Publications by authors named "Todd M Myers"

28 Publications

  • Page 1 of 1

Evaluation of adenosine A1 receptor agonists as neuroprotective countermeasures against Soman intoxication in rats.

Toxicol Appl Pharmacol 2021 Apr 22;416:115466. Epub 2021 Feb 22.

U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, United States of America. Electronic address:

Soman, an organophosphorus (OP) compound, disrupts nervous system function through inactivation of acetylcholinesterase (AChE), the enzyme that breaks down acetylcholine at synapses. Left untreated, a state of prolonged seizure activity (status epilepticus, SE) is induced, causing widespread neuronal damage and associated cognitive and behavioral impairments. Previous research demonstrated that therapeutic stimulation of A1 adenosine receptors (A1ARs) can prevent or terminate soman-induced seizure. This study examined the ability of three potent A1AR agonists to provide neuroprotection and, ultimately, prevent observable cognitive and behavioral deficits following exposure to soman. Sprague Dawley rats were challenged with a seizure-inducing dose of soman (1.2 x LD) and treated 1 min later with one of the following A1AR agonists: (6)-Cyclopentyladenosine (CPA), 2-Chloro-N6-cyclopentyladenosine (CCPA) or N-bicyclo(2.2.1)hept-2-yl-5'-chloro-5'-deoxyadenosine (cdENBA). An active avoidance shuttle box task was used to evaluate locomotor responses to aversive stimuli at 3, 7 and 14 days post-exposure. Animals treated with CPA, CCPA or cdENBA demonstrated a higher number of avoidance responses and a faster reaction to the aversive stimulus than the soman/saline control group across all three sessions. Findings suggest that A1AR agonism is a promising neuroprotective countermeasure, capable of preventing the long-term deficits in learning and memory that are characteristic of soman intoxication.
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http://dx.doi.org/10.1016/j.taap.2021.115466DOI Listing
April 2021

Organoleptic assessment and median lethal dose determination of oral aldicarb in rats.

Ann N Y Acad Sci 2020 11 5;1480(1):136-145. Epub 2020 Aug 5.

United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland.

Aldicarb, a carbamate pesticide, is an acetylcholinesterase inhibitor, with oral median lethal dose (LD ) estimates in rats ranging from 0.46 to 0.93 mg/kg. A three-phase approach was used to comprehensively assess aldicarb as an oral-ingestion hazard. First, the solubility of aldicarb in popular consumer beverages (bottled water, apple juice, and 2% milk) was assessed. Lethality was then assessed by administering aldicarb in bottled water via gavage. A probit model was fit to 24-h survival data and predicted a median lethal dose of 0.83 mg/kg (95% CI: 0.54-1.45 mg/kg; slope: 4.50). Finally, organoleptic properties (e.g., taste, smell, and texture) were assessed by allowing rats to voluntarily consume 3.0 mL of the above beverages as well as liquid eggs adulterated with aldicarb at various concentrations. This organoleptic assessment determined that aldicarb was readily consumed at lethal and supralethal doses. Overt toxic signs presented within 5 min post-ingestion, and all rats died within 20 min after consuming the highest concentration (0.542 mg/mL), regardless of amount consumed. Because rats have more developed chemoreceptive capabilities than humans, these results suggest that aldicarb may be consumed in toxic or even lethal concentrations by humans in a variety of beverages or foods.
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http://dx.doi.org/10.1111/nyas.14448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708594PMC
November 2020

Carfentanil toxicity in the African green monkey: Therapeutic efficacy of naloxone.

Toxicol Lett 2020 Jun 15;325:34-42. Epub 2020 Feb 15.

United States Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD, 21010, United States. Electronic address:

Carfentanil is an ultra-potent opioid with an analgesic potency 10,000 times that of morphine but has received little scientific investigation. Three experiments were conducted to evaluate the toxicity of carfentanil and the efficacy of naloxone in adult male African green monkeys. The first experiment determined the ED (found to be 0.71 μg/kg) of subcutaneous carfentanil for inducing bradypnea and/or loss of posture. Experiment 2 attempted to establish the ED of naloxone for rapidly reversing the bradypnea/loss of posture induced by carfentanil (1.15 μg/kg). Experiment 3 evaluated the effects of carfentanil (0.575 μg/kg) alone, the safety of naloxone (71-2841 μg/kg), and the efficacy of naloxone (71-710 μg/kg) administration at two time points following carfentanil (1.15 μg/kg) on operant choice reaction time. Collectively, these experiments characterized the temporal progression of carfentanil-induced toxic signs, determined the range of naloxone doses that restored respiratory and gross behavioral function, and determined the time course and range of naloxone doses that partially or completely reversed the effects of carfentanil on operant choice reaction time performance in African green monkeys. These results have practical relevance for the selection of opioid antagonists, initial doses, and expected functional outcomes following treatment of synthetic opioid overdose in a variety of operational/emergency response contexts.
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http://dx.doi.org/10.1016/j.toxlet.2020.02.008DOI Listing
June 2020

Survey of drug therapies against acute oral tetramethylenedisulfotetramine poisoning in a rat voluntary consumption model.

Neurotoxicology 2019 09 10;74:264-271. Epub 2019 Aug 10.

