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.     

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.     

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.     

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.     

The scopolamine-reversal paradigm in rats and monkeys: the importance of computer-assisted operant-conditioning memory tasks for screening drug candidates

RATIONALE: The scopolamine-reversal model is enjoying a resurgence of interest in clinical studies as a reversible pharmacological model for Alzheimer's disease (AD). The cognitive impairment associated with scopolamine is similar to that in AD. The scopolamine model is not simply a cholinergic model, as it can be reversed by drugs that are noncholinergic cognition-enhancing agents. OBJECTIVES: The objective of the study was to determine relevance of computer-assisted operant-conditioning tasks in the scopolamine-reversal model in rats and monkeys. MATERIALS AND METHODS: Rats were evaluated for their acquisition of a spatial reference memory task in the Morris water maze. A separate cohort was proficient in performance of an automated delayed stimulus discrimination task (DSDT). Rhesus monkeys were proficient in the performance of an automated delayed matching-to-sample task (DMTS). RESULTS: The AD drug donepezil was evaluated for its ability to reverse the decrements in accuracy induced by scopolamine administration in all three tasks. In the DSDT and DMTS tasks, the effects of donepezil were delay (retention interval)-dependent, affecting primarily short delay trials. Donepezil produced significant but partial reversals of the scopolamine-induced impairment in task accuracies after 2 mg/kg in the water maze, after 1 mg/kg in the DSDT, and after 50 mug/kg in the DMTS task. CONCLUSIONS: The two operant-conditioning tasks (DSDT and DMTS) provided data most in keeping with those reported in clinical studies with these drugs. The model applied to nonhuman primates provides an excellent transitional model for new cognition-enhancing drugs before clinical trials.     

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.     

Pre-clinical evaluation of effects of acetylcholinesterase inhibition on the cerebral cholinergic neuronal system and cognitive function: PET study in conscious monkeys

The present review described the effects of acetylcholinesterase (AChE) inhibition on the cerebral cholinergic neuronal system in the conscious monkey brains with PET. Somatosensory stimulation induced a regional cerebral blood flow (rCBF) response, revealed with [(15)O]H(2)O, in the contralateral somatosensory cortex. Scopolamine resulted in an abolished rCBF response to stimulation, and this abolished rCBF response was recovered by physostigmine, donepezil, and tacrine. Donepezil suppressed AChE activity, analyzed by [(11)C]MP4A, in all cortical regions in a dose-dependent manner. AChE inhibition by donepezil resulted in a dose-dependent increase in acetylcholine levels in the prefrontal cortex as measured by microdialysis. Binding of [(11)C](+)3-PPB to cortical muscarinic receptors was reduced by donepezil, probably in a competitive inhibition manner. Aged monkeys showed less reduction of [(11)C](+)3-PPB binding than young animals. As evaluated by an oculomotor delayed response task, aged monkeys showed impaired working memory performance compared to young monkeys, and the impaired performance was partly improved by the administration of donepezil, due to the facilitation of the cholinergic neuronal system by AChE inhibition by donepezil. These results demonstrated that PET imaging with specifically labeled compounds in combination with microdialysis and a behavioral cognition task could be a useful tool for pre-clinical evaluation of novel drugs.     

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. Received: 10 September 1996 / Final version: 7 November 1996     

Effects of an enkephalin analog on complex learning in the rhesus monkey.

Facilitation of the learning of a discrimination reversal task for a reward of food was found in rhesus monkeys after subcutaneous administration of a potent pentafluorinated enkephalin analog. (D-Ala2)-F5-Phe4-enkephalin-NH2. General activity, short-term memory, startle, and analgesia, however, were not significantly affected. In a within-subject design, each of 6 monkeys (3 males and 3 females) received each of 5 doses of the enkephalin analog (0.1, 1, 10, 100, and 1,000 microgram/kg). One daily injection was made for 7 consecutive days, including pre- and posttests on the first and last days with the diluent control. The enkephalin doses, with the exception of the 0.1 microgram/kg level, produced significantly faster learning than the diluent. Some sex differences were suggested by the data, but these effects are difficult to interpret. The results suggest that relatively small amounts of this analog given systematically can exert a reliable effect on a complex behavior such as reversal learning at doses devoid of opiate effects, due perhaps to enhanced cognitive flexibility rather than improvement in short-term memory or association formation.     

