A comprehensive assessment of the cholinergic-supporting and cognitive-enhancing effects of Rosa damascena Mill. (Damask rose) essential oil on scopolamine-induced amnestic rats.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by gradual loss of cognitive abilities (dementia) and is a major public health problem. Here, we aimed at investigating the effects of Rosa damascena essential oil (RDEO) on learning and memory functions in a rat model of amnesia induced by scopolamine, as well as on changes in acetylcholinesterase (AChE) activity, M1 muscarinic acetylcholine receptor (mAChR) expression, and brain-derived neurotrophic factor (BDNF) levels in the extracted brain tissues. METHODS: The control, amnesia (scopolamine, 1 mg/kg/i.p.) and treatment (RDEO, 100 µL/kg/p.o. or galantamine, 1.5 mg/kg/i.p.) groups were subjected to Morris water maze and new object recognition tests. AChE activity was assayed by ELISA, and M1 mAChR and BDNF concentration changes were determined by western blotting. Also, using computational tools, human M1 mAChR was modeled in an active conformation, and the major components of RDEO were docked onto this receptor. RESULTS: According to our behavioral tests, RDEO was able to mitigate the learning and memory impairments caused by scopolamine in vivo. Our in vitro assays showed that the observed positive effects correlated well with a decrease in AChE activity and an increase in M1 mAChR and BDNF levels in amnestic rat brains. We also demonstrated in an in silico setting that the major components of RDEO, specifically -citronellol, geraniol, and nerol, could be accommodated favorably within the allosteric binding pocket of active-state human M1 mAChR and anchored here chiefly by hydrogen-bonding and alkyl-π interactions. CONCLUSION: Our findings offer a solid experimental foundation for future RDEO-based medicinal product development for patients suffering from AD.

Development and characterization of an automated behavioral assessment platform for the Göttingen minipig.

The Göttingen minipig is fast becoming the standard for assessing dermal chemical hazards because, like most swine, its skin is predictive of human skin response and because this strain's smaller size makes laboratory manipulations and husbandry easier. Unfortunately, standard behavioral tests and apparatus have not been developed for behavioral assessments of this swine strain. Indeed, computer-controlled automated behavioral testing procedures are much needed. The present research advanced this goal by producing a home-cage behavioral testing system that could accommodate minipigs of various sizes (ages). An aluminum frame housed three levers for recording operant responses, and LEDs above and below each lever served as discriminative stimuli. A commercially available food pellet dispenser was attached to a specialized pellet receptacle capable of measuring pellet retrieval. Two behavioral tests were selected and adapted from our commonly used non-human primate behavioral assessments: delayed match-to-sample (a memory test) and temporal response differentiation (a time-estimation test). Minipigs were capable of learning both tests and attaining stable performance. Next, scopolamine was used to validate the sensitivity of the behavioral tests for gauging behavioral perturbations in this swine strain. Scopolamine dose-effect functions were comparable to those observed in other species, including non-human primates, wherein 37.5 µg/kg of scopolamine (administered intramuscularly) reduced responding approximately 50%. Thus, we were successful in developing the apparatus and automated operant behavioral tests necessary to characterize drug safety in this swine strain. This capability will be valuable for characterizing chemical agent toxicity as well as the safety and efficacy of medical countermeasures.

Occurrence and health risk assessment of tropane alkaloids in cereal foods consumed in Korea.

Tropane alkaloids (TA) are natural toxins found in certain plants, including cereals, of which atropine and scopolamine are the main species of concern due to their acute toxicity. This study aimed to determine the occurrence of TA in cereal foods and assess the potential health risks associated with their consumption in Korea. TA levels were analyzed in 80 raw and 71 processed cereal samples, which were distributed throughout Korea in 2021, using ultra-performance liquid chromatography-tandem mass spectrometry. At least one of the six TA species, namely atropine, scopolamine, pseudotropine, tropinone, scopine, and 6-hydroxytropinone, was detected in 10 out of the 151 samples at levels ranging from 0.12 to 88.10 µg kg-1. Dietary exposure (mean, 0.23 ng kg-1 bw day-1) to atropine and scopolamine in the Korean population was estimated to be low across all age groups. This is despite considering worst-case scenarios using the total concentrations of atropine and scopolamine in a millet sample, both of which were detected, and 95th percentile consumption for consumers of millet only. Both the hazard index and margin of exposure methods indicated that the current levels of TA exposure from millet consumption were unlikely to pose significant health risks to the Korean population.