United States Army Medical Research Institute of Chemical Defense, 8350 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, United States. Electronic address:

Ingestion of the noncompetitive GABA receptor antagonist tetramethylenedisulfotetramine (TETS) results in arrhythmias, respiratory depression, and life-threatening convulsive status epilepticus. We have previously developed a realistic model of voluntary TETS consumption, in which rats promptly consumed a piece of cereal containing a dose of TETS that led to rapid progression of toxic signs (including convulsions) and profound and enduring behavioral suppression. Recently, this model was used to survey nine different drugs from distinct drug classes over a large range of doses to identify possible therapeutics. The drugs included three benzodiazepines (diazepam, midazolam, and lorazepam), two barbiturates (phenobarbital and pentobarbital), the GABA allosteric modulator allopregnanolone, and three non-traditional therapeutics (dexmedetomidine, ketamine, and ethanol). Treatment was administered intraperitoneally 10 min after consumption of the cereal morsel containing TETS (600 μg/kg). This exposure model resulted in a survival rate of 30% in vehicle-treated rats. Diazepam (12.5 mg/kg) and midazolam (25 mg/kg), compared to vehicle, significantly increased survival (75 and 100% respectively) but at only one of the three doses tested. Lorazepam increased survival across a wide range of doses (1.56-25 mg/kg) with survival rates between 80-100%. Phenobarbital (100 mg/kg) was the only other drug and non-benzodiazepine to improve survival rates (80%). Although the four aforementioned therapeutics increased survival, TETS-induced weight loss, food wastage, and behavioral deficits remained in survivors.
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http://dx.doi.org/10.1016/j.neuro.2019.08.004DOI Listing
September 2019

Human plasma-derived butyrylcholinesterase is behaviorally safe and effective in cynomolgus macaques (Macaca fascicularis) challenged with soman.

Authors:
Todd M Myers

Chem Biol Interact 2019 Aug 24;308:170-178. Epub 2019 May 24.

United States Army Medical Research Institute of Chemical Defense, USA. Electronic address:

Organophosphorus compounds (OP) pose a significant threat. Administration of human butyrylcholinesterase (HuBChE) may reduce or prevent OP toxicity. Thus, we evaluated the safety and efficacy of HuBChE in monkeys using sensitive neurobehavioral tests while concurrently characterizing absorption and elimination in the presence and absence of high-dose soman exposure to predict time course and degree of protection. Eight young adult male cynomolgus macaques were trained on two distinct automated tests of neurobehavioral functioning. HuBChE purified under current Good Manufacturing Practices (CGMP) was injected intramuscularly at 13.1 mg/kg, producing an average peak plasma value (Cmax) of over 27 Units/ml. The apparent time to maximum concentration (Tmax) approximated 7 h, the elimination half-life approximated 102 h, and plasma levels returned to pre-administration (baseline) levels by 14 days. No behavioral disruptions following HuBChE administration were observed on either neurobehavioral test, even in monkeys injected 24 h later with an otherwise lethal dose of soman. Thus, HuBChE provided complete neurobehavioral protection from soman challenge. The present data replicate and extend previous results from our laboratory that had used a different route of administration (intravenous), a different species (rhesus macaque), and a different BChE product (non-CGMP material). The addition of two sensitive neurobehavioral tests coupled with the PK/PD results convincingly demonstrates the neurobehavioral safety of plasma-derived HuBChE at therapeutic levels. Protection against an otherwise-lethal dose of soman by a pre-exposure treatment dose that is devoid of side effects establishes a foundation for additional testing using other exposure routes and treatment times, other challenge agents/routes, or other classes of organophosphate scavengers.
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http://dx.doi.org/10.1016/j.cbi.2019.05.021DOI Listing
August 2019

Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning.

Basic Clin Pharmacol Toxicol 2019 Sep 10;125(3):289-303. Epub 2019 Apr 10.

United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland.

Sodium cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical that is highly toxic. Its availability and rapid harmful/lethal effects combine to make cyanide a potential foodborne/waterborne intentional-poisoning hazard. Effective antidotes to cyanide poisoning are currently approved only for intravenous administration. Therefore, an effective cyanide antidote that can be administered intramuscularly in pre-hospital and/or mass-casualty settings is needed. Dimethyl trisulfide (DMTS) is a naturally occurring substance used as a flavour enhancer in foods. DMTS has shown antidotal efficacy in cyanide poisoning and is thought to act as both a sulphur donor and partial methaemoglobin inducer. In this study, an intramuscular injection of DMTS (6.25-200 mg/kg) was given to rats 1 minute after an oral dose of NaCN (98.2 mg/kg; twice the median lethal dose) to test the antidotal efficacy and safety of DMTS treatment. Toxic signs and survival were examined along with behavioural function (up to 30 hour after ingestion) using a previously established operant behavioural model. A large range of DMTS doses (6.25-100 mg/kg) increased survival after oral cyanide poisoning, and the lower DMTS doses (6.25-25 mg/kg) also proved to be behaviourally and physiologically safe. Larger DMTS doses (50-200 mg/kg) produced side effects (ie, inflammation and limping) that were more severe and protracted than those observed at lower DMTS doses. The 25 mg/kg DMTS proved to be the most efficacious (increasing survival from 20% to 75%) and also produced minimal side effects (eg, inflammation) that resolved within 24-72 hour. Thus, DMTS shows promise as an intramuscularly administered cyanide antidote useful for prompt pre-hospital or mass-casualty emergency medical treatment.
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http://dx.doi.org/10.1111/bcpt.13220DOI Listing
September 2019

Behavioral, Pharmacokinetic, and Cardiovascular Evaluation of Candidate Oximes in African Green Monkeys.

Int J Toxicol 2018 Sep/Oct;37(5):352-363. Epub 2018 Jun 7.

