Delayed Matching-to-sample Performance Research Articles

Effect of short-term androgen supplementation on cognitive performance in older male rhesus macaques

Old male rhesus macaques often show cognitive impairment, and also have attenuated circulating levels of testosterone and dehydroepiandrosterone sulfate (DHEAS). However, it is unclear if these age-associated decreases in circulating androgen levels are casually related to mechanisms that support cognition. To test this possibility, old male rhesus macaques were given daily supplements of testosterone and DHEA for ∼7 months, using a paradigm designed to mimic the 24-hour circulating hormone patterns of young adults. Animals completed the Delayed Match-to-Sample (DMS) task to assess recognition, and the Delayed Response (DR) task to assess working memory. The animals all showed significant delay-dependent performance, with longer delays resulting in lower accuracy; and timepoint-dependent performance, showing improvement with the repeated opportunities for practice. However, there were no differences between the androgen supplemented animals and age-matched controls. These data indicate that the specific short-term supplementation paradigm employed here offers no obvious benefits for DMS or DR task performance.

The Effects of the M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0486846 on Cognitive Performance in Aged Nonhuman Primates

It is estimated that in the United States alone there will be nearly 70 million people over the age of 65 by the year 2030. Yet, there remains a critical unmet need to understand and identify novel therapeutic strategies to address age‐related impairments in arousal, cognitive function, and sleep architecture. Agents such as acetylcholinesterase inhibitors (AChEIs) that enhance overall cholinergic neurotransmission are approved to ameliorate the loss of cognitive function in normal aging and Alzheimer’s disease (AD) populations. However, AChEIs are associated with dose‐limiting side effect due to nonselective activation of peripheral muscarinic acetylcholine receptors (mAChRs). Accumulating evidence indicates that enhancement of central cholinergic neurotransmission through selective activation of the M1 mAChR subtype represents an exciting alternative approach for the treatment of impairments in cognition, arousal and sleep observed in normal aging and AD. Recently we successfully optimized a novel series of M1 positive allosteric modulators (PAMs) as an alternative strategy for the selective activation of M1 receptors, represented by VU0486846. The goal of the present study was to provide the first characterization of the effects of an M1 PAM on cognitive performance in aged nonhuman primates. For these studies, 16 aged (> 20 years old) female and male (N=8/sex) cynomolgus monkeys were trained under two different cognitive tasks using CANTAB touchscreens. Eight monkeys (N=4/sex) were trained under a delayed match‐to‐sample (DMS) task using three delays and 2–3 distractors. The other monkeys were trained under an attention task, the multiple‐choice serial reaction time (MCSRT) task. All monkeys were tested with the following compounds, administered 60‐min before the session: donepezil (0.1–0.56 mg/kg, IM); VU0486846 (1.0–5.6 mg/kg, PO) and d‐amphetamine (0.01–0.056 mg/kg, IM). With no published data on training of aged monkeys in a DMS task, we found that the eight aged monkeys required approximately 1 year of training prior to pharmacologic challenge. The effects of donepezil were variable across monkeys, up to doses that produced adverse effects. In contrast, VU0486846 improved working memory, at doses that did not result in any side effects. As a positive control, d‐amphetamine also improved cognitive performance. In preliminary studies, testing ineffective doses of donepezil + VU0486846 also resulted in improved DMS performance. Regarding MCSRT, effects of both donepezil and VU0486846 were determined on a reaction time task. At doses that improved working memory, VU0486846 did not affect reaction time while in some but not all monkeys, donepezil slowed reaction times. These promising preliminary data will be extended in order to examine sex‐specific and age‐related effects of chronic VU0486846 and the consequences of the M1 PAM and donepezil on sleep architecture in aged nonhuman primates.Support or Funding InformationNIH grant AG054622

Effects of the dopamine transporter gene on striatal functional connectivity in youths with attention-deficit/hyperactivity disorder.

