ChE inhibition was similar (greater than 78%) in both age groups but ChE activity recovered faster in neonates. Plasma and erythrocyte ChE activities correlated relatively well (r = 0.794-0.943) with brain ChE activity in neonatal rats at all time points between 4 h and 7 days after treatment but similar correlations between circulating and brain ChE activities in adults were more variable (r = 0.211-0.917). The results indicate that neonatal rats are more sensitive to acute lethality from these compounds and that MTD exposures produce extensive brain ChE inhibition in both age groups. Significant inhibitor-related and age-related differences in the duration of ChE inhibition can ensue, however, following such OP exposures.

High-affinity choline uptake (HACU) appears to be the rate-limiting step in the synthesis of the neurotransmitter acetylcholine. The present experiment was designed to examine the effects of irreversible inhibition of HACU by ethylcholine aziridinium chloride (ECA) on passive avoidance retention in mice. Animals were injected intracerebroventricularly, and one-trial passive avoidance retention evaluated 21 days later. A significant retention deficit was observed in ECA-treated animals upon retest 24 hours after training. ECA-induced changes in retention were accompanied by significant reductions in choline acetyltransferase (CAT) activity in only two of seven brain regions tested, hippocampus (48% of control) and cerebellum (76% of control). The results support the involvement of hippocampal cholinergic activity in mediation of passive avoidance learning.

N-ethyl-choline aziridinium (ECA) and N-ethyl-acetylcholine aziridinium (EAA) were shown to be inhibitors of high affinity choline uptake in vitro (IC50 = 0.4 microM and 1.5 microM, respectively), and intraventricular administration showed that EAA was more selective in its inhibition of hippocampal choline uptake in vivo. EAA significantly reduced the activity of choline acetyltransferase in the hippocampus 3 to 28 days following intraventricular infusion, but not in the striatum or parahippocampal cortex. Neither muscarinic receptor binding nor glutamic acid decarboxylase activity were affected in any of the three brain regions. EAA (12 or 16 nanomoles, intraventricular) significantly impaired memory performance of mice in a radial arm maze when tested two weeks after treatment. A subgroup analysis implicated long-term reference memory as the mechanism disrupted.