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     

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.     

The effects of huperzine A and IDRA 21 on visual recognition memory in young macaques

Nootropic agents or cognitive enhancers are purported to improve mental functions such as cognition, memory, or attention. The aim of our study was to determine the effects of two possible cognitive enhancers, huperzine A and IDRA 21, in normal young adult monkeys performing a visual memory task of varying degrees of difficulty. Huperzine A is a reversible acetylcholinesterase (AChE) inhibitor, its administration results in regionally specific increases in acetylcholine levels in the brain. In human clinical trials, Huperzine A resulted in cognitive improvement in patients with mild to moderate form of Alzheimer's disease (AD) showing its potential as a palliative agent in the treatment of AD. IDRA 21 is a positive allosteric modulator of glutamate AMPA receptors. It increases excitatory synaptic strength by attenuating rapid desensitization of AMPA receptors and may thus have beneficial therapeutic effects to ameliorate memory deficits in patients with cognitive impairments, including AD. The present study evaluated the effects of the two drugs in normal, intact, young adult monkeys to determine whether they can result in cognitive enhancement in a system that is presumably functioning optimally. Six young pigtail macaques (Macaca nemestrina) were trained on delayed non-matching-to-sample task, a measure of visual recognition memory, up to criterion of 90% correct responses on each of the four delays (10s, 30s, 60s, and 90s). They were then tested on two versions of the task: Task 1 included the four delays intermixed within a session and the monkeys performed it with the accuracy of 90%. Task 2 included, in each of 24 trials, a list of six objects presented in succession. Two objects from the list were then presented for choice paired with novel objects and following two of the four delays intermixed within a session. This task with a higher mnemonic demand yielded an average performance of 64% correct. Oral administration of huperzine A did not significantly affect the monkeys' performance on either task. However, a significant negative correlation was found between the baseline performance on each delay and the change in performance under huperzine A, suggesting that under conditions in which the subjects were performing poorly (55-69%), the drug resulted in improved performance, whereas no improvement was obtained when the baseline was close to 90%. In fact, when the subjects were performing very well, huperzine A tended to reduce the performance accuracy, indicating that in a system that functions optimally, the increased availability of acetylcholine does not improve performance or memory, especially when the animals are close to the maximum performance. In contrast, oral administration of IDRA 21 significantly improved performance on Task 2, especially on the longest delay. This finding supports the potential use of this drug in treatment of cognitive and memory disorders. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

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.     

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.     

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.     

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.     

Mechanism and impact of allosteric AMPA receptor modulation by the ampakine CX546.

Glutamate release at central synapses is transduced into a characteristic fast postsynaptic response by AMPA receptor gating and agonist affinity. The effect of two classes of modulators of AMPA receptor desensitization, the benzothiadiazides (cyclothiazide and IDRA 21) and the benzoylpiperidines (CX516 and CX546), were studied on gating kinetics of recombinant, native AMPA receptors and on synaptic currents. CX546 reduced the degree of desensitization more potently than CX516 or IDRA 21, but not as efficiently as cyclothiazide. In presence of CX516/CX546, desensitization of GluR2(flip) receptors was inhibited more than of GluR1(flip), whereas they had no effect upon response shape or conductance. CX546 increased agonist affinity threefold on nondesensitizing AMPA receptors by slowing agonist unbinding. Analysis of modulatory action suggests that, in contrast to cyclothiazide or IDRA 21, the Ampakine CX546 binds specifically to the agonist bound nondesensitized receptor, most likely acting by destabilizing the desensitized receptor conformation. All modulators tested showed higher efficiency on native receptors as compared to homomeric receptors. At the glutamatergic synapse, evoked synaptic amplitudes were weakly potentiated, while EPSC decay was slowed by nearly a factor of three in the presence of CX546 or cyclothiazide. In the presence of CX546, the current induced by short pulses of glutamate from recombinant GluR2 receptors decayed with a time course that was approximately twentyfold faster than EPSCs. The unique properties of CX546 may be beneficial for therapeutical use.     

Acute effects of physostigmine on complex operant behavior in rhesus monkeys

The effects of physostigmine were assessed in rhesus macaques using behavior in several complex tasks designed to model aspects of time estimation [temporal response differentiation (TRD)], short-term memory [delayed matching-to-sample (DMTS)], motivation [progressive ratio (PR)], learning [incremental repeated acquisition (IRA)], and color and position discrimination [conditioned position responding (CPR)]. The endpoints monitored included percent task completed, response rate, and accuracy. Physostigmine sulphate (0.001–0.056 mg/kg) significantly decreased the percentage of task completed and response rate in each task at 0.03 and 0.056 mg/kg. Accuracy in the TRD task was significantly decreased at 0.03 and 0.056 mg/kg, whereas accuracy in the CPR and IRA tasks was significantly decreased only at 0.056 mg/kg. DMTS accuracy was not significantly affected at any dose tested. A significant increase in accuracy was noted in learning task performance at the 0.01 mg/kg dose, although only for one-lever response sequences. Performance enhancements were not seen in any other task. These results indicate that in monkeys, low doses of physostigmine may facilitate acquisition or learning of simple one-lever spatial tasks while not significantly altering the acquisition of similar but more complex tasks. Impaired task performance at high doses may be more reflective of cholinomimetic side effects (tremor and hypothermia) that affect response rate than a central or “cognitive” impairment.     

