Manganese-enhanced magnetic resonance imaging method detects age-related impairments in axonal transport in mice and attenuation of the impairments by a microtubule-stabilizing compound.

In this study a manganese-enhanced magnetic resonance imaging (MEMRI) method was developed for mice for measuring axonal transport (AXT) rates in real time in olfactory receptor neurons, which project from the olfactory epithelium to the olfactory neuronal layer of the olfactory bulb. Using this MEMRI method, two major experiments were conducted: 1) an evaluation of the effects of age on AXT rates and 2) an evaluation of the brain-penetrant, microtubule-stabilizing agent, Epothilone D for effect on AXT rates in aged mice. In these studies, we improved upon previous MEMRI approaches to develop a method where real-time measurements (32 time points) of AXT rates in mice can be determined over a single (approximately 100 min) scanning session. In the age comparisons, AXT rates were significantly higher in young (mean age ∼4.0 months old) versus aged (mean age ∼24.5 months old) mice. Moreover, in aged mice, eight weeks of treatment with Epothilone D, (0.3 and 1.0 mg/kg) was associated with statistically significant increases in AXT rates compared to vehicle-treated subjects. These experiments conducted in a living mammalian model (i.e., wild type, C57BL/6 mice), using a new modified MEMRI method, thus provide further evidence that the process of aging leads to decreases in AXT rates in the brain and they further support the argument that microtubule-based therapeutic strategies designed to improve AXT rates have potential for age-related neurological disorders.

Differential effects of alkaloids on memory in rodents.

Nicotinic acetylcholine receptors (nAChRs) play a critical role in the neuropharmacology of learning and memory. As such, naturally occurring alkaloids that regulate nAChR activity have gained interest for understanding and potentially improving memory function. In this study, we tested the acute effects of three known nicotinic alkaloids, nicotine, cotinine, and anatabine, in suppressing scopolamine-induced memory deficit in rodents by using two classic memory paradigms, Y-maze and novel object recognition (NOR) in mice and rats, respectively. We found that all compounds were able to suppress scopolamine-induced spatial memory deficit in the Y-maze spontaneous alternation paradigm. However, only nicotine was able to suppress the short-term object memory deficit in NOR, despite the higher doses of cotinine and anatabine used to account for their potential differences in nAChR activity. These results indicate that cotinine and anatabine can uniquely regulate short-term spatial memory, while nicotine seems to have more robust and general role in memory regulation in rodents. Thus, nAChR-activating alkaloids may possess distinct procognitive properties in rodents, depending on the memory types examined.

Aged rhesus monkeys: Cognitive performance categorizations and preclinical drug testing.

Rodent models have facilitated major discoveries in neurobiology, however, the low success rate of novel medications in clinical trials have led to questions about their translational value in neuropsychiatric drug development research. For age-related disorders of cognition such as Alzheimer' disease (AD) there is interest in moving beyond transgenic amyloid-ß and/or tau-expressing rodent models and focusing more on natural aging and dissociating "healthy" from "pathological" aging to identify new therapeutic targets and treatments. In complex disorders such as AD, it can also be argued that animals with closer neurobiology to humans (e.g., nonhuman primates) should be employed more often particularly in the later phases of drug development. The purpose of the work described here was to evaluate the cognitive capabilities of rhesus monkeys across a wide range of ages in different delayed response tasks, a computerized delayed match to sample (DMTS) task and a manual delayed match to position (DMTP) task. Based on specific performance criteria and comparisons to younger subjects, the older subjects were generally less proficient, however, some performed as well as young subjects, while other aged subjects were markedly impaired. Accordingly, the older subjects could be categorized as aged "cognitively-unimpaired" or aged "cognitively-impaired" with a third group (aged-other) falling in between. Finally, as a proof of principle, we demonstrated using the DMTP task that aged cognitively-impaired monkeys are sensitive to the pro-cognitive effects of a nicotinic acetylcholine receptor (nAChR) partial agonist, encenicline, suggesting that nAChR ligands remain viable as potential treatments for age-related disorders of cognition.