The dopamine transporter gene (DAT1), striatal network dysfunction, and visual memory deficits have been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). This study aimed to examine the effects of the DAT1 rs27048 (C)/rs429699 (T) haplotype on striatal functional connectivity and visual memory performance in youths with ADHD. After excluding those who had excessive head motion, a total of 96 drug-naïve youths with ADHD and 114 typically developing (TD) youths were assessed with the resting-state functional magnetic resonance imaging and the delayed matching to sample (DMS) task for visual memory. We examined the effects of ADHD, DAT1 CT haplotype, and the ADHD × CT haplotype interaction on the functional connectivity of five striatal seeds. We also correlated visual memory performance with the functional connectivity of striatal subregions, which showed significant diagnosis × genotype interactions. Compared with TD youths, ADHD youths showed significant hypoconnectivity of the left dorsal caudate (DC) with bilateral sensorimotor clusters. Significant diagnosis × genotype interactions were found in the connectivity between the left DC and the right sensorimotor cluster, and between the right DC and the left dorsolateral prefrontal/bilateral anterior cingulate clusters. Furthermore, the connectivity of the left DC showing significant diagnosis × genotype interactions was associated with DMS performance in youths with ADHD who carried the DAT1 CT haplotype. A novel gene-brain-behavior association between the left DC functional connectivity and visual memory performance in ADHD youths with the DAT1 rs27048 (C)/rs429699 (T) haplotype suggests a differential effect of DAT1 genotype altering specific brain function causing neuropsychological dysfunction in ADHD.

Profiles of visuospatial memory dysfunction in opioid-exposed and dependent populations.

Chronic opioid exposure is common world-wide, but behavioural performance remains under-investigated. This study aimed to investigate visuospatial memory performance in opioid-exposed and dependent clinical populations and its associations with measures of intelligence and cognitive impulsivity. We recruited 109 participants: (i) patients with a history of opioid dependence due to chronic heroin use (n = 24), (ii) heroin users stabilised on methadone maintenance treatment (n = 29), (iii) participants with a history of chronic pain and prescribed tramadol and codeine (n = 28) and (iv) healthy controls (n = 28). The neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery included the Delayed Matching to Sample (DMS), Pattern Recognition Memory, Spatial Recognition Memory, Paired Associate Learning, Spatial Span Task, Spatial Working Memory and Cambridge Gambling Task. Pre-morbid general intelligence was assessed using the National Adult Reading Test. As hypothesised, this study identified the differential effects of chronic heroin and methadone exposures on neuropsychological measures of visuospatial memory (p < 0.01) that were independent of injecting behaviour and dependence status. The study also identified an improvement in DMS performance (specifically at longer delays) when the methadone group was compared with the heroin group and also when the heroin group was stabilised onto methadone. Results identified differential effects of chronic heroin and methadone exposures on various neuropsychological measures of visuospatial memory independently from addiction severity measures, such as injecting behaviour and dependence status.

Cognition in aged rhesus monkeys: effect of DHEA and correlation with steroidogenic gene expression.

Estradiol supplementation has been shown to enhance cognitive performance in old ovariectomized rhesus macaques (Macaca mulatta). To determine if similar benefits could be achieved in perimenopausal animals using alternative hormonal supplements, we administered dehydroepiandrosterone (DHEA) to old ovary-intact female rhesus macaques for ∼2.5 months. Using computerized touch screen memory tasks, including delayed response (DR) and delayed matching-to-sample (DMS), we observed improved performance with time in all of the animals but failed to detect a significant effect of DHEA. On the other hand, gene expression profiling disclosed a significant correlation between cognitive performance and the expression of several steroidogenic and steroid-responsive genes. The DR performance was positively correlated with hippocampal expression of AKR1C3 and STAR and negatively correlated with the expression of SDRD5A1. A positive correlation was also found between DMS performance and prefrontal cortical expression of AKR1C3 and a negative correlation with STAR, as well as a negative correlation with the hippocampal expression of HSD11B1 and NR3C1. Taken together, the results suggest that steroidogenic gene regulation within the brain may help to maintain cognitive function during the perimenopausal transition period, despite a decline in sex-steroid levels in the circulation.

Visual memory and sustained attention impairment in youths with autism spectrum disorders.