1 United States Army Medical Research Institute of Chemical Defense, MD, USA.

Oxime reactivators are critical antidotes after organophosphate pesticide or nerve agent poisoning, directly restoring the function of inhibited acetylcholinesterase. In the continuing search for more broad-spectrum acetylcholinesterase reactivators, this study evaluated one of the leading next-generation oxime reactivators: methoxime, (1,1'-trimethylene bis[4-(hydroxyimino)methyl]pyridinium dichloride (MMB-4). The pharmacokinetics of both salts of MMB-4 (dichloride [2Cl] and dimethanesulphonate [DMS]) were characterized across a range of relevant doses (19, 58, and 116 µmol/kg, intramuscular) in a nonhuman primate model (male African green monkeys), and only subtle differences were observed between the salts. Additionally, the behavioral and cardiovascular safety of these MMB-4 salts was compared directly to other available oximes (HI-6 2Cl, HI-6 DMS, and pyridine-2-aldoxime chloride (2-PAM Cl)) at comparable projected doses. Automated operant behavioral tests were used to examine attention, motivation, visual discrimination, concept execution, and fine motor coordination after high doses of all oxime salts, and of all oximes studied, only the highest dose of 2-PAM Cl (447 µmol/kg) disrupted behavioral performance. Likewise, the effects of a range of doses of MMB-4 2Cl or DMS, HI-6 2Cl or DMS, or 2-PAM Cl on cardiovascular parameters were measured in African green monkeys implanted with telemetry devices. Only a small transient decrease in pulse pressure was observed following administration of the highest dose of MMB-4 DMS (116 µmol/kg). Thus, MMB-4 salts, up to the 9× equivalent of a projected autoinjector dose in humans, did not produce behavioral or cardiovascular toxicity in African green monkeys in the current study, and the pharmacokinetic parameters were orderly and predictable.
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http://dx.doi.org/10.1177/1091581818779362DOI Listing
March 2019

Behavioral toxicity of sodium cyanide following oral ingestion in rats: Dose-dependent onset, severity, survival, and recovery.

Food Chem Toxicol 2018 Apr 16;114:145-154. Epub 2018 Feb 16.

United States Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Rd, Aberdeen Proving Ground, MD, 21010, United States. Electronic address:

Sodium cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical reagent that is highly toxic. Its availability and rapid harmful/lethal effects combine to make cyanide a potential foodborne/waterborne intentional-poisoning hazard. Thus, laboratory studies are needed to understand the dose-dependent progression of toxicity/lethality following ingestion of cyanide-poisoned foods/liquids. We developed an oral-dosing method in which a standard pipette was used to dispense a sodium cyanide solution into the cheek, and the rat then swallowed the solution. Following poisoning (4-128 mg/kg), overt toxic signs were recorded and survival was evaluated periodically up to 30 hours thereafter. Toxic signs for NaCN doses higher than 16 mg/kg progressed quickly from head burial and mastication, to lethargy, convulsions, gasping/respiratory distress, and death. In a follow-on study, trained operant-behavioral performance was assessed immediately following cyanide exposure (4-64 mg/kg) continuously for 5 h and again the following day. Onset of behavioral intoxication (i.e., behavioral suppression) occurred more rapidly and lasted longer as the NaCN dose increased. This oral-consumption method with concomitant operantbehavioral assessment allowed for accurate dosing and quantification of intoxication onset, severity, and recovery, and will also be valuable in characterizing similar outcomes following varying medical countermeasure drugs and doses.
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http://dx.doi.org/10.1016/j.fct.2018.02.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860990PMC
April 2018

Behavioral intoxication following voluntary oral ingestion of tetramethylenedisulfotetramine: Dose-dependent onset, severity, survival, and recovery.

Neurotoxicology 2017 Dec 7;63:21-32. Epub 2017 Sep 7.

United States Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Rd, Aberdeen Proving Ground, MD, 21010, USA. Electronic address:

Tetramethylenedisulfotetramine (tetramine, or TETS) is a highly toxic rodenticide that has been responsible for over 14,000 accidental and intentional poisonings worldwide. Although the vast majority of TETS poisonings involved tainted food or drink, the laboratory in vivo studies of TETS intoxication used intraperitoneal injection or gavage for TETS exposure. Seeking to develop and characterize a more realistic model of TETS intoxication in the present study, rats were trained to rapidly and voluntarily consume a poisoned food morsel. Initially, the overt toxic effects of TETS consumption across a large range of doses were characterized, then a focused range of doses was selected for more intensive behavioral evaluation (in operant test chambers providing a variable-interval schedule of food reinforcement). The onset of intoxication following voluntary oral consumption of TETS was rapid, and clear dose-dependent response-rate suppression was observed across multiple performance measures within the operant-chamber environment. At most doses, recovery of operant performance did not occur within 30h. Food consumption and body weight changes were also dose dependent and corroborated the behavioral measures of intoxication. This voluntary oral-poisoning method with concomitant operant-behavioral assessment shows promise for future studies of TETS (and other toxic chemicals of interest) and may be extremely valuable in characterizing treatment outcomes.
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http://dx.doi.org/10.1016/j.neuro.2017.08.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5683944PMC
December 2017

Sex and the stimulus-movement effect: Differences in acquisition of autoshaped responding in cynomolgus monkeys.

Physiol Behav 2017 03 23;171:40-49. Epub 2016 Dec 23.

United States Army Medical Research Institute of Chemical Defense, 2900 Ricketts Point Rd, Aberdeen Proving Ground, MD 21010, United States. Electronic address:

The stimulus-movement effect refers to the phenomenon in which stimulus discrimination or acquisition of a response is facilitated by moving stimuli as opposed to stationary stimuli. The effect has been found in monkeys, rats, and humans, but the experiments conducted did not provide adequate female representation to investigate potential sex differences. The current experiment analyzed acquisition of stimulus touching in a progressive series of classical conditioning procedures in cynomolgus monkeys (Macaca fascicularis) as a function of sex and stimulus movement. Classical conditioning tasks arrange two or more stimuli in relation to each other with different temporal and predictive relations. Autoshaping procedures overlay operant contingencies onto a classical-conditioning stimulus arrangement. In the present case, a neutral stimulus (a small gray square displayed on a touchscreen) functioned as the conditional stimulus and a food pellet functioned as the unconditional stimulus. Although touching is not required to produce food, with repeated stimulus pairings subjects eventually touch the stimulus. Across conditions of increasing stimulus correlation and temporal contiguity, male monkeys acquired the response faster with a moving stimulus. In contrast, females acquired the response faster with a stationary stimulus. These results demonstrate that the stimulus-movement effect may be differentially affected by sex and indicate that additional experiments with females are needed to determine how sex interacts with behavioral phenomena discovered and elaborated almost exclusively using males.
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http://dx.doi.org/10.1016/j.physbeh.2016.12.028DOI Listing
March 2017

Time Course, Behavioral Safety, and Protective Efficacy of Centrally Active Reversible Acetylcholinesterase Inhibitors in Cynomolgus Macaques.

