Delayed Nonmatching-to-sample Performance Research Articles

Behavioral Impact of Long-Term Chronic Implantation of Neural Recording Devices in the Rhesus Macaque

Ensemble recording methods are pervasive in basic and clinical neuroscience research. Invasive neural implants are used in patients with drug resistant epilepsy to localize seizure origin, in neuropsychiatric or Parkinson's patients to alleviate symptoms via deep brain stimulation, and with animal models to conduct basic research. Studies addressing the brain's physiological response to chronic electrode implants demonstrate that the mechanical trauma of insertion is followed by an acute inflammatory response as well as a chronic foreign body response. Despite use of invasive recording methods with animal models and humans, little is known of their effect on behavior in healthy populations. To quantify the effect of chronic electrode implantation targeting the hippocampus on recognition memory performance. Four healthy female rhesus macaques were tested in a delayed nonmatching-to-sample (DNMS) recognition memory task before and after hippocampal implantation with a tetrode array device. Trials to criterion and recognition memory performance were not significantly different before vs. after chronic electrode implantation. Our results suggest that chronic implants did not produce significant impairments on DNMS performance.

Systemic Blockade of the CB1 Receptor Augments Hippocampal Gene Expression Involved in Synaptic Plasticity but Perturbs Hippocampus-Dependent Learning Task.

Chronic and acute agonism as well as acute antagonism of CB1 receptors reveal modulation of learning and memory during stable performance of a delayed-nonmatch-to-sample (DNMS) memory task. However, it remains unclear how chronic blockade of the CB1 receptor alters acquisition of the behavioral task. We examined the effects of chronic rimonabant exposure during DNMS task acquisition to determine if blockade of the CB1 receptor with the antagonist rimonabant enhanced acquisition of operant task. Long-Evans rats, trained in the DNMS task before imposition of the trial delay, were surgically implanted with osmotic mini pumps to administer rimonabant (1.0 mg/kg/day) or vehicle (dimethyl sulfoxide/Tween-80/Saline). Following surgical recovery, DNMS training was resumed with the imposition of gradually longer delays (1-30 sec). The number of days required to achieve stable performance with either increasing length of delay or reversal of task contingency was compared between vehicle and rimonabant-treated rats. Following the completion of DNMS training, animals were euthanized, and both hippocampi were harvested for gene expression assay analysis. Rimonabant treatment animals required more time to achieve stable DNMS performance than vehicle-treated controls. Quantitative real-time polymerase chain reaction analysis revealed that the expressions of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunit, brain-derived neurotrophic factor, and synapsin 1 (Syn1) were significantly increased. These results are consistent with rimonabant increasing mRNAs for proteins associated with hippocampal synapse remodeling, but that those alterations did not necessarily accelerate the acquisition of an operant behavioral task that required learning new contingencies.

Remifentanil maintains lower initial delayed nonmatching-to-sample accuracy compared to food pellets in male rhesus monkeys.

Emerging human laboratory and preclinical drug self-administration data suggest that a history of contingent abused drug exposure impairs performance in operant discrimination procedures, such as delayed nonmatching-to-sample (DNMTS), that are hypothesized to assess components of executive function. However, these preclinical discrimination studies have exclusively used food as the reinforcer and the effects of drugs as reinforcers in these operant procedures are unknown. The present study determined effects of contingent intravenous remifentanil injections on DNMTS performance hypothesized to assess 1 aspect of executive function, working memory. Daily behavioral sessions consisted of 2 components with sequential intravenous remifentanil (0, 0.01-1.0 μg/kg/injection) or food (0, 1-10 pellets) availability in nonopioid dependent male rhesus monkeys (n = 3). Remifentanil functioned as a reinforcer in the DNMTS procedure. Similar delay-dependent DNMTS accuracy was observed under both remifentanil- and food-maintained components, such that higher accuracies were maintained at shorter (0.1-1.0 s) delays and lower accuracies approaching chance performance were maintained at longer (10-32 s) delays. Remifentanil maintained significantly lower initial DNMTS accuracy compared to food. Reinforcer magnitude was not an important determinant of DNMTS accuracy for either remifentanil or food. These results extend the range of experimental procedures under which drugs function as reinforcers. Furthermore, the selective remifentanil-induced decrease in initial DNMTS accuracy is consistent with a selective impairment of attentional, but not memorial, processes. (PsycINFO Database Record