An uneven neurocognitive profile is a hallmark of autism spectrum disorder (ASD). Studies focusing on the visual memory performance in ASD have shown controversial results. We investigated visual memory and sustained attention in youths with ASD and typically developing (TD) youths. We recruited 143 pairs of youths with ASD (males 93.7%; mean age 13.1, s.d. 3.5 years) and age- and sex-matched TD youths. The ASD group consisted of 67 youths with autistic disorder (autism) and 76 with Asperger's disorder (AS) based on the DSM-IV criteria. They were assessed using the Cambridge Neuropsychological Test Automated Battery involving the visual memory [spatial recognition memory (SRM), delayed matching to sample (DMS), paired associates learning (PAL)] and sustained attention (rapid visual information processing; RVP). Youths with ASD performed significantly worse than TD youths on most of the tasks; the significance disappeared in the superior intelligence quotient (IQ) subgroup. The response latency on the tasks did not differ between the ASD and TD groups. Age had significant main effects on SRM, DMS, RVP and part of PAL tasks and had an interaction with diagnosis in DMS and RVP performance. There was no significant difference between autism and AS on visual tasks. Our findings implied that youths with ASD had a wide range of visual memory and sustained attention impairment that was moderated by age and IQ, which supports temporal and frontal lobe dysfunction in ASD. The lack of difference between autism and AS implies that visual memory and sustained attention cannot distinguish these two ASD subtypes, which supports DSM-5 ASD criteria.

Facilitation of memory encoding in primate hippocampus by a neuroprosthesis that promotes task-specific neural firing

Objective. Memory accuracy is a major problem in human disease and is the primary factor that defines Alzheimer’s, ageing and dementia resulting from impaired hippocampal function in the medial temporal lobe. Development of a hippocampal memory neuroprosthesis that facilitates normal memory encoding in nonhuman primates (NHPs) could provide the basis for improving memory in human disease states. Approach. NHPs trained to perform a short-term delayed match-to-sample (DMS) memory task were examined with multi-neuron recordings from synaptically connected hippocampal cell fields, CA1 and CA3. Recordings were analyzed utilizing a previously developed nonlinear multi-input multi-output (MIMO) neuroprosthetic model, capable of extracting CA3-to-CA1 spatiotemporal firing patterns during DMS performance. Main results. The MIMO model verified that specific CA3-to-CA1 firing patterns were critical for the successful encoding of sample phase information on more difficult DMS trials. This was validated by the delivery of successful MIMO-derived encoding patterns via electrical stimulation to the same CA1 recording locations during the sample phase which facilitated task performance in the subsequent, delayed match phase, on difficult trials that required more precise encoding of sample information. Significance. These findings provide the first successful application of a neuroprosthesis designed to enhance and/or repair memory encoding in primate brain.

Latent vulnerability in cognitive performance following chronic cocaine self-administration in rhesus monkeys

Cocaine use is associated with cognitive impairment which impacts treatment outcome. A clearer understanding of those deficits, and whether particular environments exacerbate them, is needed. This study evaluated whether previously observed domain-specific cognitive deficits persisted following a 3-month cessation from chronic cocaine self-administration, as well as the impact of novel and cocaine-associated attentional distractors. Control and experimental groups of monkeys performed stimulus discrimination, stimulus reversal, and delayed match-to-sample (DMS) tasks. After establishing post-cocaine baseline performance, we examined general distractibility in both groups, using brief novel distractors counterbalanced across each task. After testing the novel distractor, an identical approach was used for exposure to an appetitive distractor previously associated with cocaine in the experimental group or water in the control group. Post-administration baseline performance was equivalent between groups on all tasks. In the cocaine group, stimulus discrimination was unaffected by either distractor, whereas reversal performance was disrupted by both the novel and appetitive distractors. DMS performance was impaired in the cocaine group in the presence of the novel distractor. The control group's performance was not affected by the presentation of either distractor on any task. Our results reveal that despite normalized performance between groups, there exists in the cocaine group a domain-specific latent vulnerability of cognitive performance to impairment by environmental distractors. The pattern of vulnerability recapitulates the frank impairments seen in drug-free animals during an active self-administration phase. A greater impact of the cocaine-associated distractor over the novel one was not observed.