Oral quetiapine treatment results in time-dependent alterations of recognition memory and brain-derived neurotrophic factor-related signaling molecules in the hippocampus of rats.

Antipsychotic drugs (APDs) have a variety of important therapeutic applications for neuropsychiatric disorders. However, they are routinely prescribed off-label across all age categories, a controversial practice given their potential for producing metabolic and extrapyramidal side effects. Evidence also suggests that chronic treatment with some APDs may lead to impairments in cognition and decreases in brain volume, although these findings are controversial. The purpose of the studies described here was to evaluate one of the most commonly prescribed APDs, quetiapine, for chronic effects on recognition memory, brain-derived neurotrophic factor (BDNF), its precursor proBDNF, as well as relevant downstream signaling molecules that are known to influence neuronal plasticity and cognition. Multiple cohorts of adult rats were treated with quetiapine (25.0 mg/kg/day) for 30 or 90 days in their drinking water then evaluated for drug effects on motor function in a catalepsy assessment, recognition memory in a spontaneous novel object recognition (NOR) task, and BDNF-related signaling molecules in the post mortem hippocampus via Western Blot. The results indicated that oral quetiapine at a dose that did not induce catalepsy, led to time-dependent impairments in NOR performance, increases in the proBDNF/BDNF ratio, and decreases in Akt and CREB phosphorylation in the hippocampus. These results indicate that chronic treatment with quetiapine has the potential to adversely affect recognition memory and neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function. Given the widespread use this APD across multiple conditions and patient populations, such long-term effects observed in animals should be considered.

α7 nicotinic acetylcholine receptors as therapeutic targets in schizophrenia: Update on animal and clinical studies and strategies for the future.

Schizophrenia is a devastating mental illness and its effective treatment is among the most challenging issues in psychiatry. The symptoms of schizophrenia are heterogeneous ranging from positive symptoms (e.g., delusions, hallucinations) to negative symptoms (e.g., anhedonia, social withdrawal) to cognitive dysfunction. Antipsychotics are effective at ameliorating positive symptoms in some patients; however, they are not reliably effective at improving the negative symptoms or cognitive impairments. The inability to address the cognitive impairments is a particular concern since they have the greatest long-term impact on functional outcomes. While decades of research have been devoted to the development of pro-cognitive agents for schizophrenia, to date, no drug has been approved for clinical use. Converging behavioral, neurobiological, and genetic evidence led to the identification of the α7-nicotinic acetylcholine receptor (α7-nAChR) as a therapeutic target several years ago and there is now extensive preclinical evidence that α7-nAChR ligands have pro-cognitive effects and other properties that should be beneficial to schizophrenia patients. However, like the other pro-cognitive strategies, no α7-nAChR ligand has been approved for clinical use in schizophrenia thus far. In this review, several topics are discussed that may impact the success of α7-nAChR ligands as pro-cognitive agents for schizophrenia including the translational value of the animal models used, clinical trial design limitations, confounding effects of polypharmacy, dose-effect relationships, and chronic versus intermittent dosing considerations. Determining the most optimal pharmacologic strategy at α7-nAChRs: agonist, positive allosteric modulator, or potentially even receptor antagonist is also discussed. article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology'.

Modulating inhibitory response control through potentiation of GluN2D subunit-containing NMDA receptors.