Neurochem Res 2017 Jul 30;42(7):1962-1971. Epub 2016 Nov 30.

Neurobehavioral Toxicology Branch, Analytical Toxicology Division, United States Army Medical Research Institute of Chemical Defense (USAMRICD), 2900 Ricketts Point Rd, Aberdeen Proving Ground, Aberdeen, MD, 21010, USA.

Galantamine hydrobromide and (-)huperzine A, centrally active reversible acetylcholinesterase inhibitors, are potentially superior to the current standard, pyridostigmine bromide, as a pretreatment for organophosphorus chemical warfare nerve agent intoxication. Galantamine, huperzine, and pyridostigmine were compared for time course of acetylcholinesterase inhibition in 12 cynomolgus macaques. Although both galantamine and huperzine shared a similar time course profile for acetylcholinesterase inhibition, huperzine was 88 times more potent than galantamine. The dose for 50% acetylcholinesterase inhibition (ID) was 4.1 ug/kg for huperzine, 362 ug/kg for galantamine, and 30.9 ug/kg for pyridostigmine. In a safety assessment, galantamine, huperzine, and pyridostigmine were examined using an operant time-estimation task. Huperzine and pyridostigmine were devoid of behavioral toxicity, whereas galantamine was behaviorally toxic at doses producing peak acetylcholinesterase inhibition of about 50% and higher. Following pretreatment with galantamine, huperzine or pyridostigmine, monkeys were challenged with the median lethal dose of soman at the time of peak acetylcholinesterase inhibition and evaluated for overt signs of soman toxicity (cholinergic crisis, convulsions). Both huperzine and galantamine were equally effective at preventing overt signs of soman toxicity, but neither drug was capable of preventing soman-induced neurobehavioral disruption. In contrast, three of four pyridostigmine-pretreated animals exposed to soman exhibited convulsions and required therapy. Full functional recovery required 3-16 days. The degree of acetylcholinesterase inhibition was lower for pyridostigmine, but rates of recovery of acetylcholinesterase activity following soman challenge were comparable for all drug pretreatments. Huperzine may be the more promising centrally active reversible acetylcholinesterase inhibitor due to its greater potency and superior safety profile.
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http://dx.doi.org/10.1007/s11064-016-2120-9DOI Listing
July 2017

VX toxicity in the Göttingen minipig.

Toxicol Lett 2016 Dec 20;264:12-19. Epub 2016 Oct 20.

Analytical Toxicology Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD, USA. Electronic address:

The present experiments determined the intramuscular LD of VX in male Göttingen minipigs at two stages of development. In pubertal animals (115 days old), the LD of VX was indeterminate, but approximated 33.3μg/kg. However, in sexually mature animals (152 days old), the LD was estimated to be only 17.4μg/kg. Signs of nerve agent toxicity in the Göttingen minipig were similar to those described for other species, with some notable exceptions (such as urticaria and ejaculation). Latencies to the onset of sustained convulsions were inversely related to the administered dose of VX in both ages of minipigs. Additionally, actigraphy was used to quantify the presence of tremor and convulsions and, in some cases, was useful for precisely estimating time of death. The main finding indicates that in minipigs, as in other species, even relatively small differences in age can substantially alter the toxicity of nerve agents. Additionally, actigraphy can serve as a non-invasive method of characterizing the tremors and convulsions that often accompany nerve agent intoxication.
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http://dx.doi.org/10.1016/j.toxlet.2016.10.011DOI Listing
December 2016

N-acetyl-aspartyl-glutamate and inhibition of glutamate carboxypeptidases protects against soman-induced neuropathology.

Neurotoxicology 2015 May 28;48:180-91. Epub 2015 Mar 28.

Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences (USUHS), 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA. Electronic address:

N-acetyl-aspartyl-glutamate (NAAG) is the most abundant neuropeptide in the mammalian brain. In a variety of animal models of brain injury, the administration of NAAG-related compounds, or inhibitors of glutamate carboxypeptidases (GCPs; the enzymes that hydrolyze NAAG), were shown to be neuroprotective. This study determined the impact of the administration of three NAAG-related compounds, NAAG, β-NAAG (a NAAG homologue resistant to degradation), and 2-phosphonomethyl pentanedioic acid (2-PMPA; an inhibitor of GCP enzymes), on the neuropathology that develops following exposure to the nerve agent, soman. When given 1 min after soman exposure, NAAG-related drug treatments did not alter the survival rate or body weight loss seen 24 h after rats were exposed to soman. Likewise, brain levels of both NAAG and its metabolite, N-acetyl-aspartate (NAA), were substantially decreased 24 h after soman, and in particularly vulnerable brain regions the drug treatments were unable to attenuate the reduction in NAA and NAAG levels. Histochemical study indicated there was a dramatic increase in Fluoro-Jade C (FJC) staining, indicative of neuron cell death, 24 h after soman exposure. However, in the amygdala and in the entorhinal and piriform limbic cortex, which sustained severe neuropathology following soman intoxication, single or combined injections of NAAG compounds and 2-PMPA significantly reduced the number of FJC-positive cells, and effect size estimates suggest that in some brain regions the treatments were effective. The findings suggest that NAAG neurotransmission in the central nervous system is significantly altered by soman exposure, and that the administration of NAAG-related compounds and 2-PMPA reduces neuron cell death in brain regions that sustain severe damage.
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http://dx.doi.org/10.1016/j.neuro.2015.03.010DOI Listing
May 2015

Novel technique for retroperitoneal implantation of telemetry transmitters for physiologic monitoring in Göttingen minipigs (Sus scrofa domesticus).

Comp Med 2014 Dec;64(6):464-70

Research Support Division, United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland, USA.