Facilitation and restoration of cognitive function in primate prefrontal cortex by a neuroprosthesis that utilizes minicolumn-specific neural firing

Objective. Maintenance of cognitive control is a major concern for many human disease conditions; therefore, a major goal of human neuroprosthetics is to facilitate and/or recover the cognitive function when such circumstances impair appropriate decision making. Approach. Minicolumnar activity from the prefrontal cortex (PFC) was recorded from nonhuman primates trained to perform a delayed match to sample (DMS), via custom-designed conformal multielectrode arrays that provided inter-laminar recordings from neurons in the PFC layer 2/3 and layer 5. Such recordings were analyzed via a previously demonstrated nonlinear multi-input–multi-output (MIMO) neuroprosthesis in rodents, which extracted and characterized multicolumnar firing patterns during DMS performance. Main results. The MIMO model verified that the conformal recorded individual PFC minicolumns responded to entrained target selections in patterns critical for successful DMS performance. This allowed the substitution of task-related layer 5 neuron firing patterns with electrical stimulation in the same recording regions during columnar transmission from layer 2/3 at the time of target selection. Such stimulation improved normal task performance, but more importantly, recovered performance when applied as a neuroprosthesis following the pharmacological disruption of decision making in the same task. Significance. These findings provide the first successful application of neuroprosthesis in the primate brain designed specifically to restore or repair the disrupted cognitive function.

Effects of nicotinic acetylcholine receptor agonists on cognition in rhesus monkeys with a chronic cocaine self-administration history

Cocaine use is associated with impaired cognitive function, which may negatively impact treatment outcomes. One pharmacological strategy to improve cognition involves nicotinic acetylcholine receptor (nAChR) stimulation. However, the effects of chronic cocaine exposure on nAChR distribution and function have not been characterized. Thus, one goal of this study was to examine nAChR availability in rhesus monkeys with an extensive cocaine self-administration history (n = 4; ∼6 years, mean intake, 1463 mg/kg) compared to age-matched cocaine-naive control monkeys (n = 5). Using [11C]-nicotine and positron emission tomography (PET) imaging, cocaine-experienced monkeys showed significantly higher receptor availability in the hippocampus compared to cocaine-naive monkeys. A second goal was to examine the effects of nAChR agonists on multiple domains of cognitive performance in these same monkeys. For these studies, working memory was assessed using a delayed match-to-sample (DMS) task, associative learning and behavioral flexibility using stimulus discrimination and reversal learning tasks. When administered acutely, the nonselective high-efficacy agonist nicotine, the low-efficacy α4β2* subtype-selective agonist varenicline and the high-efficacy α7 subtype-selective agonist, PNU-282987 significantly improved DMS performance in both cocaine-naive and cocaine-experienced monkeys. Individual doses of nicotine and varenicline that engendered maximum cognitive enhancing effects on working memory did not affect discrimination or reversal learning, while PNU-282987 disrupted reversal learning in the cocaine-naive monkeys. These findings indicate that a cocaine self-administration history influenced nAChR distribution and the effects of nAChR agonists on cognitive performance, including a reduced sensitivity to the disrupting effects on reversal learning. The cognitive enhancing effects of nAChR agonists may be beneficial in combination with behavioral treatments for cocaine addiction.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Acute cocaine induced deficits in cognitive performance in rhesus macaque monkeys treated with baclofen

Acute and/or chronic exposure to cocaine can affect cognitive performance, which may influence rate of recovery during treatment. Effects of the GABA-B receptor agonist baclofen were assessed for potency to reverse the negative influence of acute, pre-session, intravenous (IV) injection of cocaine on cognitive performance in Macaca mulatta nonhuman primates. Animals were trained to perform a modified delayed match to sample (DMS) task incorporating two types of trials with varying degrees of cognitive load that had different decision requirements in order to correctly utilize information retained over the delay interval. The effects of cocaine (0.2, 0.4, and 0.6 mg/kg, IV) alone and in combination with baclofen (0.29 and 0.40 mg/kg, IV) were examined with respect to sustained performance levels. Brain metabolic activity during performance of the task was assessed using PET imaged uptake of [(18) F]-fluorodeoxyglucose. Acute cocaine injections produced a dose-dependent decline in DMS performance selective for trials of high cognitive load. The GABA-receptor agonist baclofen, co-administered with cocaine, reversed task performance back to nondrug (saline IV) control levels. Simultaneous assessment of PET-imaged brain metabolic activity in prefrontal cortex (PFC) showed alterations by cocaine compared to PFC metabolic activation in nondrug (saline, IV) control DMS sessions, but like performance, PFC activation was returned to control levels by baclofen (0.40 mg/kg, IV) injected with cocaine. The results show that baclofen, administered at a relatively high dose, reversed the cognitive deficits produced by acute cocaine intoxication that may have implications for use in chronic drug exposure.

