Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement

ABT-418, a newly characterized centrally acting cholinergic channel activator (ChCA), was evaluated for its ability to improve performance in a delayed matching-to-sample (DMTS) task by mature macaques well trained in the task. Previous studies in rodents have indicated that ABT-418 shares the memory/cognitive enhancing actions of nicotine, but without many of nicotine's dose-limiting side effects. As DMTS provides a measure both of general cognitive function (the matching concept) and of recent memory, it was hypothesized that some doses of ABT-418 would enhance the monkeys' ability to correctly perform the DMTS task. Intramuscular administration of ABT-418 significantly enhanced DMTS performance at low (2–32.4 nmol/kg) doses. In fact, the drug was slightly more potent that nicotine in this regard, and all eight animals tested in this study exhibited enhanced performance at one or more doses. ABT-418 produced the greatest improvement in DMTS performance at the longest delay interval. In animals repeatedly tested with their individualized “Best Dose”, DMTS performance increased on average by 10.1 ± 3.5 percentage points correct, which was equivalent to an increase of 16.2% over baseline performance. ABT-418 did not significantly affect response times, i.e., latencies to make a choice between stimuli, or latencies to initiate new trials. Whereas nicotine enhanced DMTS performance both on the day of administration and on the following day (in the absence of drug), ABT-418-induced enhanced performance was detected only on the day of administration. Finally, single daily administration of the individualized best dose in three monkeys over a period of 8 days generally maintained enhancement of DMTS performance. Thus, the data were not consistent with the development of significant tolerance to the drug's mnemonic actions. In contrast to nicotine, no overt toxicity or side effects to acute or repeated administration of the drug were noted. Thus, ABT-418 represents a prototype of a new class of nicotinic agonists designed for the potential treatment of human dementias having a low profile of toxicity.     

Central nicotinic receptor agonists ABT-418, ABT-089, and (–)-nicotine reduce distractibility in adult monkeys

 Increased distractibility is associated with both Alzheimer’s disease and attention deficit disorder. The present study examined the effects of (–)-nicotine and the novel central nicotinic receptor (nAChR) agonists ABT-418 [(S)-3-methyl-2-pyrrolidinyl)isoxazole] and ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy)- pyridine dihydrochloride] on the delayed recall accuracy of adult monkeys exposed to distracting stimuli. Unpredictable exposure to a random visual array produced marked decrements in recall accuracy on trials with the shortest delay intervals, reducing the accuracy on these trials by 23.4%. Intramuscular (IM) administration of (–)-nicotine, in doses of 5.4–43.3 nmol/kg, attenuated the effect of the distractor, but did not completely prevent it. Both ABT-418 (2.0–16.2 nmol/kg, IM) and ABT-089 (16.4–32.8 nmol/kg, IM) prevented distractibility, producing increases of 7.5–25.0% in accuracy on trials disrupted by distractor exposure. Further, both compounds also improved accuracy on trials during which distractors were not presented, an effect which was not observed after (–)-nicotine administration. Nicotinic-mediated side effects were not observed following administration of any compound. Thus, nAChR stimulation reduces distractibility in adult monkeys and may, therefore, represent a target for the pharmacologic treatment of disorders associated with susceptibility to distraction. ABT-418 and ABT-089 appear to be particularly useful in this regard, a likely result of their selective agonist activity at nAChRs expressed in the brain. Received: 14 May 1997 / Final version: 19 August 1997     

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 microM, 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.     

The acute effects of dimebolin, a potential Alzheimer's disease treatment, on working memory in rhesus monkeys

BACKGROUND

Dimebolin (latrepirdine), a compound with multiple potential drug targets, is being evaluated in clinical trials for the treatment of Alzheimer''s disease (AD) and preliminary results suggest it can slow the disease process. There is also evidence that dimebolin directly improves aspects of cognition. Here we examined the acute effect of dimebolin on components of working memory in non-human primates, young adult (11–17 years old) and aged (20–31 years old) rhesus macaques.

EXPERIMENTAL APPROACH

The effects of dimebolin (3.9–118 µg kg⁻¹) on working memory, as measured by performance on delayed matching-to-sample (DMTS), were examined in the normal young adult monkeys and aged adult monkeys. All the monkeys studied were proficient in the performance of a computer-assisted DMTS task. In a subsequent experiment in the same subjects, dimebolin was administered 15 min before a cognitively-impairing dose (20 µg kg⁻¹) of scopolamine.