Telemetric monitoring of physiologic parameters in animal models is a critical component of chemical and biologic agent studies. The long-term collection of neurobehavioral and other physiologic data can require larger telemetry devices. Furthermore, such devices must be implanted in a location that is safe, well-tolerated, and functional. Göttingen minipigs (Sus scrofa domesticus) present an ideal large animal model for chemical agent studies due to their relatively small size, characterized health status, and ease of training and handling. We report an effective approach to implanting a novel device to measure transthoracic impedance to approximate respiratory tidal volume and rate in Suidae. We tested the approach using 24 male Göttingen minipigs. A ventral midline abdominal incision extending from the umbilicus to the prepuce was followed by a paramedian incision of the parietal peritoneum and dorsal blunt dissection to create a retroperitoneal pocket. The device was anchored inside the pocket to the internal abdominal musculature with 3-0 nonabsorbable suture, biopotential leads were routed through the abdominal musculature, and the pocket was closed with 3-0 absorbable suture. Paired biopotential leads were anchored intermuscularly at the level of the seventh rib midway between spine and sternum bilaterally to provide surrogate data for respiratory function. Postoperative recovery and gross pathology findings at necropsy were used to assess safety and refine the surgical procedure. Results demonstrated that this procedure permitted effective monitoring of complex physiologic data, including transthoracic impedance, without negatively affecting the health and behavior of the animals.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4275082PMC
December 2014

Characterization of human serum butyrylcholinesterase in rhesus monkeys: behavioral and physiological effects.

Neurotoxicol Teratol 2012 May-Jun;34(3):323-30. Epub 2012 Feb 28.

Division of Neuroscience, Walter Reed Army Institute of Research, Silver Spring, MD 20910-7500, USA.

The effects of a large dose of human serum butyrylcholinesterase (HuBChE) were evaluated in rhesus monkeys using a serial-probe recognition (SPR) task designed to assess attention and short-term memory. Each monkey received an intravenous injection of 150 mg (105,000 U or 30 mg/kg) of HuBChE 60 min prior to testing on the SPR task. Concurrent with the cognitive-behavioral assessment, blood was collected at various time points throughout the study and was analyzed for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) activities, anti-BChE antibody production and gross clinical pathology (i.e., complete blood count and clinical chemistry panel). HuBChE revealed a peak blood activity of 227 U/ml at 5 min after intravenous injection and a mean residence time of approximately 72 h. No cognitive-behavioral decrements of any kind in SPR performance and no toxic signs in clinical pathology were detected in any of the blood assays during the 5 weeks of observation. Anti-HuBChE antibodies peaked at about 14 days after injection, with no concomitant behavioral changes. These results demonstrate the behavioral and physiological safety of HuBChE in rhesus monkeys and support its development as a bioscavenger for the prophylaxis of chemical warfare agent toxicity in humans.
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http://dx.doi.org/10.1016/j.ntt.2012.02.002DOI Listing
October 2012

Use of operant performance to guide and evaluate medical treatment in an adult male cynomolgus macaque (Macaca fascicularis).

J Am Assoc Lab Anim Sci 2011 Nov;50(6):946-8

Neurobehavioral Toxicology Branch, Analytical Toxicology Division United States Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Aberdeen, Maryland, USA.

A 6-y-old male cynomolgus macaque presented with noticeable swelling of the left forearm and signs of discomfort, as indicated by nonuse of the arm even in a behavioral task that he previously had been well-motivated to perform. Examination under anesthesia revealed lacerations to the arm. Radiography of the forearm showed no fractures, indicating that the damage was limited to soft tissue. The daily operant behavioral session assessed the amount of force the monkey emitted when touching the screen with the affected arm and how long each touch was sustained. We then used these parameters (force and duration of touch) as objective measures of putative pain relief and recovery of function to guide the medical treatment. The affected monkey received ketoprofen, buprenorphine, or their combination but continued to perform poorly during daily operant behavioral sessions. Only after treatment with dexamethasone did performance return to preinjury levels, suggesting inflammation near the radial or ulnar nerve. These findings indicate that performance of a trained operant task performance can be useful in guiding medical treatment, evaluating pain relief, and objectively monitoring health in laboratory animals.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3228936PMC
November 2011

Delayed match-to-sample performance in African green monkeys (Chlorocebus aethiops sabaeus): effects of benzodiazepine, cholinergic, and anticholinergic drugs.

Behav Pharmacol 2011 Dec;22(8):814-23

Neurobehavioral Toxicology Branch, Analytical Toxicology Division, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland 21010, USA.

Delayed match-to-sample (DMTS) procedures are among the most commonly used attention and memory tasks in behavioral pharmacology and have been utilized in a variety of species. Although macaque species such as the rhesus and cynomolgus macaque are often used for such studies, availability and disease transmission raise concerns over their use. The present study investigated whether the African green monkey might function as a suitable alternative by evaluating operant performance on a DMTS task and comparing this species' response to some commonly used drugs (0.025-0.075 mg/kg physostigmine, 0.0033-0.03 mg/kg scopolamine, 0.014-0.44 mg/kg atropine, 0.125-1.0 mg/kg midazolam, and 0.125-2.0 mg/kg diazepam) to the responses previously reported in macaques. Results demonstrated that African green monkeys are capable of learning and performing a DMTS task, and dose-effect functions for behavioral pharmacology were quite similar to those reported for rhesus macaques and other nonhuman primate species. Thus, the African green monkey may function as a suitable alternative to macaque species in behavioral pharmacology research.
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http://dx.doi.org/10.1097/FBP.0b013e32834d6292DOI Listing
December 2011

Diet composition modifies the toxicity of repeated soman exposure in rats.

Neurotoxicology 2011 Dec 27;32(6):907-15. Epub 2011 May 27.

US Army Medical Research Institute of Chemical Defense, Analytical Toxicology Division, Neurobehavioral Toxicology Branch, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010-5400, USA.