Hippocampal Theta-Phase Modulation of Replay Correlates with Configural-Relational Short-Term Memory Performance: Figure 1.

There is now growing evidence that the hippocampus generates theta rhythms that can phase bias fast neural oscillations in the neocortex, allowing coordination of widespread fast oscillatory populations outside limbic areas. A recent magnetoencephalographic study showed that maintenance of configural-relational scene information in a delayed match-to-sample (DMS) task was associated with replay of that information during the delay period. The periodicity of the replay was coordinated by the phase of the ongoing theta rhythm, and the degree of theta coordination during the delay period was positively correlated with DMS performance. Here, we reanalyzed these data to investigate which brain regions were involved in generating the theta oscillations that coordinated the periodic replay of configural-relational information. We used a beamformer algorithm to produce estimates of regional theta rhythms and constructed volumetric images of the phase-locking between the local theta cycle and the instances of replay (in the 13-80 Hz band). We found that individual differences in DMS performance for configural-relational associations were related to the degree of phase coupling of instances of cortical reactivations to theta oscillations generated in the right posterior hippocampus and the right inferior frontal gyrus. This demonstrates that the timing of memory reactivations in humans is biased toward hippocampal theta phase.

ON THE DEVELOPMENT AND MECHANICS OF DELAYED MATCHING-TO-SAMPLE PERFORMANCE

Despite its frequent use to assess effects of environmental and pharmacological variables on short-term memory, little is known about the development of delayed matching-to-sample (DMTS) performance. This study was designed to examine the dimensions and dynamics of DMTS performance development over a long period of exposure to provide a more secure foundation for assessing stability in future research. Six pigeons were exposed to a DMTS task with variable delays for 300 sessions (i.e., 18,000 total trials; 3,600 trials per retention interval). Percent-correct and log-d measures used to quantify the development of conditional stimulus control under the procedure generally and at each of five retention intervals (0, 2, 4, 8 and 16-s) individually revealed that high levels of accuracy developed relatively quickly under the shorter retention intervals, but increases in accuracy under the longer retention intervals sometimes were not observed until 100-150 sessions had passed, with some still increasing at Session 300. Analyses of errors suggested that retention intervals induced biases by shifting control from the sample stimulus to control by position, something that was predicted by observed response biases during initial training. These results suggest that although it may require a great deal of exposure to DMTS prior to obtaining asymptotic steady state, quantification of model parameters may help predict trends when extended exposure is not feasible.

The effects of IDRA 21, a positive modulator of the AMPA receptor, on delayed matching performance by young and aged rhesus monkeys

IDRA 21, a positive allosteric modulator of the glutamate AMPA receptor, produced a concentration-dependent inhibition of glutamate-induced inactivation of membrane currents in recombinant HEK 293 (human embryonic kidney) cells stably transfected with human GluR1/2 flip receptors. IDRA 21 doubled the charge transfer at a concentration of 70 μM, suggesting that this compound can facilitate excitatory neurotransmission via GluR 1/2 receptors. We next sought to exploit this mechanism of action by examining the drug as a potential cognition-enhancing agent in non-human primates. Oral administration of IDRA 21 produced a highly significant improvement in the performance of a delayed matching-to-sample (DMTS) task by young adult rhesus monkeys. The pattern of task improvement over the dose range 0.15–10 mg/kg was maintained to 48 hr after the single dose administration. For sessions run after administration of the individualized Best Dose of IDRA 21, task accuracy for Long delay (most difficult) trials was increased by 34% of vehicle. Animals were randomly assigned fixed doses of IDRA 21 to determine whether the positive mnemonic response could be maintained. The repeated doses were separated by 3 days, thus allowing for potential cumulative effects. IDRA 21 produced a gradual increase in task accuracy that was maintained on average above vehicle performance levels over an intermittent dosing schedule during a total period of 3 weeks. A separate group of aged monkeys (>20 y) were, as a group, impaired (during vehicle testing) in DMTS performance efficiency relative to the young cohort. IDRA 21 also improved task accuracy by aged rhesus monkeys over the same dose range, but the responses were not as robust as those exhibited by young animals. Aged subjects also appeared to be more individually sensitive to drug dose, and they exhibited shorter task latencies than did the young group. Despite these differences, when the individualized Best Doses were considered, IDRA 21 produced a robust increase in DMTS accuracy of up to 18% of vehicle for trials associated with Medium delay intervals. For both study groups, no obvious untoward effects of IDRA 21 were noted. These findings support the use of AMPA modulators like IDRA 21 in the treatment of cognitive/memory disorders, including those associated with aging. They also indicate that the drug is associated with long-term effects that could limit dosing regimens to one dose every two or three days. The nature of the protracted mnemonic effects produced by the compound remains to be elucidated.