Benzodiazepine self-administration in rhesus monkeys: estazolam, flurazepam and lorazepam

The ability of three benzodiazepines to maintain self-administration behavior was studied in rhesus monkeys using a substitution procedure. Lever-press responding was maintained in six monkeys under a fixed-ratio schedule of IV pentobarbital delivery in daily sessions of 3 hr duration. Each of several doses of flurazepam, lorazepam and estazolam as well as saline and vehicle was periodically substituted for 4-13 consecutive sessions. Between dose or vehicle substitutions, responding was maintained by pentobarbital. All six monkeys self-administered flurazepam above vehicle or saline levels. In addition four of five monkeys tested with lorazepam and four of six tested with estazolam self-administered at least one dose of drug above control levels. These results indicate that self-administration performance can be reliably maintained in rhesus monkeys by certain benzodiazepines under appropriate experimental conditions.     

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.     

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.     

Acute effects of chlorpromazine in a monkey operant behavioral test battery.

The effects of acute chlorpromazine treatment were assessed using a complex operant test battery (OTB) containing five tasks thought to depend upon processes associated with short-term memory and attention [delayed-matching-to-sample (DMTS)], color and position discrimination [conditioned position responding (CPR)], motivation [progressive ratio (PR)], time perception [temporal response differentiation (TRD)], and learning [incremental repeated acquisition (IRA)]. Adult male rhesus monkeys were tested 15 min after IV injection of saline or chlorpromazine (0.010, 0.030, 0.100, or 0.175 mg/kg). Behavioral endpoints measured included percent task completed, response rate or latency, and response accuracy. The order of task sensitivity to disruption by chlorpromazine was TRD = PR = IRA = DMTS = CPR in which sensitivity was defined as a significant alteration in any aspect of task performance. Chlorpromazine slowed response rates in all tasks except TRD but did decrease accuracy in that task. These effects were similar to those noted in previous studies of acute chlorpromazine treatment. Specific motoric effects suggested decreased task initiation at doses that left general motor ability intact. This finding is similar to that noted in parkinsonism caused by chronic chlorpromazine treatment.     

Delayed match-to-sample performance in African green monkeys (Chlorocebus aethiops sabaeus): effects of benzodiazepine, cholinergic, and anticholinergic drugs

Delayed match-to-sample (DMTS) procedures are among the most commonly used attention and memory tasks in behavioral pharmacology and have been utilized in a variety of species. Although macaque species such as the rhesus and cynomolgus macaque are often used for such studies, availability and disease transmission raise concerns over their use. The present study investigated whether the African green monkey might function as a suitable alternative by evaluating operant performance on a DMTS task and comparing this species' response to some commonly used drugs (0.025-0.075 mg/kg physostigmine, 0.0033-0.03 mg/kg scopolamine, 0.014-0.44 mg/kg atropine, 0.125-1.0 mg/kg midazolam, and 0.125-2.0 mg/kg diazepam) to the responses previously reported in macaques. Results demonstrated that African green monkeys are capable of learning and performing a DMTS task, and dose-effect functions for behavioral pharmacology were quite similar to those reported for rhesus macaques and other nonhuman primate species. Thus, the African green monkey may function as a suitable alternative to macaque species in behavioral pharmacology research.     

Opposing effects of AMPA and 5-HT1A receptor blockade on passive avoidance and object recognition performance: correlation with AMPA receptor subunit expression in rat hippocampus

It has been suggested that antagonists at serotonin 5-HT1A receptors may exert a procognitive effect by facilitating glutamatergic neurotransmission. Here we further explored this issue by looking for the ability of a 5-HT1A antagonist to prevent the learning deficit induced by AMPA receptor blockade in two behavioural procedures in rats, and for concomitant molecular changes presumably involved in memory formation in the hippocampus. Pretraining administration of the competitive AMPA receptor antagonist, NBQX, produced a dose-related retention impairment in a passive avoidance task 24h later, and also impaired retention in a novel object recognition test when an intertrial interval of 3h was selected. Pretreatment with the selective 5-HT1A receptor antagonist, WAY-100635, prevented the learning deficit induced by NBQX in the two behavioural procedures. In biochemical studies performed on rat hippocampus after the retention tests, we found that learning increased the membrane levels of AMPA receptor GluR1 and GluR2/3 subunits, as well as the phosphorylated forms of GluR1, effects that were abolished by NBQX administration before the training session. Pretreatment with WAY-100635 counteracted the NBQX effects and restored the initial learning-specific increase in Ca2+/calmodulin-dependent protein kinase II (CaMKII) function and the later increase in GluR2/3 and phosphorylated GluR1 surface expression. Moreover, administration of WAY-100635 before object recognition training improved recognition memory 24h later and potentiated the learning-associated increase in AMPA receptor subunits. The results support the proposed utility of 5-HT1A antagonists in the treatment of cognitive disorders.     