Screening of the Active Substances for the Assessment of Walnut Kernel in the Treatment of Scopolamine-Induced AD Animals.

SCOPE: Alzheimer's disease (AD) has been a challenge and hotspot in the field of neuroscience research due to the high morbidity. As we all know, walnut kernel (WK) ingestion has been linked to benefits to brain health and has the function of improving memory. This study follows the AD model induced by scopolamine to reveal the active fractions and substances of walnut in the treatment of AD. METHODS AND RESULTS: The histopathological analysis and brain tissue biochemistry assay are revealed the active fractions of WK, and this result determines that walnut kernel organic acids have significant therapeutic effect on AD. The strategy of studying ingredients pointed at lesions is integrated to ascertain the selected brain-targeted effective substances of WK for blood-brain barrier by ultra-performance liquid chromatography-quadrupole/electrostatic field orbitrap mass spectrometry, and a total of eight organic acids are figured out definite absorptivity in rat brains. Finally, the binding interaction between the effective substances and target proteins is analyzed by molecular docking, and the main function related active markers are ascertained as glansreginin A, glansreginic acid, ellagic acid, and ellagic acid 4-O-xyloside. CONCLUSIONS: The comprehensive process is helpful to the clinical application of WK as a promising cholinesterase inhibitors for nutritional intervention.

Assessment of tropane alkaloid levels in Brazilian buckwheat flour products: A novel LC-UHPLC-MS/MS approach using solid-liquid extraction at low temperature.

In recent years, the monitoring of tropane alkaloids, specifically hyoscyamine and scopolamine, in food has become a pressing concern. This is due to increasing reports of food contamination with these compounds worldwide, raising awareness about the potential risks associated with their consumption. A novel method is proposed here for the determination of the sum of (+)-hyoscyamine, (-)-hyoscyamine, and (-)-scopolamine in buckwheat-based matrices, using solid-liquid extraction at low temperature and quantification by bidimensional chromatography coupled to tandem mass spectrometry. The validated method presented a linear response in the concentration range of 2.5-15 µg kg-1 (r > 0.99). The precision and accuracy were in the ranges from 0.8 to 11.0 % and from 96 to 103 %, respectively. The limit of quantification (LOQ) was 2.5 µg kg-1. No contamination was found at levels above the LOQ in any of the 18 samples analyzed (buckwheat flour, grains, and gluten-free mix).

Ultrasonographic Assessment of Small Intestinal Motility Following Hyoscine Butylbromide Administration in Horses: A Pilot Study.

Horses commonly receive hyoscine butylbromide (HB) prior to hospital admission for colic. This could alter the appearance of the small intestine (SI) on ultrasound scan and affect clinical decision making. The aim of this study was to assess the impact of HB on ultrasonographically assessed SI motility and heart rate. Six horses hospitalised for medical colic with no significant abnormalities on baseline abdominal ultrasound examination were included. Ultrasound was performed in three locations (right inguinal, left inguinal and hepatoduodenal window) before and at 1, 5, 15, 30, 45, 60, 90, and 120 minutes after intravenous injection of 0.3 mg/kg HB. Three blinded reviewers assessed SI motility using a subjective grading scale from 1 to 4, one being normal motility and four being no motility. Moderate interindividual and interobserver variability was observed, but none of the included horses developed dilated turgid loops of SI. Hyoscine butylbromide did not significantly reduce SI motility grade in any location (P = .60 left inguinal, P = .16 right inguinal, P = .09 duodenum). Heart rate (mean ± SD) was 33 ± 3 prior to HB injection and peaked at 71.3 ± 9 one-minute postinjection. Heart rate was significantly increased until 45 minutes (48 ± 9) after HB administration (P = .04). The appearance of dilated turgid SI loops common with strangulating intestinal lesions did not appear to develop following HB administration. Hyoscine butylbromide administered shortly before abdominal ultrasound examination would not be expected to affect clinical decision making in horses without small intestinal disease.