NMDA receptors containing GluN2D subunits are expressed in the subthalamic nucleus and external globus pallidus, key nuclei of the indirect and hyperdirect pathways of the basal ganglia. This circuitry integrates cortical input with dopaminergic signaling to select advantageous behaviors among available choices. In the experiments described here, we characterized the effects of PTC-174, a novel positive allosteric modulator (PAM) of GluN2D subunit-containing NMDA receptors, on response control regulated by this circuitry. The indirect pathway suppresses less advantageous behavioral choices, a manifestation of which is suppression of locomotor activity in rats. Systemic administration of PTC-174 produced a dose-dependent reduction in activity in rats placed in a novel open field or administered the stimulants MK-801 or amphetamine. The hyperdirect pathway controls release of decisions from the basal ganglia to the cortex to optimize choice processing. Such response control was modeled in rats as premature responding in the 5-choice serial reaction time (5-CSRT) task. PTC-174 produced a dose-dependent reduction in premature responding in this task. These data suggest that potentiation of GluN2D receptor activity by PTC-174 facilitates the complex basal ganglia information processing that underlies response control. The behavioral effects occurred at estimated free PTC-174 brain concentrations predicted to induce 10-50% increases in GluN2D activity. The present findings suggest the potential of GluN2D PAMs to modulate basal ganglia function and to treat neurological disorders related to dysfunctional response control.

Chronic oral treatment with risperidone impairs recognition memory and alters brain-derived neurotrophic factor and related signaling molecules in rats.

Antipsychotic drugs (APDs) are essential for the treatment of schizophrenia and other neuropsychiatric illnesses such as bipolar disease. However, they are also extensively prescribed off-label for many other conditions, a practice that is controversial given their potential for long-term side effects. There is clinical and preclinical evidence that chronic treatment with some APDs may lead to impairments in cognition and decreases in brain volume, although the molecular mechanisms of these effects are unknown. The purpose of the rodent studies described here was to evaluate a commonly prescribed APD, risperidone, for chronic effects on recognition memory, brain-derived neurotrophic factor (BDNF), its precursor proBDNF, as well as relevant downstream signaling molecules that are known to influence neuronal plasticity and cognition. Multiple cohorts of adult rats were treated with risperidone (2.5 mg/kg/day) or vehicle (dilute acetic acid solution) in their drinking water for 30 or 90 days. Subjects were then evaluated for drug effects on recognition memory in a spontaneous novel object recognition task and protein levels of BDNF-related signaling molecules in the hippocampus and prefrontal cortex. The results indicated that depending on the treatment period, a therapeutically relevant daily dose of risperidone impaired recognition memory and increased the proBDNF/BDNF ratio in the hippocampus and prefrontal cortex. Risperidone treatment also led to a decrease in Akt and CREB phosphorylation in the prefrontal cortex. These results indicate that chronic treatment with a commonly prescribed APD, risperidone, has the potential to adversely affect recognition memory and neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function.

Atomoxetine improves memory and other components of executive function in young-adult rats and aged rhesus monkeys.

Atomoxetine is a norepinephrine reuptake inhibitor and FDA-approved treatment for attention deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. While there is some evidence that atomoxetine may improve additional domains of cognition beyond attention in both young adults and aged individuals, this subject has not been extensively investigated. Here, we evaluated atomoxetine (in low mg/kg doses) in a variable stimulus duration (vSD) and a variable intertrial interval (vITI) version of the five choice-serial reaction time task (5C-SRTT), and an eight-arm radial arm maze (RAM) procedure in young-adult rats. The compound was further evaluated (in µg/kg-low mg/kg doses) along with nicotine (as a reference compound) and the Alzheimer's disease treatment donepezil in a distractor version of a delayed match to sample task (DMTS-D) in aged monkeys (mean age = 21.8 years). Atomoxetine (depending on the dose) improved accuracy (sustained attention) as well as behaviors related to impulsivity, compulsivity and cognitive inflexibility in both the vSD and vITI tasks and it improved spatial reference memory in the RAM. In the DMTS-D task, both nicotine and atomoxetine, but not donepezil attenuated the effects of the distractor on accuracy at short delays (non-spatial working/short term memory). However, combining sub-effective doses of atomoxetine and donepezil did enhance DMTS-D accuracy indicating the potential of using atomoxetine as an adjunctive treatment with donepezil. Collectively, these animal studies support the further evaluation of atomoxetine as a repurposed drug for younger adults as well older individuals who suffer from deficits in attention, memory and other components of executive function.