KEY RESULTS

In both the young adult and aged monkeys, dimebolin significantly increased the DMTS task accuracies. In young adults, the task improvement was associated with long (retention/retrieval) delay trials, and a protracted enhancement was observed for sessions run 24 h post administration of a single dose. Dimebolin did not significantly attenuate the scopolamine-induced impairment. In the aged monkeys, dimebolin significantly improved the reduced task accuracies associated with long delay intervals.

CONCLUSIONS AND IMPLICATIONS

Here we demonstrated that dimebolin is able to improve components of working memory in monkeys and to induce a protracted response for at least 24 h after administration of a single dose.     

Clonidine enhances delayed matching-to-sample performance by young and aged monkeys

Clonidine, an alpha-2 noradrenergic agonist, has been shown to alter cognitive performance in humans and animals. Included among the evidence are studies which differ in their conclusions regarding the question of whether clonidine administration improves delayed response (DR) performance by nonhuman primates. The present results indicated that clonidine administration to both young and aged monkeys results in a modest performance improvement as measured by one of the commonly employed versions of DR performance-delayed matching-to-sample (DMTS). The clonidine-induced enhancement of DMTS had a duration of at least 24 h in both age groups.     

Memory-related task performance by aged rhesus monkeys administered the muscarinic M(1)-preferring agonist,talsaclidine

RATIONALE: Muscarinic-acetylcholine receptor agonists are yet to be used clinically for the treatment of Alzheimer's disease (AD) even though laboratory evidence continues to support the potential for such an approach. OBJECTIVES: The purpose of this study was to evaluate the M(1)-preferring agonist talsaclidine in aged monkeys for effects on working memory. METHODS: Three doses (0.6, 1.2, and 2.4 mg/kg, PO) of talsaclidine and two time intervals (45 min and 8 h) after drug administration were evaluated in seven aged rhesus macaques trained to perform a computer-assisted delayed matching-to-sample (DMTS) task. The relative effectiveness of talsaclidine was also compared with another M(1)-preferring agonist WAY-132983 that was previously studied in this laboratory. RESULTS: Talsaclidine improved DMTS accuracy only during sessions initiated 8 h after administration of one of the doses (i.e. 0.6 mg/kg). The drug's enhanced effectiveness at the 8-h time point relative to the 45-min time point was surprising in view of the fact that plasma concentrations were highest 45 min after administration. A higher dose of talsaclidine (4.7 mg/kg) resulted in side effects (lethargy and excessive drooling) in some animals. Individualized optimal doses of talsaclidine were associated with 7.4% and 10.6% improvement in overall (all trials averaged) DMTS accuracy during the 45 min and 8 h post-administration sessions, respectively. Under similar experimental conditions WAY-132983 increased DMTS accuracy by up to 15.6% above control levels. CONCLUSION: Both talsaclidine and WAY-132983 provide at least modest improvements in DMTS accuracy in aged monkeys at some doses; however, challenges remain regarding the achievement of an adequate level of efficacy and reliability while minimizing side effects with these compounds. The positive findings do, however, support further study of the potential use of direct muscarinic agonists in the treatment age-related disorders of memory function.     