Hesperetin-loaded polymeric nanofibers: assessment of bioavailability and neuroprotective effect.

OBJECTIVE: The purpose of the study is to assess the bioavailability and neuroprotective effect of hesperetin (Hesp)-loaded nanofibers. METHODS: Electrospinning was used to create and characterize polyvinyl pyrrolidone-based Hesp-loaded nanofibers. To evaluate the produced nanofibers, preclinical studies were conducted. The study involved five groups of Wistar rats, and the treatments were administered as follows. Group 1 (control) was given regular saline for 14 d. On the 14th day, Group 2 was given scopolamine. Group 3 was given donepezil for 14 d and then scopolamine on the 14th. Group 4 was given Hesp for 14 d and then scopolamine on the 14th. Group 5 was given Hesp-loaded nanofibers for 14 d, followed by scopolamine on the 14th. On the 14th day, rats' memory was tested using Cook's pole climbing apparatus and the Morris water maze (MWM). On the 15th day, rats from each group were slaughtered, brain tissues were separated, and biochemical and histological analyses were performed. In addition, in vitro dissolution experiments and pharmacokinetic studies were carried out. RESULTS: When compared to the control group, scopolamine-treated rats had considerably longer escape latency times, as well as increased acetylcholinesterase (AChE) activity, lipid peroxidation, degeneration, and inflammation in the hippocampus. These parameters were greatly recovered by donepezil and Hesp-loaded nanofibers that had been pretreated. Because of the greatly improved bioavailability of Hesp, the Hesp-loaded nanofibers significantly protected rats from scopolamine-induced amnesia. CONCLUSIONS: Hesp-loaded nanofibers have an excellent neuroprotective effect against scopolamine-induced amnesia due to enhanced bioavailability.

LC-MS/MS approach for simultaneous assessment of hyoscine N-butyl bromide and ketoprofen in biological fluids and pharmaceuticals.

The mixture of hyoscine N-butyl bromide (HBB) and ketoprofen (KTP) is commonly used for the handling of abdominal spasms and pain relief. There are two challenges that restrict the simultaneous assessment of HBB and KTP in biological fluids and pharmaceuticals. The first issue is the difficulty of elution of HBB and the second one is the presence of KTP as a racemic mixture in all pharmaceutical formulations, which obscures its appearance as a single peak. An ultrasensitive and highly efficient liquid chromatography-mass/mass spectrometric (LC-MS/MS) method is designed and validated for the first concurrent assessment of HBB and KTP in spiked human serum and urine, and pharmaceutical formulations. The estimated linearity ranges for HBB and KTP were respectively, 0.5-500 and 0.05-500 ng/ml, with excellent correlation coefficients. Validation results showed that the value of relative standard deviations were <2% for HBB and KTP. The mean extraction recoveries for HBB and KTP were, respectively, 91.04 and 97.83% in Spasmofen® ampoules; 95.89 and 97.00% in spiked serum; and 97.31 and 95.63% in spiked urine. The presented innovative chromatographic approach was utilized for the measurement of trace amounts of coexisting pharmaceuticals in pharmacokinetics studies and routine therapeutic medication monitoring.

An automated home-cage-based 5-choice serial reaction time task for rapid assessment of attention and impulsivity in rats.

RATIONALE: The 5-choice serial reaction time task (5-CSRTT) is a widely used operant task for measuring attention and motor impulsivity in rodents. Training animals in this task requires an extensive period of daily operant sessions. Recently, a self-paced, automated version of this task has been developed for mice, which substantially reduces training time. Whether a similar approach is effective for rats is currently unknown. OBJECTIVE: Here, we tested whether attention and impulsivity can be assessed in rats with a self-paced version of the 5-CSRTT. METHODS: Operant boxes were connected to home-cages with tunnels. Two groups of rats self-paced their training by means of an automated script. The first group of animals was allowed unlimited access (UA) to start trials in the task; for the second group, trial availability was restricted to the first 2.5 h of the dark cycle (TR). Task parameter manipulations, such as variable inter-trial intervals and stimulus durations as well as pharmacological challenges with scopolamine, were tested to validate the task. RESULTS: Self-paced training took less than 1 week. Animals in the UA group showed higher levels of omissions compared with the TR group. In both protocols, variable inter-trial intervals increased impulsivity, and variable stimulus durations decreased attentional performance. Scopolamine affected cognitive performance in the TR group only. CONCLUSIONS: Home-cage-based training of the 5-CSRTT in rats, especially the TR protocol, presents a valid and fast alternative for measuring attention and impulsivity.

