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     

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.     

Tyrosine ameliorates a cold-induced delayed matching-to-sample performance decrement in rats

Exposure to cold stress has been shown to impair short-term, or working, memory which may be related to a reduction in brain catecholamines. Administration of the catecholamine precursor tyrosine may alleviate a cold-stress-induced memory impairment by preventing a deficit in brain catecholamine levels. To test this hypothesis, eight rats performed a delayed matching-to-sample (DMTS) task at an ambient temperature of either 2°C (cold) or 22°C, following intraperitoneal administration of saline or tyrosine (50, 100 or 200 mg/kg). Rats administered saline prior to 22°C exposure demonstrated a characteristic delay gradient in which accuracy decreased as the delay interval between sample and comparison stimuli increased from 1 to 16 s. Consistent with previous research, and relative to 22°C exposure sessions, matching accuracy during 2°C exposure sessions was reduced, which is attributed to the effect of cold on short-term, or working, memory. In particular, during cold exposure sessions matching accuracy was significantly reduced at the longer delay intervals, relative to matching accuracy at 22°C. Additional analysis of cumulative matching errors within sessions showed that during exposure to cold, errors occurred at a constant rate throughout the session, indicating rats' performance was equally debilitated by the stressor over the entire session. During cold exposure sessions, the higher doses of 100 and 200 mg/kg tyrosine significantly improved overall matching accuracy relative to saline, but did not completely reverse the effect of cold exposure, as overall matching accuracy did not increase entirely to levels obtained at 22°C. A linear slope analysis of cumulative errors within cold sessions indicated that, relative to saline, the higher doses of tyrosine also significantly reduced errors, but did not reduce these errors to levels obtained during exposure to 22°C. It appears that supplemental tyrosine was effective in partially ameliorating the effects of cold stress on DMTS performance, possibly by preventing a cold-stress-induced reduction in brain catecholamine levels.Experiments reported herein were conducted according to the principles set forth in the Guide for the Care and Use of Laboratory Animal Resources, National Research Council, DHHS Publication (NIH) 86-23, (1985). The opinions and assertions contained herein are those of the authors and are not to be construed as official or reflecting the views of the Navy Department or the Naval Service at large. The research was supported by Naval Medical Research and Development Command research and technology work units 61152N.MR04120.00D.1383 and 62233 N.MR03C30.004-1002.This research was conducted while the first author held a National Research Council-NMRI Research Associateship     

Protracted cognitive effects produced by clonidine in Macaca nemestrina performing a delayed matching task

Introduction

The α₂-adrenergic receptor agonist clonidine was examined for its ability to improve working memory in monkeys.

Materials and methods

Clonidine (0.116–34.8 μg/kg) was administered to six pigtail macaques in their performance of a computer-assisted delayed matching-to-sample (DMTS) task.

Results and discussion

During DMTS sessions initiated 1 hour after dosing, there was a slight improvement in mean task accuracy (long delay trials; 0.116-μg/kg). On the following day, there was continued and added improvement in accuracies associated with the long delay trials. On the day following 1.16-μg/kg, the entire memory retention curve was shifted to the right of vehicle. When the animals were again tested 48 hours after dosing (no pretreatment), these two patterns of task enhancement were continued and enhanced. Mean task accuracy associated with long delay trials was significantly increased by 14.2% trials correct when animals were originally treated with 0.116-μg/kg of clonidine. Mean task accuracy associated with medium delay trials was significantly increased by 11.8% trials correct when animals were treated with 1.16-μg/kg. On the sixth day after clonidine, task accuracies were still significantly improved during medium delay trials after 0.116-μg/kg. Median sample and choice latencies were not significantly influenced by clonidine treatment. These findings are consistent with the ability of clonidine to induce a protracted improvement in aspects of working memory.

Conclusion

Early (attentional) and late (retention) components of memory appeared to be differentially sensitive to the dose of clonidine. Central α₂-adrenergic receptors should be considered legitimate drug targets for future compound development for cognition enhancement.     

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.     

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.     

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.     

Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning

Sodium cyanide (NaCN) is a commonly and widely used industrial and laboratory chemical that is highly toxic. Its availability and rapid harmful/lethal effects combine to make cyanide a potential foodborne/waterborne intentional‐poisoning hazard. Effective antidotes to cyanide poisoning are currently approved only for intravenous administration. Therefore, an effective cyanide antidote that can be administered intramuscularly in pre‐hospital and/or mass‐casualty settings is needed. Dimethyl trisulfide (DMTS) is a naturally occurring substance used as a flavour enhancer in foods. DMTS has shown antidotal efficacy in cyanide poisoning and is thought to act as both a sulphur donor and partial methaemoglobin inducer. In this study, an intramuscular injection of DMTS (6.25‐200 mg/kg) was given to rats 1 minute after an oral dose of NaCN (98.2 mg/kg; twice the median lethal dose) to test the antidotal efficacy and safety of DMTS treatment. Toxic signs and survival were examined along with behavioural function (up to 30 hour after ingestion) using a previously established operant behavioural model. A large range of DMTS doses (6.25‐100 mg/kg) increased survival after oral cyanide poisoning, and the lower DMTS doses (6.25‐25 mg/kg) also proved to be behaviourally and physiologically safe. Larger DMTS doses (50‐200 mg/kg) produced side effects (ie, inflammation and limping) that were more severe and protracted than those observed at lower DMTS doses. The 25 mg/kg DMTS proved to be the most efficacious (increasing survival from 20% to 75%) and also produced minimal side effects (eg, inflammation) that resolved within 24‐72 hour. Thus, DMTS shows promise as an intramuscularly administered cyanide antidote useful for prompt pre‐hospital or mass‐casualty emergency medical treatment.     

Differential effects of neuroleptic drugs on the delayed matching-to-sample performance of pigeons

The effects of clozapine, thiothixene, sulpiride, chlorpromazine and loxapine were examined in pigeons responding under a delayed matching-to-sample (DMTS) procedure using 0-, 2- and 8-sec delay intervals. Chlorpromazine (3-100 mg/kg), thiothixene (0.03-1.7 mg/kg), clozapine (0.1-5.6 mg/kg) and loxapine (0.1-10 mg/kg) produced dose-related decreases in the percent of correct responses (accuracy). With the exception of chlorpromazine, the relative magnitude of the accuracy-decreasing effects were unrelated to the length of the delay interval and the nondrug levels of accuracy. In contrast to these accuracy-decreasing effects, sulpiride (3-300 mg/kg) failed to decrease accuracy across the range of doses evaluated. Chlorpromazine, loxapine and clozapine increased response rates at low doses and then decreased response rates as the dose was increased. Thiothixene and sulpiride only decreased response rates in a dose-dependent fashion. The order of potency for the rate-suppressing effects of these drugs was thiothixene greater than clozapine = loxapine greater than chlorpromazine greater than sulpiride. The results of the present investigation suggest that, despite similar dopamine antagonist properties, neuroleptics produce qualitatively different effects in pigeons responding under DMTS procedures.     

Guanfacine and Clonidine,Alpha2-Agonists,Improve Paired Associates Learning,but not Delayed Matching to Sample,in Humans

The present study compares the effects of two alpha2-agonists, clonidine (0.5, 2, and 5 μg/kg, PO) and guanfacine (7 and 29 μg/kg, PO) in young healthy volunteers on their performance in visual paired associates learning (PAL) and delayed matching to sample (DMTS) visual short-term recognition memory tests. In the PAL test, clonidine 2 and guanfacine 29 μg/kg improved the subjects’ performance. In the DMTS test, clonidine at 5 μg/kg delay-dependently impaired performance accuracy, and at 2 and 5 μg/kg it also slowed responses. Guanfacine had no effect on DMTS test performance. Clonidine 5 and guanfacine 29 μg/kg equally increased subjective feelings of sedation and reduced blood pressure. The results suggest that both clonidine and guanfacine facilitated PAL learning by improving “frontal strategies,” but only clonidine disrupted “mnemonic processing” decreasing DMTS accuracy. The greater selectivity of guanfacine for alpha2A-adrenoceptor subtype may explain the different profile of action of the drugs.     