Velnacrine maleate improves delayed matching performance by aged monkeys

Velnacrine maleate is a novel, orally active acetylcholinesterase inhibitor of the acridine class with a longer duration of action than physostigmine. Velnacrine has shown efficacy in the treatment of Alzheimer's disease and in improving both normal and experimentally impaired mnemonic function in animals and humans. To characterize this action further, the present study evaluated velnacrine for its ability to ameliorate the decline in short-term memory associated with aging in non-human primates at two time points after velnacrine administration: (1) 30 min and (2) 24 h. Initially, doses of 1, 2, 4, and 6 mg/kg, PO (free base corrected) were administered once to each of six aged (25–40 years), memory-impaired macaques that had been trained to perform a delayed matching-to-sample (DMTS) paradigm. The dose associated with the greatest improvement in session performance was administered three more times to the same individual. Four of the six monkeys showed improved DMTS performance during the repeated best dose phase (phase 2). Almost all of the improvement occurred during long-delay trials. Compared to placebo trials, velnacrine induced a significant improvement of long delay DMTS (58.0–66.7%, 13.4% of the placebo value). Long delay DMTS remained significantly improved during the test session conducted 24 h following velnacrine administration. Pharmacokinetic analysis following administration of 4 or 6 mg/kg velnacrine to three aged monkeys revealed peak plasma concentrations ranging from 27 to 166 ng/ml, 30–60 min after dosing. Six hours after dosing velnacrine plasma levels decreased to 5.1–11.8 ng/ml; and 24 h after dosing, velnacrine plasma levels were less than the limit of quantitation (5 ng/ml). Thus, the improved DMTS performance observed 0.5–1.5 h after velnacrine administration coincided with the peak absorption of the drug in plasma; however, the improved DMTS performance observed 24 h post-dosing was not explained by plasma levels. Possibly, the 24-h improvement was induced by some secondary process, such as long term potentiation.     

Profile of nicotinic acetylcholine receptor agonists ABT-594 and A-582941, with differential subtype selectivity, on delayed matching accuracy by young monkeys

ABT-594 and A-582941 are high affinity neuronal nicotinic acetylcholine receptor agonists with differential selectivity for the alpha4beta2 and the alpha7 subtypes, respectively. This study was designed to determine whether either compound, like nicotine also possesses cognitive-enhancing ability. The compounds were administered by intramuscular injection to young adult Rhesus monkeys trained to perform two versions of a computer-assisted delayed matching-to-sample (DMTS) task. ABT-594 (0.115-3.7 microg/kg) significantly improved DMTS accuracies, shifting the retention curve (accuracy-delay relationship) to the right in a parallel fashion. DMTS accuracy also was maintained during the sessions initiated 24h after compound administration. Because task accuracy was improved during short delay trials, a separate study was performed in which non-predictable distractors were inserted within the DMTS format to impair accuracy. The 0.115 microg/kg dose of ABT-594 almost completely reversed distractor-impaired performance associated with short delay trials. The alpha7 nAChR agonist, A-582941 (1.14-38 microg/kg) also significantly improved DMTS accuracies. The compound produced a significant improvement during long delay trials. The effect was twice as robust for long delay as compared with short delay trials and A-582941 was not as effective as ABT-594 in improving short delay trial accuracy. A-582941 also failed to sustain task improvement during sessions run 24h after dosing. These data are consistent with the ability of subtype-preferring nicotinic receptor agonists to enhance specific components of working memory and cognitive function, and they suggest that differential subtype selectivity could result in varied pharmacological response profiles.     

Differential improvement in memory-related task performance with nicotine by aged male and female rhesus monkeys

Central nicotinc acetylcholine receptors have been targeted for the development of novel treatments for memory deficits in Alzheimer's disease (AD) and other neurodegenerative disorders. Nicotine itself has been shown to improve memory-related task performance in aged animals and in AD patients. Administration of nicotinic receptor agonists to laboratory animals, and the effects of cigarette smoking in humans attributed to nicotine, have in many instances been shown to exert sexually dimorphic actions. Low doses (2.5-20 microg/kg, intramuscularly) of nicotine have been shown to improve the performance of an automated delayed matching-to-sample (DMTS) task in aged rhesus monkeys. The purpose of this study was to determine whether aged females receive the same level of benefit to the positive mnemonic action of nicotine as do males. In this study six male (21.7+/-1.2 years) and seven female (22.5+/-0.9 years) rhesus monkeys each received an ascending series of four doses of nicotine over 5 weeks. Most control parameters were similar between the two sexes, although task latencies were longer and more variable in the female subjects. The males maintained a significant improvement in task performance over the entire nicotine dose range. This level of improvement extended to 24 h after nicotine administration. Task accuracy by females appeared to improve only after they received the two higher doses of nicotine, and their responses exhibited considerable variability over the entire dose range. However, in calculating an individualized 'Best Dose', males and females exhibited a similar level of task improvement (15-30% above baseline). Therefore, aged female subjects may require a greater level of individualized treatment and perhaps higher doses of nicotinic agonists to achieve the maximal mnemonic benefit.     