Treatment with the noradrenergic alpha-2 agonist clonidine, but not diazepam, improves spatial working memory in normal young rhesus monkeys.

Noradrenergic alpha-2 agonists such as clonidine and guanfacine improve working memory performance in aged monkeys. Guanfacine also improves cognition in young monkeys, but there are conflicting reports of the effects of clonidine in young adult human and nonhuman primates. In the present study, high doses of clonidine (0.02-0.1 mg/kg) significantly improved performance of the delayed response task, a test of spatial working memory, in young adult monkeys. Lower doses (0.0001-0.01 mg/kg), similar to those used in human studies (0.001-0.003 mg/kg), had no effect on task performance. In contrast, monkeys experimentally depleted of catecholamines by chronic reserpine treatment have been improved by both dose ranges. These results provide further support for the hypothesis that alpha-2 agonists improve cognition via actions at post-synaptic alpha-2 receptors, and suggest that conflicting results with clonidine in previous studies of prefrontal cortical function may result from insufficient dosage.     

Scopolamine effects on Hamilton search task performance in monkeys

The Hamilton search task, a test of spatial memory, was given to adult monkeys after administration of scopolamine. Three monkeys had been exposed to lead during development and two were controls. The task consisted of opening eight boxes, one per trial, for food reinforcement, with a 20 second delay between trials. The monkey had to remember which boxes it had already opened and avoid them to obtain the remaining reinforcements. Percent correct response, openings-to-repeat, trials per session, repetitive index and response latency were measured. There were no significant lead-related effects. Significant scopolamine-induced deficits were detected with four of the measures. The low doses of scopolamine (1-3 micrograms/kg) did not affect response accuracy, but 15 and 30 micrograms/kg caused impairments. Only 30 micrograms/kg substantially increased latency. This is like other memory tests in monkeys and rats in that it is sensitive to anticholinergic challenge. Cognitive performance deficits were detected at a dose (15 micrograms/kg) which did not cause increased response latency. The Hamilton search task is a flexible and sensitive memory task for monkeys, analogous to the radial arm maze in the rat.     

Differential effects of bremazocine on oral phencyclidine (PCP) self-administration in male and female rhesus monkeys

Sex differences exist in many phases of drug abuse, but few studies have focused on sex differences in drug abuse treatment. In this study, the effects of bremazocine, a kappa-opioid receptor agonist, were compared in age-matched male and female rhesus monkeys self-administering orally delivered phencyclidine (PCP). Bremazocine (0.00032. 0.001, and 0.0025 mg/kg, intramuscular) was administered for 5 consecutive days. 15 min prior to daily 3-hr sessions when PCP (0.25 mg/ml) and water were available under concurrent fixed-ratio schedules. Bremazocine dose-dependently decreased PCP-maintained responding and consumption (mg/kg) in males and females, and these measures were suppressed at a lower bremazocine dose in females than in males. The percentage reduction in PCP-maintained responding and intake (mg/kg) was significantly greater in females than it was in males at the low and middle doses of bremazocine, suggesting that females may be more responsive to kappa agonist treatment than males.     

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.     

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     

A reversible model of the cognitive impairment associated with schizophrenia in monkeys: Potential therapeutic effects of two nicotinic acetylcholine receptor agonists

In monkeys proficient in the performance of a computer-assisted delayed response task, administration of sub-sedative doses of ketamine significantly impaired task performance after the 2 mg/kg dose, producing a decrease in accuracies across all four delay intervals. Ketamine elicited occasional and inconsistent increases in task latencies. But in general processing speed was not dramatically affected by the test dose. Pretreatment with the α7 nicotinic receptor agonist GTS-21 (DMXB-A) [3-[(3E)-3-[(2,4-dimethoxyphenyl) methylidene]-5,6-dihydro-4H-pyridin-2-yl]pyridine] produced a dose-dependent attenuation of ketamine-induced decreases in task accuracies. In fact, the best dose of GTS-21 completely reversed the effects of ketamine. The nicotine metabolite cotinine is a cognitive-enhancer, and active in models predictive of antipsychotic activity. Pretreatment with cotinine did not reverse the task deficits produced by ketamine, and selection of a best dose was necessary to show the activity of cotinine. However, the best dose of cotinine, like GTS-21, completely reversed the ketamine-induced task deficits. Task accuracies were increased relative to their non-ketamine baselines during sessions run 24 h later. The cotinine–ketamine order of administration was reversed to provide a more clinically relevant model, and cotinine post-treatment regimen produced a clear reversal of the ketamine-induced task deficits. The protracted task improvement also was still evident. The DMTS task impairment induced by ketamine was capable of being completely reversed by two compounds that are known to improve working memory and cognition. The model could provide a means of late stage preclinical evaluation of new compounds that address the cognitive impairment associated with major psychotic disease.     