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.     

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.     

Dopaminergic modulation of visual attention and working memory in the rodent prefrontal cortex.

Converging evidence suggests that dopaminergic projections to the prefrontal cortex (PFC) modulate both attention and working memory processes that may be related to either insufficient or excessive dopamine activity specific to a D1 receptor mechanism. We examined the effects of bilateral intraprefrontal cortical infusions of the D1 agonist (SKF 81297) on a novel task specifically designed to assess the animals' ability to attend to a visual target (0.7 or 0.5 s) and then remember the location of that target over a variable delay (0-16 s) within the same test session. Bilateral prefrontal infusions of the low dose of SKF 81297 (0.01 microg) had no effect on visual attention or memory throughout the entire testing schedule. The medium (0.06 microg) dose preferentially increased attention to the stimulus target but only improved memory for that stimulus at a duration of 0.7 s, although in a delay-independent manner. The high dose (0.3 microg) of the D1 agonist also increased attentional accuracy. However, it was only under the more attention challenging condition (0.5 s) that this high dose also produced a baseline delay-dependent modulation of memory for the stimulus target. Specifically, good memory at the short delay was impaired and poor memory at the long delay was improved. These data provide the first demonstration that dopamine D1 receptor stimulation sufficient to improve attentional accuracy, can also disrupt, and facilitate short-term working memory performance in a delay-dependent manner.     

Effects of vinconate on scopolamine-induced memory impairment in rhesus monkeys.

Effects of vinconate on specifically impaired short-term memory were studied in rhesus monkeys. Monkeys were trained to perform for orange juice reinforcement under a matching-to-sample response procedure. In the procedure, monkeys had to choose one of two stimuli that had the same color as the sample stimulus. Half of a daily session consisted of simultaneous trials where the sample stimulus was present during the time of choice. The other half of the session consisted of delayed trials where the sample stimulus had been presented but withheld at the time of choice. After the repeated training, the matching-to-sample responses were established with the percentage of correct choice responses (CR%) in both types of trials exceeding 90%. The doses of scopolamine, intervals between administration of this drug and the start of test session, and delay times in delayed trials were adjusted from one monkey to another so that delayed matching-to-sample responses were impaired by scopolamine while simultaneous matching-to-sample responses were less impaired by this drug. Scopolamine (32 or 45 micrograms/kg, s.c.) decreased the CR% for delayed trials more markedly than the CR% for simultaneous trials in four monkeys. Intragastrically administered vinconate at 16 mg/kg attenuated the scopolamine-induced short-term memory impairment. These results suggested that vinconate possesses specific ameliorating action on memory impairment caused by hypofunction of the cholinergic system in the brain.     

Multiple behavioral effects of diazepam in rhesus monkeys

The acute effects of diazepam (Valium) were assessed using a battery of complex food-reinforced operant tasks that included responding in delayed matching to sample (DMTS, n = 5), conditioned position response (CPR, n = 7) progressive ratio (PR, n = 8), temporal response differentiation (TRD, n = 4), and incremental repeated acquisition (IRA, n = 9) tests. Diazepam (0.25-4.0 mg/kg IV) produced significant dose-dependent decreases in the number of reinforcers obtained in the TRD and IRA tasks only. TRD accuracy was significantly decreased at doses of 0.25, 1.0, 2.0, and 4.0 mg/kg when compared to vehicle injections. Significant decreases in IRA accuracy generally did not occur at doses below 1.0 mg/kg. DMTS accuracy was decreased at 0.5 mg/kg for some time delays but showed no clear dose-delay interaction. Performance in the CPR and PR tests showed no significant effects of diazepam exposure over the dose range tested. These results indicate that diazepam selectively disrupts performance of operant tasks in monkeys designed to model human correlates of time perception, learning ability and visual attention/short-term memory while not affecting tasks designed to model motivation and position/color discrimination.     