An Educational Intervention to Decrease Drug Costs Related to Terminal Secretions in a Hospice Organization.

Terminal secretions is a common symptom seen in hospice patients. Antimuscarinic drugs are commonly used to treat this symptom despite a lack of supporting data. Wide variability in cost exists among these treatments. Hospice program data were assessed to identify high-use and high-cost medications. An educational intervention (EI) was developed to target one such medication, transdermal scopolamine. The EI focused on efficacy, safety, and actual cost (by unit and total expenditure) for each possible treatment of terminal secretions. Following the EI, drug utilization data was re-evaluated. Prior to the deployment of the EI, total monthly hospice drug costs averaged $91,405 (SD 1,444) with an average drug cost per patient per day of $11.42 (SD 0.54). Monthly costs of drugs frequently employed to treat terminal secretions averaged $7,187.67 (SD 2,253) pre-intervention. Following the EI, monthly drug costs decreased 22.5%, average daily patient drug costs decreased 11.1%, and total anti-secretion costs decreased 28.5% after adjusting for difference in census. Education regarding the use and cost of medications to treat symptoms at end-of-life in hospice patients can be an intervention used to lead to significant cost savings to hospice organizations while maintaining appropriate symptom management for patients. Future interventions to target additional high-cost medications are warranted.

Nicotine increases impulsivity and decreases willingness to exert cognitive effort despite improving attention in "slacker" rats: insights into cholinergic regulation of cost/benefit decision making.

Successful decision making in our daily lives requires weighing an option's costs against its associated benefits. The neuromodulator acetylcholine underlies both the etiology and treatment of a number of illnesses in which decision making is perturbed, including Alzheimer's disease, attention-deficit/hyperactivity disorder, and schizophrenia. Nicotine acts on the cholinergic system and has been touted as a cognitive enhancer by both smokers and some researchers for its attention-boosting effects; however, it is unclear whether treatments that have a beneficial effect on attention would also have a beneficial effect on decision making. Here we utilize the rodent Cognitive Effort Task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, to examine cholinergic contributions to both attentional performance and choice based on attentional demand. Following the establishment of baseline behavior, four drug challenges were administered: nicotine, mecamylamine, scopolamine, and oxotremorine (saline plus three doses for each). As per previous rCET studies, animals were divided by their baseline preferences, with "worker" rats choosing high-effort/high-reward options more than their "slacker" counterparts. Nicotine caused slackers to choose even fewer high-effort trials than at baseline, but had no effect on workers' choice. Despite slackers' decreased willingness to expend effort, nicotine improved their attentional performance on the task. Nicotine also increased measures of motor impulsivity in all animals. In contrast, scopolamine decreased animals' choice of high-effort trials, especially for workers, while oxotremorine decreased motor impulsivity for all animals. In sum, the cholinergic system appears to contribute to decision making, and in part these contributions can be understood as a function of individual differences. While nicotine has been considered as a cognitive enhancer, these data suggest that its modest benefits to attention may be coupled with impulsiveness and decreased willingness to work hard, especially in individuals who are particularly sensitive to effort costs (i.e. slackers).

Effects of acute administration of nicotinic and muscarinic cholinergic agonists and antagonists on performance in different cost-benefit decision making tasks in rats.