Dose‐specific improvements in memory‐related task performance by rats and aged monkeys administered the nicotinic‐cholinergic antagonist mecamylamine

The centrally acting nicotinic‐cholinergic antagonist mecamylamine (mec) is well documented to produce amnestic effects in animals and humans. However, in certain circumstances the compound has enhanced performance of some memory‐related tasks in animals and further investigation of this paradoxical effect is warranted. The present study was designed to determine under what conditions mec would enhance memory‐task performance in rats and aged nonhuman primates. Mec (various doses) or saline was administered IP to rats tested in the Morris Water Maze (MWM), to rats trained to perform a delayed stimulus discrimination task (DSDT), and IM to aged rhesus monkeys (average age 24.6 years) trained to perform a delayed matching to sample task (DMTS). In rats, mec 1.0 mg/kg improved location of the hidden platform on day 1 of the MWM, but inhibited learning in subsequent trials, while several μg/kg doses improved DSDT accuracy. Further, some μg/kg doses of mec also improved accuracy in aged monkeys in DMTS at both 10 min and 24 h after administration. Mec had no effect on swim speeds in the MWM, response latencies in the DSDT, or on choice or response latencies in the DMTS task. Collectively, the results indicate that some doses of mec can mimic certain memory‐enhancing effects produced by nicotinic‐acetylcholine receptor agonists. It is not clear whether mec is acting as a partial agonist in this regard, or whether low‐level nicotinic antagonism produces a cellular response that is in some way analogous to nicotine‐induced receptor desensitization. Drug Dev. Res. 47:127–136, 1999. © 1999 Wiley‐Liss, Inc.     

Enhanced delayed matching performance in younger and older macaques administered the 5-HT4 receptor agonist, RS 17017

 Recent evidence indicates that the 5-HT₄ subtype of serotonin receptor may modulate central cholinergic activity in regions of the mammalian CNS important to memory such as the frontal cortex, hippocampus and amygdala. These receptors could represent targets for drugs designed for the symptomatic therapy of Alzheimer’s disease (AD) and other disorders of memory. In the present study, the binding activity of RS 17017 (previously described as a selective 5-HT₄ agonist) was assessed across a number of neurotransmitter receptors and binding sites, pharmacokinetic data were obtained, and the compound was evaluated in macaques for mnemonic effects via a computer-assisted delayed matching-to-sample task (DMTS). Binding data confirmed the 5-HT₄ selectivity of the compound, while pharmacokinetic results revealed low oral bioavailability, but a large volume of distribution of the compound. Significant and reproducible improvements in DMTS accuracy were observed after oral administration of the compound across a dose-effect series in both younger and older monkeys. The results suggest that RS 17017 offers a potential for memory enhancement in disorders involving cognitive decline, and are consistent with a role for central 5-HT₄ receptors in memory. Improvements in DMTS performance in aged monkeys may have particular implications for neurodegenerative conditions such as AD, whereas positive results in the younger monkeys indicate that RS 17017 (or similar compounds) may have additional potential in the therapeutics of memory disorders not necessarily associated with advanced age. Received: 29 May 1997 / Final version: 1 August 1997     

Cholinergic channel activator,ABT-418, enhances delayed-response accuracy in rats

The purpose of this study was to evaluate ABT-418, a recently developed isoxasole bioisostere of nicotine and cholinergic channel activator (ChCA), in rats trained to perform a delayed-response task, the Delayed Stimulus Discrimination Task (DSDT). In dose-effect studies, ABT-418 improved DSDT performance, while mecamylamine decreased accuracy of the task. The improvements afforded by optimal doses of ABT-418 were further substantiated by repeated administration on a separate occasion. Surprisingly, mecamylamine (1.0 mg/kg), when combined with optimal doses of ABT-418, failed to prevent improvements in accuracy of the task, as it had in a previous study with nicotine. The basis for this effect is unclear but may be related to the purported subtype selectivity of ABT-418. None of the drug-induced changes in DSDT accuracy was modality specific (i.e., whether the stimulus was the presented light or tone), and none of the drug manipulations produced significant changes in response latencies. Overall, the data confirm findings of previous rodent and nonhuman primate studies, which indicate that the nicotinic ligand has the potential to improve memory. Drug Dev. Res. 40:304–312, 1997. © 1997 Wiley-Liss, Inc.     