Sex differences in the escalation of oral phencyclidine (PCP) self-administration under FR and PR schedules in rhesus monkeys

Rationale Studies with male rats indicate that long access (LgA) vs short access (ShA) to i.v. cocaine and heroin self-administration leads to an escalation of drug intake and a subsequent upward shift of the dose-response function.Objective The purpose of this experiment was to extend these results to male and female rhesus monkeys and oral phencyclidine (PCP) self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules.Methods Adult rhesus monkeys (seven females and nine males) orally self-administered PCP (0.25 mg/ml) and water under concurrent FR 16 FR 16 schedules during daily ShA 3-h sessions. Since females weighed less than males, each liquid delivery (0.6 ml) represented a higher unit dose mg/kg for females than males, but drug concentration mg/ml remained constant. Concurrent PR PR schedules were then used to obtain a concentration-response function (0.125, 0.25, 0.5, and 1.0 mg/ml). Next, PCP and water were available during LgA 6-h sessions under concurrent FR 16 FR 16 schedules for 21 days. The monkeys were then retested under the concurrent FR 16 FR 16 and PR PR conditions during ShA sessions.Results Under the initial ShA concurrent FR 16 FR 16 schedules, females and males did not differ on PCP deliveries or intake (mg/kg); however, during LgA, males and females had more PCP deliveries compared with ShA. During LgA, males exceeded females in PCP deliveries, but females were higher than males in mg/kg PCP intake. Also, PCP (but not water) deliveries and mg/kg PCP intake significantly increased from the first 3 days to the last 3 days of the 21-day LgA period in both males and females. The subsequent ShA FR 16 FR 16 performance did not differ by sex, but it was significantly elevated above the first ShA period in both sexes. The concentration-response function for PCP break point under the PR PR schedules and PCP intake (mg/kg) were significantly shifted upward during the second (vs first) ShA period, and females mg/kg intake significantly exceeded males.Conclusions Male and female rhesus monkeys both showed escalation of PCP self-administration during LgA to PCP and during ShA that occurred after (vs before) LgA. Both showed vertical upward shifts in the concentration×intake (mg/kg) function under the PR schedule, and females exceeded males on this measure. These findings with PCP and monkeys are consistent with vertical upward shifts of cocaine dose-response functions in previous escalation studies in male rats and reports of sex differences (F>M) during several other phases of drug abuse.     

Effects of nicotinic agonists and antagonists on spatial working memory in normal adult and aged rats

The present study had two goals (1) to examine the effects of treatments with nicotinic agonist (nicotine) and antagonist (mecamylamine) on working memory in normal adult rats (14 months of age), and (2) to determine if treating aged (36 to 42 months of age), memory-impaired rats with nicotine could improve their memory function. Memory testing was carried out using a delayed non-matching to position paradigm in a T-maze. Rats were trained to run down one arm of the maze (e.g., right) on an information run and then, after a variable memory delay period of 10, 90, or 180 sec, run down the other arm (e.g., left). In normal adult rats after water injection, memory accuracy was inversely related to memory delay (> 90, 75, and 67% accuracy at the 10, 90, and 180 sec delays, respectively). Administration of nicotine (0.1 or 0.4 mg/kg), or mecamylamine (2.5 or 5 mg/kg), or combinations of these drugs had no significant effects on memory in these rats. However, mecamylamine alone or in combination with nicotine reduced running speed in the T-maze in normal adults, indicating that the drugs did produce some behavioral effects. In aged rats, memory accuracy after water injection was much lower than that of younger adults, averaging 64, 57, and 50% at 10, 90, and 180 sec delays. Interestingly, nicotine injections of 0.1 or 0.4 mg/kg resulted in highly significantly improved accuracy in the memory task. The deficit in memory accuracy in aged rats, evident even at the shortest delay period (10 sec), suggests that the rats may have had impairments in attention or visual discriminatory ability. If this is so, then the beneficial effects of nicotine observed in this study may be more related to its effects on attention rather than memory directly. © 1994 Wiley-Liss, Inc.     