Associations of Perioperative Renal Oximetry Via Near-Infrared Spectroscopy, Urinary Biomarkers, and Postoperative Acute Kidney Injury in Infants After Congenital Heart Surgery: Should Creatinine Continue to Be the Gold Standard?

OBJECTIVES: Examine the relationship between perioperative renal regional tissue oximetry, urinary biomarkers, and acute kidney injury in infants after congenital cardiac surgery with cardiopulmonary bypass. DESIGN: Prospective, observational. SETTING: Cardiac operating room and cardiac ICU. PATIENTS: Neonates and infants without history of kidney injury or anatomic renal abnormality. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Renal regional tissue oximetry was measured intraoperatively and for 48 hours postoperatively. Urinary levels of neutrophil gelatinase-associated lipocalin and tissue inhibitor of metalloproteinases 2 together with insulin-like growth factor-binding protein 7 were measured preoperatively, 2, 12, and 24 hours postoperatively. Patients were categorized as no acute kidney injury, stage 1, or Stage 2-3 acute kidney injury using the Kidney Disease: Improving Global Outcomes criteria with 43 of 70 (61%) meeting criteria for any stage acute kidney injury. Stage 2-3 acute kidney injury patients had higher tissue inhibitor of metalloproteinases 2, insulin-like growth factor-binding protein 7 at 2 hours (0.3 vs 0.14 for stage 1 acute kidney injury and 0.05 for no acute kidney injury; p = 0.052) and 24 hours postoperatively (1.71 vs 0.27 for stage 1 acute kidney injury and 0.19 for no acute kidney injury, p = 0.027) and higher neutrophil gelatinase-associated lipocalin levels at 24 hours postoperatively (10.3 vs 3.4 for stage 1 acute kidney injury and 6.2 for no acute kidney injury, p = 0.019). Stage 2-3 acute kidney injury patients had lower mean cardiac ICU renal regional tissue oximetry (66% vs 79% for stage 1 acute kidney injury and 84% for no acute kidney injury, p = 0.038). Regression analyses showed that tissue inhibitor of metalloproteinases 2, insulin-like growth factor-binding protein 7 at 2 hours postoperatively and nadir intraoperative renal regional tissue oximetry to be independent predictors of postoperative kidney damage as measured by urinary neutrophil gelatinase-associated lipocalin. CONCLUSIONS: We observed modest differences in perioperative renal regional tissue oximetry and urinary biomarker levels compared between acute kidney injury groups classified by creatinine-dependent Kidney Disease: Improving Global Outcomes criteria, but there were significant correlations between renal regional tissue oximetry, tissue inhibitor of metalloproteinases 2, insulin-like growth factor-binding protein 7, and postoperative neutrophil gelatinase-associated lipocalin levels. Kidney injury after infant cardiac surgery may be undetectable by functional assessment (creatinine) alone, and continuous monitoring of renal regional tissue oximetry may be more sensitive to important subclinical acute kidney injury.

Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery.

Interest in nicotinic acetylcholine receptor (nAChR) ligands as potential therapeutic agents for cognitive disorders began more than 30 years ago when it was first demonstrated that the tobacco alkaloid nicotine could improve cognitive function in nicotine-deprived smokers as well as nonsmokers. Numerous animal and human studies now indicate that nicotine and a variety of nAChR ligands have the potential to improve multiple domains of cognition including attention, spatial learning, working memory, recognition memory, and executive function. The purpose of this review is to (1) discuss several pharmacologic strategies that have been developed to enhance nAChR activity (eg, agonist, partial agonist, and positive allosteric modulator) and improve cognitive function, (2) provide a brief overview of some of the more common rodent behavioral tasks with established translational validity that have been used to evaluate nAChR ligands for effects on cognitive function, and (3) briefly discuss some of the topics of debate regarding the development of optimal therapeutic strategies using nAChR ligands. Because of their densities in the mammalian brain and the amount of literature available, the review primarily focuses on ligands of the high-affinity α4ß2* nAChR ("*" indicates the possible presence of additional subunits in the complex) and the low-affinity α7 nAChR. The behavioral task discussion focuses on representative methods that have been designed to model specific domains of cognition that are relevant to human neuropsychiatric disorders and often evaluated in human clinical trials. IMPLICATIONS: The preclinical literature continues to grow in support of the development of nAChR ligands for a variety of illnesses that affect humans. However, to date, no new nAChR ligand has been approved for any condition other than nicotine dependence. As discussed in this review, the studies conducted to date provide the impetus for continuing efforts to develop new nAChR strategies (ie, beyond simple agonist and partial agonist approaches) as well as to refine current behavioral strategies and create new animal models to address translational gaps in the drug discovery process.