It was previously demonstrated that diet potently modulates the toxic effects of an acute lethal dose of the nerve agent soman. The current investigation was undertaken to examine the influence of diet on the cumulative toxicity of repeated soman administration. Rats were fed one of four distinct diets (standard, choline-enriched, glucose-enriched, or ketogenic) for four weeks prior to and throughout a repeated soman dosing and recovery regimen. Each diet group included animals exposed to an equivalent volume of saline that served as negative controls. In exposure Week 1, animals received three consecutive daily doses of 0.4 LD(50) soman. In exposure Week 2, animals received four consecutive daily doses of 0.5 LD(50) soman. In exposure Week 3, animals received five consecutive daily doses of 0.5 LD(50) soman. Week 4 constituted a post-exposure recovery evaluation. Throughout the experiment, behavioral function was assessed by a discriminated avoidance test that required intact sensory and motor function. Survival and body weight changes were recorded daily. Differences in toxicity as a function of diet composition became apparent during the first week. Specifically, rats fed the glucose-enriched diet showed pronounced intoxication during Week 1, resulting in imperfect survival, weight loss, and deteriorated avoidance performance relative to all other groups. All rats fed the glucose-enriched diet died by the end of exposure Week 2. In contrast, only 10% of animals fed the standard diet died by the end of Week 2. Also in Week 2, weight loss and disrupted avoidance performance were apparent for all groups except for those fed the ketogenic diet. This differential effect of diet composition became even more striking in Week 3 when survival in the standard and choline diet groups approximated 50%, whereas survival equaled 90% in the ketogenic diet group. Avoidance performance and weight loss measures corroborated the differential toxicity observed across diet groups. Upon cessation of soman exposure during the final week, recovery of weight and avoidance performance in survivors was comparable across diet groups. These results systematically replicate previous findings demonstrating that diet composition exacerbates or attenuates toxicity in rodents exposed acutely to organophosphorus compounds.
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http://dx.doi.org/10.1016/j.neuro.2011.05.006DOI Listing
December 2011

Diet composition exacerbates or attenuates soman toxicity in rats: implied metabolic control of nerve agent toxicity.

Neurotoxicology 2011 Jun 17;32(3):342-9. Epub 2011 Mar 17.

US Army Medical Research Institute of Chemical Defense, Analytical Toxicology Division, Neurobehavioral Toxicology Branch, Aberdeen Proving Ground, MD 21010-5400, United States.

To evaluate the role of diet composition on nerve agent toxicity, rats were fed four distinct diets ad libitum for 28 d prior to challenge with 110 μg/kg (1.0 LD(50), sc) soman. The four diets used were a standard rodent diet, a choline-enriched diet, a glucose-enriched diet, and a ketogenic diet. Body weight was recorded throughout the study. Toxic signs and survival were evaluated at key times for up to 72 h following soman exposure. Additionally, acquisition of discriminated shuttlebox avoidance performance was characterized beginning 24h after soman challenge and across the next 8 d (six behavioral sessions). Prior to exposure, body weight was highest in the standard diet group and lowest in the ketogenic diet group. Upon exposure, differences in soman toxicity as a function of diet became apparent within the first hour, with mortality in the glucose-enriched diet group reaching 80% and exceeding all other groups (in which mortality ranged from 0 to 6%). At 72 h after exposure, mortality was 100% in the glucose-enriched diet group, and survival approximated 50% in the standard and choline-enriched diet groups, but equaled 87% in the ketogenic diet group. Body weight loss was significantly reduced in the ketogenic and choline-enriched diet groups, relative to the standard diet group. At 1 and 4h after exposure, rats in the ketogenic diet group had significantly lower toxic sign scores than all other groups. The ketogenic diet group performed significantly better than the standard diet group on two measures of active avoidance performance. The exacerbated soman toxicity observed in the glucose-enriched diet group coupled with the attenuated soman toxicity observed in the ketogenic diet group implicates glucose availability in the toxic effects of soman. This increased glucose availability may enhance acetylcholine synthesis and/or utilization, thereby exacerbating peripheral and central soman toxicity.
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http://dx.doi.org/10.1016/j.neuro.2011.03.001DOI Listing
June 2011

The oxime pro-2-PAM provides minimal protection against the CNS effects of the nerve agents sarin, cyclosarin, and VX in guinea pigs.

Toxicol Mech Methods 2011 Jan 30;21(1):53-62. Epub 2010 Nov 30.

Research and Analytical Toxicology Divisions, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010-5400, USA.

This study examined whether pro-2-PAM, a pro-drug dihydropyridine derivative of the oxime 2-pralidoxime (2-PAM) that can penetrate the brain, could prevent or reverse the central toxic effects of three nerve agents; sarin, cyclosarin, and VX. The first experiment tested whether pro-2-PAM could reactivate guinea pig cholinesterase (ChE) in vivo in central and peripheral tissues inhibited by these nerve agents. Pro-2-PAM produced a dose-dependent reactivation of sarin- or VX-inhibited ChE in both peripheral and brain tissues, but with substantially greater reactivation in peripheral tissues compared to brain. Pro-2-PAM produced 9-25% reactivation of cyclosarin-inhibited ChE in blood, heart, and spinal cord, but no reactivation in brain or muscle tissues. In a second experiment, the ability of pro-2-PAM to block or terminate nerve agent-induced electroencephalographic seizure activity was evaluated. Pro-2-PAM was able to block sarin- or VX-induced seizures (16-33%) over a dose range of 24-32 mg/kg, but was ineffective against cyclosarin-induced seizures. Animals that were protected from seizures showed significantly less weight loss and greater behavioral function 24 h after exposure than those animals that were not protected. Additionally, brains were free from neuropathology when pro-2-PAM prevented seizures. In summary, pro-2-PAM provided modest reactivation of sarin- and VX-inhibited ChE in the brain and periphery, which was reflected by a limited ability to block or terminate seizures elicited by these agents. Pro-2-PAM was able to reactivate blood, heart, and spinal cord ChE inhibited by cyclosarin, but was not effective against cyclosarin-induced seizures.
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http://dx.doi.org/10.3109/15376516.2010.529190DOI Listing
January 2011

Stimulus-food pairings produce stimulus-directed touch-screen responding in cynomolgus monkeys (macaca fascicularis) with or without a positive response contingency.