Spatial working memory ability is a marker of risk-for-psychosis.

Working memory has been identified as a core cognitive deficit in schizophrenia that is associated with negative symptoms, but it is unclear whether it is impaired prior to onset of psychosis in symptomatic patients. Thirty-eight young people at ultra high-risk (UHR) of developing psychosis (of whom nine later became psychotic) were compared with 49 healthy controls on tests of spatial working memory (SWM) and delayed matching-to-sample (DMTS). Both SWM and DMTS performance was significantly poorer in the UHR groups. Those who later became psychotic generally performed more poorly than those who did not, although this did not reach significance for any measure. A significant association between SWM errors and negative symptoms was seen in the later-psychotic group only (P = 0.02). Spatial working memory abilities are impaired in those at high-risk for psychosis. The relationship between working memory and negative symptoms may be useful as a predictive tool.

Nonspatial and Subdivision-Specific Working Memory Deficits after Selective Lesions of the Avian Prefrontal Cortex

Association areas in the avian forebrain are shown to subserve higher cognitive functions, including working memory. One of these areas, the neostriatum caudolaterale (NCL) of pigeons, has been functionally compared with the mammalian prefrontal cortex (PFC) because of its prominent role in spatial delay and reversal tasks and its innervation by the dopaminergic system that modulates these functions. However, whereas the PFC maintains in working memory information of different domains, the essential role of the NCL in working memory has been demonstrated only for spatial tasks. To investigate whether the avian NCL is also crucial for nonspatial working memory functions, pigeons were tested in an object-related (color) delayed matching-to-sample (DMTS) task. Bilateral lesions were placed in the entire, dorsal, or ventral NCL to test for possible functional subdivisions that were proposed to exist on the basis of neurochemical and behavioral data. Pigeons with total, dorsal, and ventral NCL lesions showed significant deficits in their DMTS performance, whereas controls were not impaired. Thus, the avian NCL is critically involved in nonspatial working memory processes. Recovery from performance deficits was observed in animals with ventral or total NCL lesions, whereas animals with dorsal NCL lesions showed no improvement. Ventral NCL may mediate perseverative behavior, whereas dorsal NCL might be involved in active working memory. Differences in the connections of these subdivisions with striatal areas and other association areas in the frontomedial forebrain underline functional differences. The data indicate a possible segregation of functions in the avian NCL.

Effects of chlordiazepoxide and FG 7142 on a rat model of diencephalic amnesia as measured by delayed-matching-to-sample performance.

The intralaminar thalamic nuclei (ILn) have been implicated as a critical site of pathology in amnesia. Lesions of the ILn have been found to produce behavioral effects comparable to benzodiazepine (BDZ) receptor agonists. We compared the effects of chlordiazepoxide (CDP), a BDZ agonist, and FG 7142, a partial inverse agonist at the BDZ receptor, in rats with thalamic lesions and in unlesioned controls. Delayed matching-to sample (DMS) performances were studied during treatment with ascending doses of CDP, counterbalanced trials with 2.5 mg/kg CDP and saline, ascending doses of FG 7142, and (for unlesioned controls only) counterbalanced trials with saline and higher doses of CDP. CDP had effects similar to the ILn lesion, decreasing response speed and percent correct responding in a delay-independent fashion. These effects were additive with the impairments associated with the ILn lesion. The effects of FG 7142 were more complex. At lower doses, it increased response speed without affecting response accuracy. At higher doses, it diminished both the speed and the accuracy of DMS responding. These results support the hypothesis that ILn lesions and BDZ agonists have similar effects on DMS performance. The biphasic effects observed for FG 7142 are consistent with other evidence that low doses of this drug enhance while higher doses impair memory performance. Although DMS accuracy was not improved, the enhancement observed for response speed provides evidence that partial inverse BDZ agonists have potential utility as treatments for cognitive impairments associated with amnesia.