RATIONALE: Alterations in cost-benefit decision making accompany numerous neuropsychiatric conditions, including schizophrenia, attention deficit hyperactivity disorder, and addiction. Central cholinergic systems have been linked to the etiology and/or treatment of many of these conditions, but little is known about the role of cholinergic signaling in cost-benefit decision making. OBJECTIVES: The goal of these experiments was to determine how cholinergic signaling is involved in cost-benefit decision making, using a behavioral pharmacological approach. METHODS: Male Long-Evans rats were trained in either "probability discounting" or "delay discounting" tasks, in which rats made discrete-trial choices between a small food reward and a large food reward associated with either varying probabilities of omission or varying delays to delivery, respectively. The effects of acute administration of different doses of nicotinic and muscarinic acetylcholine receptor agonists and antagonists were assessed in each task. RESULTS: In the probability discounting task, acute nicotine administration (1.0 mg/kg) significantly increased choice of the large risky reward, and control experiments suggested that this was due to robust nicotine-induced impairments in behavioral flexibility. In the delay discounting task, the muscarinic antagonists scopolamine (0.03, 0.1, and 0.3 mg/kg) and atropine (0.3 mg/kg) both significantly increased choice of the small immediate reward. Neither mecamylamine nor oxotremorine produced reliable effects on either of the decision making tasks. CONCLUSIONS: These data suggest that cholinergic receptors play multiple roles in decision making contexts which include consideration of reward delay or probability. These roles should be considered when targeting these receptors for therapeutic purposes.

Using MRI for the assessment of paraoxon-induced brain damage and efficacy of antidotal treatment.

Organophosphate intoxication induces neural toxicity as demonstrated in histological analysis of poisoned animals. Diffusion-weighted magnetic resonance imaging (DWMRI) enables early noninvasive characterization of biological tissues based on their water diffusion characteristics. Our objectives were to study the application of MRI for assessment of paraoxon-induced brain damage and the efficacy of antidotal treatments. Seventy-six rats were poisoned with paraoxon followed by treatment with atropine and obidoxime. The rats were then divided into five treatment groups consisting of midazolam after 1 or 30 min, scopolamine after 1 or 30 min and a no anticonvulsant treatment group. Five untreated rats served as controls. Animals underwent MRI on days 1, 8, 15, 29 and 50 post poisoning. Histological evaluation was performed on representative rat brains. Acute DWMRI effects, such as enhancement of temporal brain regions, and chronic effects such as ventricular enlargement and brain atrophy, depicted on T2-weighted MRI, were significantly more prominent in late anticonvulsant treatment groups. There was no significant difference between the neuroprotective effects of midazolam and scopolamine as shown by DWMRI. Early MRI abnormalities were found to correlate significantly with histological analysis of samples obtained 15 days post treatment. In conclusion, our results demonstrate the feasibility of using DWMRI for depiction of early cytotoxic response to paraoxon and T2-weighted MRI for later changes, thus enabling assessment of early/late brain damage as well as treatment efficacy in rats. The ability to depict these changes early and noninvasively may be applied clinically in the acute phase of organophosphate poisoning.

Validation of an air-puff passive-avoidance paradigm for assessment of aversive learning and memory in rat models of chronic pain.

Chronic pain is associated with cognitive deficits. Considerable overlap in brain regions involved in pain and aversion suggests that aversive learning and memory may be affected during chronic pain. Passive-avoidance paradigms traditionally use foot-shock to induce context-conditioned avoidance and may be unsuitable for use in animal models of chronic pain, which are commonly associated with hypersensitivity of the hind-paws. The aim of the present study was to develop and validate a novel passive-avoidance paradigm in rats, employing air-puff as the aversive stimulus, and to use this paradigm to assess aversive learning and memory in rat models of chronic inflammatory and neuropathic pain. Air-puff exposure produced a significant passive-avoidance and this response was attenuated following administration of scopolamine. Nerve-ligated rats and rats injected with complete Freund's adjuvant developed allodynia and hyperalgesia. Air-puff produced a significant passive-avoidance response in both chronic pain models. However, there was no difference in the response between either model and its respective control group. Thus, air-puff can be used as an alternative to foot-shock to induce a passive-avoidance response. The data generated using this model suggest that aversive learning and memory remain intact in the rat spinal nerve ligation and complete Freund's adjuvant models of chronic neuropathic and inflammatory pain, respectively.