Comparative effects of the α7 nicotinic partial agonist,S 24795, and the cholinesterase inhibitor,donepezil, against aging-related deficits in declarative and working memory in mice

Introduction The comparative effects of a newly described specific α7 nAChR partial agonist, S 24795, and a cholinesterase inhibitor, donepezil, currently used as a symptomatic Alzheimer’s disease treatment were studied in two mouse models of aging-related memory deficits. Materials and methods We employed radial arm-maze paradigms assessing short-term working memory (STWM, experiment A) and mnemonic flexibility, a cardinal property of long-term declarative (LTDM, experiment B). Both compounds were administered daily at 0.3 and 1 mg/kg subcutaneously (∼3 weeks). Results In the STWM experiment, vehicle-treated aged mice displayed a severe and persistent deficit in the retention of successive arm visits in comparison to younger controls. S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at 0.3 mg/kg (but not 1 mg/kg) exerted beneficial effects on this deficit: The performance of aged mice treated with these drugs remarkably increased across the testing days and almost reached young adult performance level. In the critical test trials of memory flexibility (i.e., LTDM), in experiment B, S 24795 at 1 mg/kg (trends at 0.3 mg/kg) and donepezil at the dose of 1 mg/kg (but not 0.3 mg/kg) improved aged mice performance. Conclusion This preclinical demonstration that S 24795 restored specific age-related memory deficits with as much efficacy as donepezil adds to recent literature in highlighting the potential interest of an α7 nAChR drug as a symptomatic AD therapeutic.     

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.     

Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer’s disease

Rationale Acetylcholinesterase inhibitors are widely used for the treatment of patients with Alzheimer’s disease (AD). However, the relationship between the capacity of such drugs to ameliorate the symptoms of AD and their ability to alter the underlying disease process is not well understood. Transgenic mice that overexpress the human form of amyloid precursor protein and develop deposits of β-amyloid (Aβ) and behavioral deficits during adulthood are useful for investigating this question. Objectives The effects of administration of two acetylcholinesterase inhibitors, physostigmine and donepezil, on Aβ plaque formation and memory-related behaviors were investigated in the Tg2576-transgenic mouse model of AD. At 9–10 months of age, Tg2576-transgenic [Tg(+)] mice develop Aβ plaques and impairments on paradigms related to learning and memory as compared to transgene-negative [Tg(−)] mice. Methods Beginning at 9 months of age, increasing doses of physostigmine (0.03, 0.1, and 0.3 mg/kg), donepezil (0.1, 0.3, and 1.0 mg/kg), or saline were administered over 6 weeks to cohorts of Tg(+) and Tg(−) mice. Performance on tests of spatial reversal learning and fear conditioning was evaluated at each drug dose throughout the period of drug administration. After drug administration was completed, the animals were sacrificed and Aβ plaque number was quantified. Results Administration of physostigmine and donepezil improved deficits in contextual and cued memory in Tg(+) mice so that their behaviors became more similar to Tg(−) mice. However, administration of physostigmine and donepezil tended to improve cued memory and deficits in spatial learning in both Tg(+) and Tg(−) mice. Physostigmine administration demonstrated more prominent effects in improving contextual memory than donepezil, while donepezil was more effective than physostigmine in improving deficits in the acquisition of the spatial memory paradigm. Administration of neither drug altered the deposition of Aβ plaques. Conclusions These studies suggest that acetylcholinesterase inhibitors can ameliorate memory deficits in Tg(+) mice without necessarily altering the deposition of Aβ plaques. Tg2576 mice may be useful as an animal model to further investigate the mechanisms by which aceytlcholinesterase inhibitors improve cognitive deficits in patients with AD.