J Exp Anal Behav 2009 Jul;92(1):41-55

United States Army Medical Research Institute of Chemical Defense.

Acquisition and maintenance of touch-screen responding was examined in naïve cynomolgus monkeys (Macaca fascicularis) under automaintenance and classical conditioning arrangements. In the first condition of Experiment 1, we compared acquisition of screen touching to a randomly positioned stimulus (a gray square) that was either stationary or moving under automaintenance (i.e., banana pellet delivery followed an 8-s stimulus presentation or immediately upon a stimulus touch). For all subjects stimulus touching occurred within the first session and increased to at least 50% of trials by the end of four sessions (320 trials). In the subsequent condition, stimulus touching further increased under a similar procedure in which pellets were only delivered if a stimulus touch occurred (fixed ratio 1 with 8-s limited hold). In Experiment 2, 6 naive subjects were initially exposed to a classical conditioning procedure (8-s stimulus preceded pellet delivery). Despite the absence of a programmed response contingency, all subjects touched the stimulus within the first session and responded on about 50% or more of trials by the second session. Responding was also sensitive to negative, neutral, and positive response contingencies introduced in subsequent conditions. Similar to other species, monkeys engaged in stimulus-directed behavior when stimulus presentations were paired with food delivery. However, stimulus-directed behavior quickly conformed to response contingencies upon subsequent introduction. Video recordings of sessions showed topographies of stimulus-directed behavior that resembled food acquisition and consumption.
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http://dx.doi.org/10.1901/jeab.2009.92-41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707138PMC
July 2009

Systemic administration of the potential countermeasure huperzine reversibly inhibits central and peripheral acetylcholinesterase activity without adverse cognitive-behavioral effects.

Pharmacol Biochem Behav 2010 Jan 11;94(3):477-81. Epub 2009 Nov 11.

United States Army Medical Research Institute of Chemical Defense, 3100 Ricketts Point Road, Aberdeen Proving Ground, MD 21010, USA.

Huperzine A is potentially superior to pyridostigmine bromide as a pretreatment for nerve agent intoxication because it inhibits acetylcholinesterase both peripherally and centrally, unlike pyridostigmine, which acts only peripherally. Using rhesus monkeys, we evaluated the time course of acetylcholinesterase and butyrylcholinesterase inhibition following four different doses of -(-)huperzine A: 5, 10, 20, and 40 microg/kg. Acetylcholinesterase inhibition peaked 30 min after intramuscular injection and varied dose dependently, ranging from about 30% to 75%. Subsequently, cognitive-behavioral functioning was also evaluated at each dose of huperzine A using a six-item serial-probe recognition task that assessed attention, motivation, and working memory. Huperzine did not impair performance, but physostigmine did. The results demonstrate that huperzine A can selectively and reversibly inhibit acetylcholinesterase without cognitive-behavioral side effects, thus warranting further study.
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http://dx.doi.org/10.1016/j.pbb.2009.10.011DOI Listing
January 2010

Bioscavenger for protection from toxicity of organophosphorus compounds.

J Mol Neurosci 2006 ;30(1-2):145-8

Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.

Current antidotal regimens for organophosphorus compound (OP) poisoning consist of a combination of pretreatment with a spontaneously reactivating AChE inhibitor such as pyridostigmine bromide, and postexposure therapy with anticholinergic drugs such as atropine sulfate and oximes such as 2-PAM chloride (Gray, 1984). Although these antidotal regimens are effective in preventing lethality of animals from OP poisoning, they do not prevent postexposure incapacitation, convulsions, performance deficits, or, in many cases, permanent brain damage (Dunn and Sidell, 1989). These problems stimulated the development of enzyme bioscavengers as a pretreatment to sequester highly toxic OPs before they reach their physiological targets. Several studies over the last two decades have demonstrated that exogenously administered human serum butyrylcholinesterase (Hu BChE) can be used successfully as a safe, efficacious, and single prophylactic treatment to counteract the toxicity of OPs. It also has potential use for first responders (civilians) reacting to terrorist nerve gas release, pesticide overexposure, or succinylcholine-induced apnea. A dose of 200 mg of Hu BChE in humans is envisioned as a prophylactic treatment that can protect from exposure of 2-5 x LD50 of nerve agents (Ashani, 2000).
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http://dx.doi.org/10.1385/jmn:30:1:145DOI Listing
February 2007

Serial-probe recognition in rhesus macaques: effects of midazolam.

Pharmacol Biochem Behav 2006 Nov 1;85(3):555-61. Epub 2006 Dec 1.

Walter Reed Army Institute of Research, Division of Neurosciences, Silver Spring, MD, 20910-7500, USA.

A serial-probe recognition task was used to assess the effects of midazolam on visual attention and short-term memory in three rhesus monkeys. On each trial, six unique alphanumeric sample stimuli (list items) were presented sequentially followed by a choice period. Choosing the 'probe' stimulus was correct if the probe matched one of the list items; otherwise, choosing the 'default' stimulus (a white square) was correct. Behavior was examined under a range of doses of midazolam (0.065, 0.13, 0.26, and 0.52 mg/kg IM). Midazolam did not significantly reduce choice accuracy or change the shape of the serial position function and did not significantly reduce choice responding. However, choice reaction time was significantly increased by the two highest doses of midazolam. Responding directed at the sample stimuli was reduced at the two highest doses of midazolam. Furthermore, 0.52 mg/kg midazolam significantly increased sample-stimulus reaction time at all six serial positions. Overall, these data suggest that the two highest doses of midazolam tested increase reaction time, but do not directly impair short-term visual recognition memory. This is noteworthy because such doses appear capable of protecting against nerve agent-induced seizures.
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http://dx.doi.org/10.1016/j.pbb.2006.10.009DOI Listing
November 2006

Effects of physostigmine and human butyrylcholinesterase on acoustic startle reflex and prepulse inhibition in C57BL/6J mice.

Pharmacol Biochem Behav 2005 Jul;81(3):497-505

Division of Neurosciences, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.