Preclinical performance of a pediatric mechanical circulatory support device: The PediaFlow ventricular assist device.

OBJECTIVES: The PediaFlow (HeartWare International, Inc, Framingham, Mass) is a miniature, implantable, rotodynamic, fully magnetically levitated, continuous-flow pediatric ventricular assist device. The fourth-generation PediaFlow was evaluated in vitro and in vivo to characterize performance and biocompatibility. METHODS: Supported by 2 National Heart, Lung, and Blood Institute contract initiatives to address the limited options available for pediatric patients with congenital or acquired cardiac disease, the PediaFlow was developed with the intent to provide chronic cardiac support for infants as small as 3 kg. The University of Pittsburgh-led Consortium evaluated fourth-generation PediaFlow prototypes both in vitro and within a preclinical ovine model (n = 11). The latter experiments led to multiple redesigns of the inflow cannula and outflow graft, resulting in the implantable design represented in the most recent implants (n = 2). RESULTS: With more than a decade of extensive computational and experimental efforts spanning 4 device iterations, the AA battery-sized fourth-generation PediaFlow has an operating range of 0.5 to 1.5 L/min with minimal hemolysis in vitro and excellent hemocompatibility (eg, minimal hemolysis and platelet activation) in vivo. The pump and finalized accompanying implantable components demonstrated preclinical hemodynamics suitable for the intended pediatric application for up to 60 days. CONCLUSIONS: Designated a Humanitarian Use Device for "mechanical circulatory support in neonates, infants, and toddlers weighing up to 20 kg as a bridge to transplant, a bridge to other therapeutic intervention such as surgery, or as a bridge to recovery" by the Food and Drug Administration, these initial results document the biocompatibility and potential of the fourth-generation PediaFlow design to provide chronic pediatric cardiac support.

Intermittent stimulation in the nucleus basalis of meynert improves sustained attention in rhesus monkeys.

Sustained attention is essential in important behaviors in daily life. Many neuropsychiatric disorders are characterized by a compromised ability to sustain attention, making this cognitive domain an important therapeutic target. In this study, we tested a novel method of improving sustained attention. Monkeys were engaged in a continuous performance task (CPT) while the nucleus basalis of Meynert (NB), the main source of cholinergic innervation of the neocortex, was stimulated. Intermittent NB stimulation improved the animals' performance by increasing the hit rate and decreasing the false alarm rate. Administration of the cholinesterase inhibitor donepezil or the muscarinic antagonist scopolamine alone impaired performance, whereas the nicotinic antagonist mecamylamine alone improved performance. Applying NB stimulation while mecamylamine or donepezil were administered impaired CPT performance. Methylphenidate, a monoaminergic psychostimulant, was applied in conjunction with intermittent stimulation as a negative control, as it does not directly modulate cholinergic output. Methylphenidate also improved performance, and it produced further improvement when combined with NB stimulation. The additive effect of the combination suggested NB stimulation altered behavior independently from methylphenidate effects. We conclude that basal forebrain projections contribute to sustained attention, and that intermittent NB stimulation is an effective way of improving performance.

Tropisetron enhances recognition memory in rats chronically treated with risperidone or quetiapine.