A critical examination of best dose analysis for determining cognitive-enhancing potential of drugs: studies with rhesus monkeys and computer simulations

Rationale

Best dose analysis involves identifying the dose associated with the greatest improvement in performance for each subject and comparing performances associated with these individually determined best doses to control performances.

Objectives

The current experiments were conducted to examine whether significant best dose effects might result from the selective analysis of data rather than an actual drug effect.

Methods

Experiment 1 examined the effects of nicotine and methylphenidate on delayed matching-to-sample (DMTS) and self-ordered spatial search (SOSS) performances in rhesus monkeys (DMTS: n?=?7; SOSS: n?=?6) to determine the validity and reliability of best dose effects. Experiment 2 used Monte Carlo computer simulations to estimate the likelihood of obtaining a significant outcome when the best dose method was applied to randomly generated data sets for which no difference existed.

Results

Significant effects were obtained when the best dose analysis was applied to performances from nondrug sessions, and best dose performances were not significantly different from the best nondrug performances. The doses identified as best doses from two nicotine dose–response curve determinations were unrelated, and the improvement associated with the best dose observed during the first dose–response curve determination was not reliable when the dose was administered repeatedly. Finally, there was a high likelihood of obtaining a statistically significant difference when no real difference existed.

Conclusions

Best dose analysis for the identification of potential therapeutic agents should be replaced by single-subject designs.     

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.     

Assessment of the abuse potential of acetorphan, an enkephalinase inhibitor

The discriminative stimulus properties, reinforcing effects and physical dependence potential of acetorphan, a parenterally-active enkephalinase (E.C. 3.4.21.11) inhibitor, were assessed in the present studies. Rats trained to discriminate 2 mg/kg morphine from saline did not generalize to acetorphan at any dose tested (5-50 mg/kg). Acetorphan also had minimal reinforcing effects in rhesus monkeys. When acetorphan was substituted for cocaine, one dose (300 micrograms/kg per inj.) maintained responding somewhat above the range of vehicle values in only two of the four monkeys tested. In physical dependence studies, acetorphan also failed to produce opioid-like effects. In morphine-dependent monkeys and rats, acetorphan failed to suppress withdrawal. Additionally, there were no overt withdrawal signs observed following the termination of chronic acetorphan infusion in the rat. Together, these results indicate that acetorphan appears to have minimal abuse potential.     

Effects of morphine sulfate on operant behavior in rhesus monkeys

The acute effects of morphine sulfate were assessed using a battery of complex food-reinforced operant tasks that included temporal response differentiation (TRD, n = 5), delayed matching-to-sample (DMTS, n = 6), progressive ratio (PR, n = 9), incremental repeated acquisition (IRA, n = 9), and conditioned position responding (CPR, n = 7) tasks. Performance in these tasks is thought to depend upon specific brain functions such as time perception (TRD), learning (IRA), short-term memory and attention (DMTS), color and position discrimination (CPR), and motivation to work for food (PR). Morphine sulfate (0.1-5.6 mg/kg IV), given 15 min presession, produced significant dose-dependent decreases in the number of reinforcers obtained in each task. Response accuracy was significantly decreased at doses greater than or equal to 1.0 mg/kg for TRD when compared to saline injections. Accuracy was not consistently affected in any other task in the test battery. Response rates decreased or response latencies increased significantly at doses of 1.0 mg/kg and above for the PR task, at 3.0 mg/kg and above for the IRA and TRD tasks, and only at the highest dose 5.6 mg/kg in the CPR and DMTS tasks. Percent task completed was decreased following doses of 1.0 mg/kg and higher for the IRA, PR and TRD tasks, at doses of 3.0 mg/kg and higher for the DMTS task, and at the high dose of 5.6 mg/kg for the CPR task. These results indicate that in monkeys, the performance of operant tasks designed to model learning ability (IRA), time perception (TRD) and motivation (PR) are more sensitive to the disruptive effects of morphine than is performance in tasks designed to model short-term memory and attention (DMTS). The task which models color and position discrimination (CPR) was the least sensitive to disruption by morphine.