Enhancement of sustained attention performance by the nicotinic acetylcholine receptor agonist ABT-418 in intact but not basal forebrain-lesioned rats

  Rationale: Loss of telencephalic cholinergic projections has been postulated to contribute significantly to the cognitive decline associated with aging and dementia. Objective: The effects of the nicotinic acetylcholine receptor agonist ABT-418, a potential therapeutic drug for the treatment of the age- and dementia-associated cognitive disorders, were tested in an animal model of the cortical cholinergic deafferentation-induced impairments in sustained attention. Methods: Animals were trained in an operant task designed to test sustained attention performance. A partial loss of cortical cholinergic inputs was produced by infusions of 192 IgG-saporin into the basal forebrain. The effects of the systemic administration of ABT-418 (0.04, 0.13, 0.39 mg/kg) and the psychostimulant methylphenidate (0.2, 0.4, 0.8 mg/kg) were assessed. Results: Compared with sham-lesioned animals, this lesion resulted in a decrease in the relative number of hits while the relative number of correct rejections remained unaffected. Administration of ABT-418 significantly improved the relative number of hits. Furthermore, this effect of ABT-418 interacted with the effects of the lesion. Unexpectedly, this interaction was based on a significant enhancement of the performance of sham-lesioned animals while no effects were found in 192 IgG-saporin-lesioned animals. Administration of methylphenidate did not affect performance. Conclusions: While these data do not support the hypothesis that administration of ABT-418 attenuates the impairments in attentional performance that result from loss of cortical cholinergic inputs, they support previous notions about this drug’s ability to enhance cognitive processes in intact subjects. Received: 1 October 1998 / Final version: 5 December 1998     

Selective serotonin 5-HT<Subscript>2A</Subscript> receptor antagonist EMD 281014 improves delayed matching performance in young and aged rhesus monkeys

Rationale The superior cognitive effects of atypical neuroleptics over typical agents reported in the schizophrenia literature are often attributed to the more prominent antagonist activity of the atypical drugs at serotonin 5HT_2A receptors. However, atypical neuroleptics also have activity at many additional neurotransmitter receptors and few studies have specifically (and prospectively) tested the hypothesis that 5HT_2A antagonism alone results in enhanced cognitive function.Objectives The purpose of this study was to evaluate the selective 5-HT_2A antagonist, 7-{4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl}-1H-indole-3-carbonitrile HCl (EMD 281014) in young and aged monkeys in a test designed to assess working memory function.Methods Four oral doses (0.1, 1.0, 3.0, and 10.0 mg/kg) of EMD 281014 were evaluated in six young adult (mean age=9.2 years) and eight aged rhesus macaques (mean age=24.9 years) trained to perform a computer-assisted delayed matching-to-sample (DMTS) task.Results Depending on dose, EMD 281014 improved DMTS accuracy in young and aged monkeys primarily at either the medium or long retention intervals. While the latencies associated with incorrect color selections (choices latencies) tended to be longer than those associated with correct selections (particularly in the aged subjects) under baseline conditions, there were no significant effects of EMD 281014 on either sample or choice latencies in either age group. In addition, no adverse effects were observed across the range of doses evaluated in either cohort of animals.Conclusion These experiments, conducted in a non-human primate model, suggest that selective 5HT_2A antagonists such as EMD 281014 could offer therapeutic benefit to younger and older psychiatric patients by improving working memory function.This revised version was published online in January 2005 with corrections to the authors affiliations.     

Sex dimorphisms in the cognitive-enhancing action of the Alzheimer's drug donepezil in aged Rhesus monkeys