While impairments of cognition in schizophrenia have the greatest impact on long-term functional outcome, the currently prescribed treatments, antipsychotic drugs (APDs), do not effectively improve cognition. Moreover, while more than 20 years have been devoted to the development of new drugs to treat cognitive deficits in schizophrenia, none have been approved to date. One area that has not been given proper attention at the preclinical or clinical stage of drug development is the chronic medication history of the test subject. Hence, very little is known about how chronic treatment with drugs that affect multiple receptors like APDs influence the response to a potential pro-cognitive agent. Therefore, the purpose of this study was to evaluate the α7 nicotinic acetylcholine receptor (α7 nAChR) partial agonist, tropisetron in rats chronically treated with APDs with distinct pharmacological profiles. Rats were treated orally with either risperidone (2.5 mg/kg/day) or quetiapine (25.0 mg/kg/day) for 30 or 90 days and then an acute injection of vehicle or tropisetron (3.0 mg/kg) was administered before training in a novel object recognition (NOR) task. After a 48 h delay (when recollection of the familiar object was impaired in vehicle-treated animals) neither 30 nor 90 days of risperidone or quetiapine treatment improved NOR performance. In contrast, tropisetron markedly improved NOR performance in rats treated with either APD for 30 or 90 days. These animal data reinforce the argument that two commonly prescribed APDs are not pro-cognitive agents and that α7 nAChR ligands like tropisetron have potential as adjunctive treatments in schizophrenia.

Intermittent Stimulation of the Nucleus Basalis of Meynert Improves Working Memory in Adult Monkeys.

Acetylcholine in the neocortex is critical for executive function [1-3]. Degeneration of cholinergic neurons in aging and Alzheimer's dementia is commonly treated with cholinesterase inhibitors [4-7]; however, these are modestly effective and are associated with side effects that preclude effective dosing in many patients [8]. Electrical activation of the nucleus basalis (NB) of Meynert, the source of neocortical acetylcholine [9, 10], provides a potential method of improving cholinergic activation [11, 12]. Here we tested whether NB stimulation would improve performance of a working memory task in a nonhuman primate model. Unexpectedly, intermittent stimulation proved to be most beneficial (60 pulses per second, for 20 s every minute), whereas continuous stimulation often impaired performance. Pharmacological experiments confirmed that the effects depended on cholinergic activation. Donepezil, a cholinesterase inhibitor, restored performance in animals impaired by continuous stimulation but did not improve performance further during intermittent stimulation. Intermittent stimulation was rendered ineffective by either nicotinic or muscarinic receptor antagonists. In the months after stimulation began, performance also improved in sessions without stimulation. Our results reveal that intermittent NB stimulation can improve working memory, a finding that has implications for restoring cognitive function in aging and Alzheimer's dementia.

Serum Neuronal Biomarkers in Neonates With Congenital Heart Disease Undergoing Cardiac Surgery.

BACKGROUND: Newborns with congenital heart disease have associated brain damage that affects short-and long-term neurodevelopment. Several neuronal biomarkers exist that could predict brain damage. We investigated the pattern of neuron-specific enolase (NSE) and s100B levels after cardiopulmonary bypass surgery in neonates with congenital heart disease. METHODS: We completed a prospective observational study of neonates with congenital heart disease who were undergoing cardiopulmonary bypass surgery. NSE and s100B levels were measured from serum samples obtained preoperatively, immediately postoperatively, and once daily on postoperative days one to seven. Cranial ultrasounds were obtained preoperatively and postoperatively and findings were scored using an internally developed scoring system. RESULTS: Eighteen neonates were included. Immediate postoperative and peak levels of both NSE (58.0 [21.6] and 68.1 [55.7] µg/L) and s100B (0.14 [0.3] and 0.14 [0.3] µg/L) were significantly increased when compared with preoperative levels (34.0 [21.6] µg/L; P < 0.01 and 0.08 [0.1] µg/L; P < 0.02). By postoperative day seven, NSE and s100B levels were lower than preoperative levels: NSE (18 [5.7]; P = 0.09) and s100B (0.03 [0.05]; P < 0.01). Postoperative s100B levels were negatively correlated with age at surgery and positively correlated with circulatory arrest time. Although there was no significant correlation between either NSE or s100B levels and intensive care unit length of stay, hospital length of stay, and pediatric cerebral performance category score, there was a negative correlation between postoperative levels of NSE and ventriculomegaly. CONCLUSIONS: NSE and s100B levels increase after bypass surgery and return below preoperative baseline levels by postoperative day seven. The levels of s100B were positively correlated with circulatory arrest time and negatively correlated with age at time of surgery. This finding may be supportive of pre-existing prenatal brain injury that could be enhanced by longer surgical times but also of some brain protection effect associated with longer wait until surgery.