Improvement in accuracy of delayed recall in aged and non-aged, mature monkeys after intramuscular or transdermal administration of the CNS nicotinic receptor agonist ABT-418.

ABT-418 was evaluated for its ability to enhance accuracy on a delayed matching-to-sample (DMTS) task by aged monkeys following intramuscular administration, and in non-aged mature monkeys following transdermal application. Aged monkeys were impaired in their performance of the DMTS task such that the longest delay intervals performed at above-chance levels extended only to 20 s. In contrast, for non-aged, mature animals, delay intervals extended to 140 s. In aged monkeys, the response to ABT-418 was highly individualized with animals responding to one or more doses in the range of 2-259 nmol/kg. A systematic dose-dependent enhancement of DMTS accuracy was not observed. When the individualized "best dose" was administered on a separate occasion, overall DMTS accuracy was increased by 12.6%. By 24 h after administration, accuracy was at control levels. In young monkeys, a significant dose-dependent enhancement of DMTS performance (an overall increase of 11.25% above baseline accuracy) was observed 5 h after application of a transdermal patch designed to maintain steady-state plasma levels of ABT-418 of 40-60 ng/ml over a 24-h period. Again there was some individual responsiveness to one of the three doses. When data included only the individualized best doses of ABT-418 for each animal, a similar enhancement of accuracy was observed for both the 5-h and 24-h test intervals. In neither the aged nor the young cohorts was enhancement of performance associated with altered response latencies or with any overt side effects of ABT-418. Thus, these data are consistent with the ability of ABT-418 to improve DMTS performance in both young and aged monkeys. In aged monkeys, this response was observed only after administration of individualized optimal doses for different monkeys. In young monkeys, a more systematic enhancement of DMTS accuracy was observed. Further, transdermal delivery of ABT-418 in non-aged monkeys demonstrated prolonged performance enhancement compared with IM injection to at least 24 h after patch administration.

The 5-HT3 receptor antagonist, RS-56812, enhances delayed matching performance in monkeys.

Substantial evidence indicates that serotonin receptors are involved in the regulation of acetylcholine release in CNS regions important to mnemonic processes, and may thus be exploited pharmacologically as targets for memory improvement. In the present study, the (R) and (S) isomers of a potent serotonin (5-HT3) receptor ligand, RS-56812 were evaluated for potential memory effects in five macaques trained to perform a delayed matching-to-sample (DMTS) task. While both isomers enhanced certain aspects of task performance, the (R) isomer produced more systematic improvements. This differential sensitivity to the isomers in regard to DMTS performance appears to parallel the higher 5-HT3 receptor affinity of the R enanantiomer. The results are consistent with a potential therapeutic role for RS-56812 in disorders involving cognitive decline.

Cognitive effects of nicotinic cholinergic receptor agonists in nonhuman primates

The centrally acting cholinesterase inhibitor tacrine was compared with three nicotinic acetylcholine receptor (nAChR) agonists for their abilities to enhance performance of mature adult macaques performing a computer-automated version of the delayed matching-to-sample (DMTS) task. All four drugs enhanced DMTS performance at one or more doses, although ABT-418 [(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole] may be the most potent and the most effective of the four. Nicotine was less potent and less effective than ABT-418 but was more potent than either tacrine or isoarecolone. At each animal's respective maximally effective dose, task improvement ranged from approximately 14 to 30% over vehicle performance levels. Despite the significantly enhanced levels of performance improvement obtained on the day of drug administration, when the animals were tested 24 h later (in the absence of drug), only nicotine-treated animals exhibited a significant improvement in performance. In an attempt to help explain this protracted improvement in DMTS performance to nicotine, cell surface nerve growth factor (NGF) receptors were measured in cultured PC-12 cells before and after exposure to nicotine. Exposure to nicotine for 24 h resulted in a significant increase in cell surface NGF in the cells. However, even after nicotine was removed from the culture medium, NGF receptor protein continued to increase for an additional 24 h. The results of this study are consistent with the possibility that stimulation of central nAChRs may be employed to improve cognitive function in cognitively impaired individuals. They also suggest that one potential mechanism for the protracted beneficial effect of nicotine may involve the enhanced expression of brain NGF receptors.