Brain acetylcholinesterase has been targeted for the development of novel treatments for memory deficits associated with Alzheimer's disease (AD) and other neurodegenerative disorders. The long-acting AChE inhibitor donepezil (Aricept) is used to improve memory and other aspects of cognition in AD patients. Because donepezil and other cholinesterase inhibitors are effective in a restricted population of AD patients, this study was to designed to determine whether aged females monkeys receive the same level of benefit to the mnemonic action of donepezil as do males. In this study, six male and six female rhesus monkeys (>20 years) who were proficient in the performance of a delayed matching-to-sample task each received an ascending series of four doses of donepezil (0.01-0.1 mg/kg) over 5 weeks. As a group, male subjects exhibited improvement in task accuracy across the three highest doses, with the maximum effect occurring after the 0.025 mg/kg dose. However, the females exhibited increased task accuracy only after the highest dose. When data were combined for sessions run 10 min after drug administration and for sessions run 24 h later (in the absence of drug), improvements in task accuracy were greater on average for males. Most of this difference was attributed to the fact that task accuracy by females actually declined during sessions run after the two lowest doses of donepezil. When task performance after donepezil was determined as the individualized Best Dose, as a group, males responded maximally to less than half the dose that was maximal for females. These findings support the concept that aged males and females respond differently to this class of agents, perhaps representing fundamental sex-related differences in memory processing, or in the manner that age affects these processes.     

ABT-594 improves performance in the 5-choice serial reaction time task under conditions of increased difficulty, sub-chronic dosing, and in poorly-performing subjects

Several studies have tested nicotinic receptor ligands in the 5-Choice Serial Reaction Time Task (5-CSRTT) with varying results. Some investigators have increased attentional demands by modifying task parameters or using aged or poor performing rats to observe treatment effects. This study examined the α4β2 nicotinic agonist ABT-594 in the 5-CSRTT using a variety of manipulations to determine optimal conditions for observing enhancement. ABT-594 had no effect in drug-naïve adult rats that self-initiated trials. Constant trial presentation decreased accuracy and omissions, with the latter significantly attenuated by acute administration of ABT-594 (0.019-0.062 μmol/kg). Sub-chronic treatment (0.019 μmol/kg) initially impaired drug-naïve subjects, but significant improvements in accuracy and decreased omissions were observed after 5 days of dosing. In 18-22 month-old rats, attentional demands were altered by interspersing blocks of trials with different stimulus durations. Acute ABT-594 (0.062 μmol/kg) enhanced accuracy performance in poor performing rats (< 70% accuracy) but not in those that performed well (> 80% accuracy), while omissions were decreased in both groups. Sub-chronic treatment with (0.019 μmol/kg) decreased omissions in all rats, but enhanced accuracy primarily in poor performing rats. These experiments demonstrate that an α4β2 nicotinic agonist can enhance attention, but accuracy effects may only be observed under specific conditions. Moreover, a reduction in omissions was more reliably observed than improvements in accuracy, resulting in a net increase in signals successfully detected.     

Effects of the cholinergic channel activator ABT-418 on cortical EEG: Comparison with (−)-nicotine

ABT-418[(S)-3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole] is a novel cholinergic channel activator (ChCA) and, like the prototypic ChCA (−)-nicotine, has cognition enhancing and anxiolytic effects. It appears, however, to have fewer central nervous system (CNS) or peripheral side effects compared to (−)-nicotine. The purpose of this study was to determine whether ABT-418 also is distinguishable from (−)-nicotine on neocortical EEG parameters affected by neuronal nicotinic acetylcholine receptor (nAChR) stimulation. Acute administration of ABT-418 (0.62–6.2 μmol/kg) did not have a significant effect on EEG amplitude using FFT frequency band analysis. In contrast, acute administration of (−)-nicotine (1.9 μmol/kg) produced a sustained EEG desynchronization which was reflected in significantly lowered EEG amplitude, an effect indicative of generalized cortical stimulation. Like (−)-nicotine, however, ABT-418 (0.62–6.2 μmol/kg) dose-dependently reduced the incidence of spontaneous 6–8 Hz neocortical spike wave discharges (high voltage spindles, HVS) in awake 12-month-old rats. The HVS effect of ABT-418 was blocked by the nicotinic antagonist mecamylamine (5.0 μmol/kg), consistent with the inhibition of HVS discharges being due to activation of nAChRs. (−)-Nicotine (6.0 μmol/kg/day) reduced total slow wave sleep (SWS) time during 15 days of subcutaneous infusion. In contrast, ABT-418 (14.0 μmol/kg/day) did not affect SWS time on day 1, but did reduce SWS by day 15 of infusion. On day 15, total SWS duration was reduced 26% and 20% by (−)-nicotine and ABT-418, respectively. The fewer effects of ABT-418 on neocortical EEG and sleep distinguishes this compound from (−)-nicotine. This study suggests that the previously reported behavioral effects ABT-418 may not be a simple consequence of neocortical activation, as ABT-418 did not induce EEG activation at doses which have been found to evoke behavioral responses. © 1996 Wiley-Liss, Inc.     