Does a perioperative belladonna and opium suppository improve postoperative pain following robotic assisted laparoscopic radical prostatectomy? Results of a single institution randomized study.

INTRODUCTION: Robotic assisted laparoscopic radical prostatectomy (RALP) is a common treatment for localized prostate cancer. Despite a primary advantage of improved postoperative pain, patients undergoing RALP still experience discomfort. Belladonna, containing the muscarinic receptor antagonists atropine and scopolamine, in combination with opium as a rectal suppository (B & O) may improve post-RALP pain. This study evaluates whether a single preoperative B & O results in decreased postoperative patient-reported pain and analgesic requirements. MATERIALS AND METHODS: Patients undergoing RALP at Virginia Mason Medical Center between November 2008 and July 2009 were offered the opportunity to enter a randomized, double-blind, placebo-controlled trial. Exclusion criteria included: glaucoma, bronchial asthma, convulsive disorders, chronic pain, chronic use of analgesics, or a history of alcohol or opioid dependency. Surgeons were blinded to suppository placement which was administered after induction of anesthesia. All patients underwent a standardized anesthesia regimen. Postoperative pain was assessed by a visual analog scale (VAS) and postoperative narcotic use was calculated in intravenous morphine equivalents. RESULTS: Ninety-nine patients were included in the analysis. The B & O and control groups were not significantly different in terms of age, body mass index, operative time, nerve sparing status or prostatic volume. Postoperative pain was significantly improved during the first two postoperative hours in the B & O group. Similarly, 24-hour morphine consumption was significantly lower in patients who received a B & O. No adverse effects secondary to suppository placement were identified. CONCLUSION: Preoperative administration of B & O suppository results in significantly decreased postoperative pain and 24-hour morphine consumption in patients undergoing RALP.

The effects of stimulation of acupressure point p6 on postoperative nausea and vomiting: a review of literature.

Postoperative nausea and vomiting (PONV) can complicate and delay patient recovery from general and neuraxial anesthesia. Even with a new generation of anesthetic drugs and antiemetics, a high number of patients are affected by PONV. PONV has a multifactor etiology, but there are ways to reduce its occurrence. Although it is not a traditionally recognized method, stimulation of acupressure points, specifically P6, has been identified as a potentially effective method of reducing PONV. This study is a state of the science paper reviewing research on both pharmacologic and nonpharmacologic prophylaxis and various methods of acupressure. It was conducted to add information to the currently available knowledge regarding PONV in hopes of stimulating the use of acupressure for treatment of PONV. The study is divided into six categories: pathophysiology of PONV, background studies of PONV, nonpharmacologic prophylaxis, pharmacological prophylaxis, acupressure and related techniques, and benefits of routine antiemetic prophylaxis.

Widespread hyoscine hydrobromide toxicity due to contract manufacturer malpractice : the travacalm episode.

An outbreak of hyoscine hydrobromide toxicity was detected through the Australian pharmacovigilance system. The unexpectedly wide variation in hyoscine hydrobromide content between individual tablets within single packets created difficulties in initially explaining the clinical experiences. Strict time requirements for review of incoming adverse drug reaction reports and close involvement of the highly skilled national drug regulatory laboratory resulted in early identification of the cause of the outbreak and led in turn to the identification of malpractice by the contract manufacturer.

Scopolamine in Brugmansia suaveolens (Solanaceae): defense, allocation, costs, and induced response.