Effects of drugs of abuse on response accuracy and bias under a delayed matching-to-sample procedure in squirrel monkeys

The effects on memory of drugs of abuse from several pharmacological classes were examined in four adult male squirrel monkeys responding under a delayed matching-to-sample schedule of food presentation. Subjects were required to emit 20 responses on a sample key transilluminated by either a constant white or a flashing blue light. The twentieth response initiated a 3-second delay followed by presentation of two comparison stimuli. If a response was made to the key that matched the sample stimulus (correct match), a single food pellet (97 mg) was delivered. Pentobarbital (0.32-10 mg/kg), diazepam (0.1-5.6 mg/kg), phencyclidine (0.01-0.32 mg/kg) and cocaine (0.1-3.2 mg/kg) dose-dependently reduced accuracy of matching performance towards chance levels. Amphetamine (0.01-1.0 mg/kg) resulted in a small, but statistically significant, reduction in accuracy at a dose of 0.56 mg/kg, while 1.0 mg/kg completely suppressed responding. Analyses indicated that pentobarbital, diazepam and cocaine produced either position or color biases in responding, and in some cases these biases in responding were associated with decreases in accuracy. No such response biases were observed with phencyclidine or D-amphetamine. These results suggest that drug effects on working memory performance can, in some cases, be the result of non-mnemonic processes. Thus, they illustrate the importance of examining behavioral endpoints in addition to task accuracy when interpreting drug effects on working memory in laboratory animals.     

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.     

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.     

Effects of neuropeptide Y on the discriminative stimulus and antinociceptive properties of morphine.

Previous research indicates that opioid receptor blockade diminishes the effects of neuropeptide Y (NPY) on feeding and memory. Conversely, NPY attenuates naloxone-precipitated morphine withdrawal. The present study evaluated the effects of NPY on the discriminative stimulus and antinociceptive effects produced by the prototypical mu opioid, morphine. Rats were trained to discriminate 5.6 mg/kg morphine (IP) from saline using a standard two-lever, food-reinforced, drug discrimination procedure. Across a range of doses (3.0, 5.0, and 10 microg), intracerebroventricular (ICV) injection of NPY failed to substitute for, antagonize, or potentiate the discriminative stimulus effects of morphine. A warm-water tail-withdrawal procedure was used to examine the antinociceptive effects of morphine and NPY, alone and in combination. NPY (3.0 and 10 microg, ICV) failed to alter tail-withdrawal latencies from 52 degrees and 56 degrees C water, whereas morphine (1.0-30 mg/kg, IP) produced a dose-related increase in latencies at both water temperatures. A 10-microg dose of NPY also failed to alter the antinociceptive effects of morphine. This study does not support the idea that the discriminative stimulus and antinociceptive effects of morphine are dependent on an NPYergic pathway.     

Contrasting effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 on performance of an operant delayed matching to position task in rats

The effects of the competitive NMDA antagonist CPP and the non-competitive NMDA antagonist MK 801 (dizolcipine) on short term working memory in the rat were investigated. The behavioural paradigm used was discrete trial, operant delayed matching to position, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. These delays generated an orderly forgetting curve in control rats, with matching accuracy decreasing from approximately 100% at 0-s delay to approximately 75% at 30-s delay. Intraperitoneal (IP) administration of CPP (10 mg/kg) produced a markeddelay dependent impairment in performance, suggesting a specific effect on short term working memory. This effect was accompanied by a minor decrease in the speed of responding, and a slight increase in the number of missed trials. Lower doses of CPP had no significant effects on either matching accuracy or sedation. In contrast, IP administration of MK 801 (0.1 and 0.2 mg/kg) caused a markeddelay independent impairment in the accuracy of delayed matching performance, suggesting a non-specific disruption of performance. A lower dose (0.05 mg/kg) of MK 801 had no significant effect on matching accuracy. The two lower doses of MK 801 increased the number of nose pokes made during the delays and tended to increase the speed of responding, suggesting a stimulant-like action. The highest dose of MK 801 had the opposite effects and also decreased the number of trials completed. The results with CPP therefore support the hypothesized role of NMDA receptors in learning and memory, and the contrasting effects of these two NMDA antagonists support previous suggestions of different behavioural effects resulting from administration of competitive and non-competitive NMDA antagonists.