Tropisetron sensitizes α7 containing nicotinic receptors to low levels of acetylcholine in vitro and improves memory-related task performance in young and aged animals.

Tropisetron, a 5-HT3 receptor antagonist commonly prescribed for chemotherapy-induced nausea and vomiting also exhibits high affinity, partial agonist activity at α7 nicotinic acetylcholine receptors (α7 nAChRs). α7 nAChRs are considered viable therapeutic targets for neuropsychiatric disorders such as Alzheimer's disease (AD). Here we further explored the nAChR pharmacology of tropisetron to include the homomeric α7 nAChR and recently characterized heteromeric α7ß2 nAChR (1:10 ratio) and we evaluated its cognitive effects in young and aged animals. Electrophysiological studies on human nAChRs expressed in Xenopus oocytes confirmed the partial agonist activity of tropisetron at α7 nAChRs (EC50 ∼2.4 µM) with a similar effect at α7ß2 nAChRs (EC50 ∼1.5 µM). Moreover, currents evoked by irregular pulses of acetylcholine (40 µM) at α7 and α7ß2 nAChRs were enhanced during sustained exposure to low concentrations of tropisetron (10 and 30 nM) indicative of a "priming" or co-agonist effect. Tropisetron (0.1-10 mg/kg) improved novel object recognition performance in young Sprague-Dawley rats and in aged Fischer rats. In aged male and female rhesus monkeys, tropisetron (0.03-1 mg/kg) produced a 17% increase from baseline levels in delayed match to sample long delay accuracy while combination of non-effective doses of donepezil (0.1 mg/kg) and tropisetron (0.03 and 0.1 mg/kg) produced a 24% change in accuracy. Collectively, these animal experiments indicate that tropisetron enhances cognition and has the ability to improve the effective dose range of currently prescribed AD therapy (donepezil). Moreover, these effects may be explained by tropisetron's ability to sensitize α7 containing nAChRs to low levels of acetylcholine.

Effects of the nicotinic agonist varenicline on the performance of tasks of cognition in aged and middle-aged rhesus and pigtail monkeys.

RATIONALE: Due to the rising costs of drug development especially in the field of neuropsychiatry, there is increasing interest in efforts to identify new clinical uses for existing approved drugs (i.e., drug repurposing). OBJECTIVES: The purpose of this work was to evaluate in animals the smoking cessation agent, varenicline, a partial agonist at α4ß2 and full agonist at α7 nicotinic acetylcholine receptors, for its potential as a repurposed drug for disorders of cognition. METHODS: Oral doses of varenicline ranging from 0.01 to 0.3 mg/kg were evaluated in aged and middle-aged monkeys for effects on the following: working/short-term memory in a delayed match to sample (DMTS) task, distractibility in a distractor version of the DMTS (DMTS-D), and cognitive flexibility in a ketamine-impaired reversal learning task. RESULTS: In dose-effect studies in the DMTS and DMTS-D tasks, varenicline was not associated with statistically significant effects on performance. However, individualized "optimal doses" were effective when repeated on a separate occasion (i.e., improving DMTS accuracy at long delays and DMTS-D accuracy at short delays by approximately 13.6 and 19.6 percentage points above baseline, respectively). In reversal learning studies, ketamine impaired accuracy and increased perseverative responding, effects that were attenuated by all three doses of varenicline that were evaluated. CONCLUSIONS: While the effects of varenicline across the different behavioral tasks were modest, these data suggest that varenicline may have potential as a repurposed drug for disorders of cognition associated with aging (e.g., Alzheimer's disease), as well as those not necessarily associated with advanced age (e.g., schizophrenia).