Brugmansia suaveolens (Solanaceae) contains tropane alkaloids (TAs), which can act as chemical defenses. Selective pressures might modulate the allocation of alkaloids within the plant, as postulated by optimal-defense theory. By tracing scopolamine, the most abundant TA in this species, we found that scopolamine in an artificial diet, in concentrations similar to those in leaves of B. suaveolens, increased mortality and prolonged developmental time of the larvae of the generalist noctuid moth Spodoptera frugiperda. A diet of undamaged leaves of B. suaveolens also showed a large negative effect on the growth of larvae of S. frugiperda compared to a diet of leaves of Ricinus communis, a species that did not have negative effects on this moth; more valuable plant parts, such as young leaves, flowers, and unripe fruits with seeds, have higher scopolamine concentrations than other tissues; leaves of B. suaveolens increase their content of scopolamine after artificial damage. The highest induction was found 24 hr after the damage, and after that, scopolamine content decreased to constitutive levels. This increase represented a cost, because in another experiment, a treatment with methyl jasmonate, an elicitor hormone, increased scopolamine production 9.5-fold and decreased leaf growth 2.3-fold; a diet of artificially damaged leaves of B. suaveolens showed a negative effect on the growth of larvae of S. furgiperda compared to undamaged leaves, suggesting that damage by herbivores induces resistance. Our data are in line with the optimal-defense theory, but experiments in the field with herbivores that share an evolutionary history with B. suaveolens must be undertaken to understand the dynamics of TA allocation in response to herbivory.

Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat.

It is well known that modafinil is an effective wake-promoting agent, but there is growing evidence to suggest that modafinil may also enhance some aspects of cognition. In man, modafinil has been shown to enhance vigilance in sleep-deprived and/or narcoleptic subjects and also to improve executive-type functioning (predominantly inhibitory response control processes) across a variety of human patient population groups. Preclinically, a delay-dependent improvement has been reported with modafinil in a mouse T-maze test of working memory. To investigate further the role of modafinil as a potential cognition enhancer, the effects of modafinil on attentional processes were assessed in the rat. The aim of the present study was to evaluate the potential of modafinil to enhance five-choice serial reaction time test (5-CSRT) performance. Lister Hooded rats received 32-128 mg/kg modafinil and 5-CSRT performance was assessed under standard and test parametric conditions in which the attentional load was increased, and also under conditions of scopolamine pre-treatment. Modafinil failed to significantly enhance 5-CSRT performance under standard conditions. Similarly, modafinil was unable to reverse the deficits in accuracy and/or increased omission errors induced by either parametric or pharmacological manipulations. Indeed, at higher doses, modafinil caused an increase in premature responding under certain test conditions, suggestive of increased impulsivity. The present findings suggest that, although modafinil may enhance vigilance in sleep-deprived human subjects, attentional processes in normal awake rats remain unaffected. No evidence was found to support a modafinil-induced improvement in response control; rather, under conditions of increased attentional load, modafinil appeared to facilitate impulsive responding. Finally, the failure of modafinil to improve a scopolamine-induced performance deficit suggests that modafinil does not act on the cholinergic system directly.

Rapid assessment of in vivo cholinergic transmission by amperometric detection of changes in extracellular choline levels.

Conventional microdialysis methods for measuring acetylcholine (ACh) efflux do not provide sufficient temporal resolution to relate cholinergic transmission to individual stimuli or behavioral responses, or sufficient spatial resolution to investigate heterogeneities in such regulation within a brain region. In an effort to overcome these constraints, we investigated a ceramic-based microelectrode array designed to measure amperometrically rapid changes in extracellular choline as a marker for cholinergic transmission in the frontoparietal cortex of anesthetized rats. These microelectrodes exhibited detection limits of 300 nm for choline and selectivity (> 100 : 1) of choline over interferents such as ascorbic acid. Intracortical pressure ejections of choline (20 mm, 66-400 nL) and ACh (10 and 100 mm, 200 nL) dose-dependently increased choline-related signals that were cleared to background levels within 10 s. ACh, but not choline-induced signals, were significantly attenuated by co-ejection of the acetylcholinesterase inhibitor neostigmine (Neo; 100 mm). Pressure ejections of drugs known to increase cortical ACh efflux, potassium (KCl; 70 mm, 66, 200 nL) and scopolamine (Scop; 10 mm, 200 nL), also markedly increased extracellular choline signals, which again were inhibited by Neo. Scop-induced choline signals were also found to be tetrodotoxin-sensitive. Collectively, these findings suggest that drug-induced increases in current measured with these microelectrode arrays reflect the oxidation of choline that is neuronally derived from the release and subsequent hydrolysis of ACh. Choline signals assessed using enzyme-selective microelectrode arrays may represent a rapid, sensitive and spatially discrete measure of cholinergic transmission.