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.

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.

Potential for intermittent stimulation of nucleus basalis of Meynert to impact treatment of alzheimer's disease.

The brain's cholinergic arousal pathways decline in parallel with the brain's executive functions in aging and Alzheimer's Disease. The frontline and currently most effective approach to treating Alzheimer's disease is the administration of cholinesterase inhibitors, which, in a dose dependent manner, improve the symptoms of cognitive decline over the first months of treatment before further decline occurs. We recently showed that intermittent deep brain stimulation of the nucleus basalis of Meynert improves working memory function in young adult monkeys, and that this improvement depended on cholinergic function. Within minutes, the monkeys' ability to remember stimuli over a delay period improved. Over months, the monkeys performed the working memory task better even in the absence of stimulation. Here, we show historical data from our monkey colony in which more than two dozen animals have performed the same behavioral task to asymptotic performance levels. Using a distribution based on our historical data, we estimate that the monkeys receiving intermittent stimulation leapt over the performance level of 32-44 percent of peer animals in the first several months after stimulation was initiated. Implications for a parallel increase in cognitive function for early Alzheimer's patients are discussed.

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).

Alpha 2A adrenergic receptor agonist, guanfacine, attenuates cocaine-related impairments of inhibitory response control and working memory in animal models.

There is considerable evidence that centrally acting α2A adrenergic receptor agonists can attenuate impairments in executive function that result from dysfunction of the prefrontal cortex. Such positive effects resulted in the recent approval by the United States Food and Drug Administration (FDA) of the α2A agonists clonidine and guanfacine for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD), but also suggest that they could have beneficial effects in substance abuse disorders and other neuropsychiatric conditions. The purpose of this study was to evaluate guanfacine for its ability to attenuate behavioral alterations associated with acute cocaine exposure in rats trained to perform a task of sustained attention, the five choice serial reaction time task (5C-SRTT) and monkeys trained to perform a task of working/short term memory, the delayed match to sample (DMTS) task. In the rodent 5C-SRTT acute intraperitoneal (i.p.) administration of cocaine (3.5-15.0mg/kg) did not affect accuracy, but was associated with dose-dependent increases in premature responses and timeout responses. Guanfacine (0.1-1.0mg/kgi.p.) dose-dependently decreased premature responses and timeout responses associated with cocaine and it attenuated similar deficits in inhibitory response control observed in a variable ITI version of the 5C-SRTT. In the DMTS task in monkeys, acute intramuscular (i.m.) administration of cocaine (4.0mg/kg) was associated with impairments in accuracy at long delay intervals, an effect that was attenuated by guanfacine (0.4mg/kg). These animal studies suggest that guanfacine may have therapeutic potential for treating impairments of executive function that are associated with the abuse of cocaine.