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders.

The challenges associated with developing more effective treatments for neurologic and psychiatric illness such as Alzheimer's disease and schizophrenia are considerable. Both the symptoms and the pathophysiology of these conditions are complex and poorly understood and the clinical presentations across different patients can be very heterogeneous. Moreover, it has become apparent that the reductionist approach to drug discovery for these illnesses that has dominated the field for decades (i.e., the development of highly selective compounds or other treatment modalities focused on a very specific pathophysiologic target) has not been widely successful. Accordingly, a variety of new strategies have emerged including the development of "multitarget-directed ligands" (MTDLs), the development and/or identification of compounds that exhibit "multifunctional" activity (e.g., pro-cognitive plus neuroprotective, pro-cognitive plus antipsychotic activity), "repurposing" strategies for existing compounds that have other clinical indications, and novel "adjunctive" treatment strategies that might enhance the efficacy of the currently available treatments. Interestingly, a variety of ligands at nicotinic acetylcholine receptors (nAChRs) appear to have the potential to fulfill one or more of these desirable properties (i.e., multifunctional, repurposing, or adjunctive treatment potential). The purpose of this review (while not all-inclusive) is to provide an overview of a variety of nAChR ligands that demonstrate potential in these categories, particularly, "multifunctional" properties. Due to their densities in the mammalian brain and the amount of literature available, the review will focus on ligands of the high affinity α4ß2 nAChR and the low affinity α7 nAChR.

Pharmacokinetics of cotinine in rats: a potential therapeutic agent for disorders of cognitive function.

BACKGROUND: Attention has been paid to cotinine (COT), one of the major metabolites of nicotine (NIC), for its pro-cognitive effects and potential therapeutic activities against Alzheimer's disease (AD) and other types of cognitive impairment. In order to facilitate pharmacological and toxicological studies on COT for its pro-cognitive activities, we conducted a pharmacokinetic (PK) study of COT in rats, providing important oral and intravenously (iv) PK information. METHODS: In this study, plasma samples were obtained up to 48 h after COT was dosed to rats orally and iv at a dose of 3mg/kg. Plasma samples were prepared and analyzed using a sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) bioanalytical method, providing concentration profiles of COT and metabolites after oral and iv administrations. RESULTS: The data were fitted into a one-compartment model and a two-compartment model for the oral and iv groups, respectively, providing important PK information for COT including PK profiles, half-life, clearance and bioavailability. The results suggested fast absorption, slow elimination and high bioavailability of COT in rats. CONCLUSIONS: Several important facts about the PK properties in rats suggested COT could be a potential pro-cognitive agent. Information about the pharmacokinetics of COT in rats revealed in this study is of great importance for the future studies on COT or potential COT analogs as agents for improving cognition.

Attention.

The ability to focus one's attention on important environmental stimuli while ignoring irrelevant stimuli is fundamental to human cognition and intellectual function. Attention is inextricably linked to perception, learning and memory, and executive function; however, it is often impaired in a variety of neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, depression, and attention deficit hyperactivity disorder (ADHD). Accordingly, attention is considered as an important therapeutic target in these disorders. The purpose of this chapter is to provide an overview of the most common behavioral paradigms of attention that have been used in animals (particularly rodents) and to review the literature where these tasks have been employed to elucidate neurobiological substrates of attention as well as to evaluate novel pharmacological agents for their potential as treatments for disorders of attention. These paradigms include two tasks of sustained attention that were developed as rodent analogues of the human Continuous Performance Task (CPT), the Five-Choice Serial Reaction Time Task (5-CSRTT) and the more recently introduced Five-Choice Continuous Performance Task (5C-CPT), and the Signal Detection Task (SDT) which was designed to emphasize temporal components of attention.