The use of exogenously administered cholinesterases as bioscavengers of highly toxic organophosphorus nerve agents is a viable prophylactic against this threat. To use this strategy, cholinesterases must provide protection without disrupting behavior when administered alone. To assess behavioral safety, the acoustic startle reflex and prepulse inhibition (PPI) of C57BL/6J mice were investigated following administration of human plasma-derived butyrylcholinesterase (HuBChE). Two hours before testing, four groups of mice (n=10 per group) were pretreated with saline or HuBChE (2000 U, ip). Fifteen minutes before testing, subjects received either saline or the carbamate physostigmine (0.4 mg/kg, sc). Mice exposed to physostigmine exhibited a significant attenuation of the startle reflex, an increased time to peak startle amplitude, and significantly increased PPI. This effect was partially mitigated in mice pretreated with HuBChE. HuBChE alone did not change startle behavior or PPI significantly compared to saline controls. The circulatory time-course of butyrylcholinesterase was assessed in a separate group of mice and revealed levels approximately 600 times the physiological norm 2-4 h post administration. Thus, HuBChE does not appear to significantly alter startle or PPI behavior at a dose 30-fold higher than that estimated to be necessary for protection against 2LD50 of soman in humans.
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http://dx.doi.org/10.1016/j.pbb.2005.04.006DOI Listing
July 2005

Recovery from ischemic brain injury in the rat following a 10 h delayed injection with MLN519.

Pharmacol Biochem Behav 2005 May;81(1):182-9

Department of Applied Neurobiology, Division of Psychiatry and Neuroscience, Walter Reed Army Institute of Research, 503 Robert Grant Ave, Room 2A40, Silver Spring, MD 20910, USA.

In the present study, we evaluated delayed treatment effects of the proteasome inhibitor and anti-inflammatory agent MLN519 (initiated 10 h post-injury) to improve recovery following ischemic brain injury in rodents. Male rats were exposed to 2 h of middle cerebral artery occlusion (MCAo) and treated with MLN519 (1.0 mg/kg, i.v. @ 10, 24, and 48 h post-occlusion) or vehicle. By 2 weeks post-injury, 60% (6/10) of vehicle animals survived, which was improved (although non-significantly) to 78% (7/9) following MLN519 treatment. The percent loss of tissue in the ipsilateral brain hemisphere (at 2 weeks) was significantly reduced from 27+/-4% (vehicle) to 15+/-4% (MLN519). MLN519 treated animals also lost significantly less body weight (39%) and showed significant improvement in overall neurological function across the 2-week recovery period. However, no significant treatment effects were observed to reduce foot-fault deficits (balance beam) or improve recovery of operant performance (active avoidance test). Overall, delayed treatment with MLN519 provided significant improvement in 3 of 6 test metrics (histopathology, body weight, and neurological dysfunction) supporting improved outcome for brain-injured subjects.
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http://dx.doi.org/10.1016/j.pbb.2005.03.011DOI Listing
May 2005

Air and shock two-way shuttlebox avoidance in C57BL/6J and 129X1/SvJ mice.

Physiol Behav 2003 Jan;78(1):117-23

Division of Neurosciences, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA.

Despite multiple advantages of the use of electric shock as an aversive stimulus, reasons exist for considering alternative aversive stimuli. In the present study, we examined and compared the acquisition of two-way shuttlebox avoidance with 275.8-kPa (40-psi) pulsed air and continuous 0.4-mA shock in two strains of mice commonly employed in targeted gene mutation research, C57BL/6J and 129X1/SvJ. Each trial consisted of a 5-s warning stimulus (WS, light) during which shuttling to the other side cancelled delivery of the aversive stimulus. Once initiated, the aversive stimulus remained active for 20 s or until an escape response occurred. For C57BL/6J mice, air and shock were equally and highly effective aversive stimuli. In contrast, air was less effective than shock for 129X1/SvJ mice. C57BL/6J mice outperformed 129X1/SvJ mice for both stimulus types. For 129X1/SvJ mice, longer escape latencies were observed initially for air, suggesting that shock is more effective. However, these differences in latency dissipated within the first seven sessions. Nevertheless, by the end of the 17-day study, asymptotic levels of avoidance proficiency were substantially lower for air than for shock in 129X1/SvJ mice. These results indicate that air is a suitable substitute for shock as an aversive stimulus in shuttlebox active avoidance; however, the relative efficacies of these aversive stimuli appear to depend upon the strain chosen for study.
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http://dx.doi.org/10.1016/s0031-9384(02)00944-7DOI Listing
January 2003

Effects of anticholinergics on serial-probe recognition accuracy of rhesus macaques (Macaca mulatta).

Pharmacol Biochem Behav 2002 Nov;73(4):829-34

Division of Neurosciences, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910-7500, USA.

Potential deleterious behavioral effects of the anticholinergics biperiden and scopolamine were examined via the performance of rhesus monkeys on a serial-probe recognition (SPR) procedure. On each trial, six unique stimuli (list items) were presented sequentially followed by a choice phase. In the choice phase, two stimuli were presented, a standard or 'default' stimulus (a white rectangle) and a 'probe' stimulus that differed with each choice trial. Choosing the probe stimulus was considered correct if the probe matched one of the list items; otherwise, choosing the default stimulus was considered correct. Behavior was examined under a range of doses of biperiden (0.001-1.0 mg/kg) and scopolamine (0.0056-0.03 mg/kg). Scopolamine (0.01-0.03 mg/kg) and biperiden (0.3-1.0 mg/kg) reduced overall accuracy. At the highest dose, scopolamine, but not biperiden, reduced the number of trials completed per session. The results suggest that doses of scopolamine and biperiden necessary to prevent or eliminate organophosphate induced seizures may affect performance adversely. However, because the degree of impairment from biperiden was modest, further examination of this anticonvulsant may be warranted.
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http://dx.doi.org/10.1016/s0091-3057(02)00909-7DOI Listing
November 2002