The α-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys

 In aged monkeys with naturally occurring catecholamine depletion, α-2 adrenergic agonists such as guanfacine have repeatedly been shown to improve dorsolateral prefrontal cortical function, as assessed by the spatial delayed response task. Both low (0.0001–0.001 mg/kg) and high (0.5 mg/kg) but not intermediate (0.01–0.05 mg/kg) doses of guanfacine improve spatial working memory performance in aged animals. However, it is not known whether guanfacine would similarly improve performance in young animals. In the present study, the effects of guanfacine on delayed response performance were characterized in seven young adult rhesus monkeys. Low doses of guanfacine (0.0001–0.01 mg/kg) had no effect on task performance, while high doses of guanfacine (0.1–0.7 mg/kg) significantly improved task performance. The highest doses produced mild sedation that was independent of drug effects on delayed response. The most effective dose of guanfacine was challenged with the α-2 antagonist idazoxan (0.1 mg/kg). This dose of idazoxan had no effect on task performance when given alone. Consistent with an α-2 mechanism, idazoxan significantly decreased delayed response performance in guanfacine-treated animals. These results support the hypothesis that delayed response performance in young intact animals can be improved through actions at α-2 adrenergic receptors. Received: 25 January 1997 / Final version: 15 October 1997     

Short-term memory in the rhesus monkey: effects of dopamine blockade via acute haloperidol administration.

The effects of dopaminergic blockade on recent or short-term memory (STM) were evaluated in test-sophisticated rhesus monkeys. Each monkey was tested under several doses of the antidopaminergic haloperidol (0.006 to 0.05 mg/kg), in an automated, delayed-response procedure. The same procedure and test apparatus had previously been used to demonstrate profound STM impairments in aged rhesus monkeys and strikingly similar deficits in young monkeys given the anticholinergic scopolamine. The results of this study do not support the notion that dopaminergic mechanisms play a critical role in primate STM. Although significant impairments in delayed-response accuracy were observed with the higher doses of haloperidol, this impairment was unrelated to the duration of the retention interval, implying a more general, non-mnemonic dysfunction. Since the qualitative nature of this deficit to dissimilar to, and not as specific as that previously found in aged rhesus monkeys (or young monkeys given scopolamine), it is suggested that age-related changes observed in the dopaminergic system are less likely to be responsible for the aged STM impairments than comparable age-related changes in the cholinergic system.     

Visual recognition memory in squirrel monkeys: effects of serotonin antagonists on baseline and hypoxia-induced performance deficits.

Cognitive deficits resulting from neuropathological brain changes such as Alzheimer's Disease or normal aging are most likely due to alterations in multiple neurotransmitter systems. While the majority of preclinical studies have focused on the effects of acetylcholine (ACh), it has been shown that activation of the serotonergic (5-HT) pathways in the central nervous system interferes with passive avoidance retention in rats. In contrast, decreased 5-HT activity has been shown to improve learning and memory in rats using similar procedures. In the present experiment, 5-HT antagonists were evaluated for their effects on performance in a delayed match to sample task (DMTS) in two groups of squirrel monkeys: one in which the baseline level of performance was low (less than 65% correct, N = 5; group 1) and another in which DMTS performance was high (greater than 80% correct, N = 3; group 2) but impaired by exposure to hypoxia. Initial parametric tests exposing group 2 to various levels of oxygen deprivation were conducted to determine optimal conditions for performance deficits. Each monkey in both normoxia (group 1) and hypoxia (group 2) served as his own control and received an individualized range of doses for each test compound. For both groups, ketanserin and mianserin, the 5-HT2-selective antagonists, produced dose-dependent increases in DMTS performance at 0.3-1.5 mg/kg PO and 0.05-1.5 mg/kg PO, respectively. Pirenperone, another 5-HT2-selective antagonist, was active in improving performance in group 1 at 0.001 to 0.2 mg/kg PO but was not effective against hypoxia-induced performance deficits.(ABSTRACT TRUNCATED AT 250 WORDS)