Effects of environmental and pharmacological manipulations on a novel delayed nonmatching-to-sample ‘working memory’ procedure in unrestrained rhesus monkeys

BackgroundWorking memory is a domain of ‘executive function.’ Delayed nonmatching-to-sample (DNMTS) procedures are commonly used to examine working memory in both human laboratory and preclinical studies. New methodThe aim was to develop an automated DNMTS procedure maintained by food pellets in rhesus monkeys using a touch-sensitive screen attached to the housing chamber. Specifically, the DNMTS procedure was a 2-stimulus, 2-choice recognition memory task employing unidimensional discriminative stimuli and randomized delay interval presentations. ResultsDNMTS maintained a delay-dependent decrease in discriminability that was independent of the retention interval distribution. Eliminating reinforcer availability during a single delay session or providing food pellets before the session did not systematically alter accuracy, but did reduce total choices. Increasing the intertrial interval enhanced accuracy at short delays. Acute Δ9-THC pretreatment produced delay interval-dependent changes in the forgetting function at doses that did not alter total choices. Acute methylphenidate pretreatment only decreased total choices. Comparison with existing methodsAll monkeys were trained to perform NMTS at the 1s training delay within 60 days of initiating operant touch training. Furthermore, forgetting functions were reliably delay interval-dependent and stable over the experimental period (∼6 months). ConclusionsConsistent with previous studies, increasing the intertrial interval improved DNMTS performance, whereas Δ9-THC disrupted DNMTS performance independent of changes in total choices. Overall, the touchscreen-based DNMTS procedure described provides an efficient method for training and testing experimental manipulations on working memory in unrestrained rhesus monkeys.

Short-term testosterone manipulations modulate visual recognition memory and some aspects of emotional reactivity in male rhesus monkeys

The role of testosterone (T) in modulating cognitive function and emotion in men remains unclear. The paucity of animal studies has likely contributed to the slow progress in this area. In particular, studies in nonhuman primates have been lacking. Our laboratory has begun to address this issue by pharmacologically manipulating T levels in intact male rhesus monkeys, using blind, placebo-controlled, crossover designs. We previously found that T-suppressed monkeys receiving supraphysiological T for 4weeks had lower visual recognition memory for long delays and enhanced attention to videos of negative social stimuli (Lacreuse et al., 2009, 2010) compared to when treated with oil. To further delineate the conditions under which T affects cognition and emotion, the present study focused on the short-term effects of physiological T. Six intact males were treated with the gonadotropin-releasing hormone antagonist degarelix (3mg/kg) for 7days and received one injection of T enanthate (5mg/kg) followed by one injection of oil vehicle 7days later (n=3), or the reverse treatment (n=3). Performance on two computerized tasks, the Delayed-non-matching-to-sample (DNMS) with random delays and the object-Delayed Recognition Span test (object-DRST) and one task of emotional reactivity, an approach/avoidance task of negative, familiar and novel objects, was examined at baseline and 3–5days after treatment. DNMS performance was significantly better when monkeys were treated with T compared to oil, independently of the delay duration or the nature (emotional or neutral) of the stimuli. Performance on the object-DRST was unaffected. Interestingly, subtle changes in emotional reactivity were also observed: T administration was associated with fewer object contacts, especially on negative objects, without overt changes in anxious behaviors. These results may reflect increased vigilance and alertness with high T. Altogether, the data suggest that changes in general arousal may underlie the beneficial effects of T on DNMS performance. This hypothesis will require further study with objective measures of physiological arousal.

Memory encoding in hippocampal ensembles is negatively influenced by cannabinoid CB1 receptors

It has previously been demonstrated that the detrimental effect on the performance of a delayed nonmatch to sample (DNMS) memory task by exogenously administered cannabinoid (CB1) receptor agonist, WIN 55212-2 (WIN), is reversed by the receptor antagonist rimonabant. In addition, rimonabant administered alone elevates DNMS performance, presumably through the suppression of negative modulation by released endocannabinoids during normal task performance. Other investigations have shown that rimonabant enhances encoding of DNMS task-relevant information on a trial-by-trial, delay-dependent basis. In this study, these reciprocal pharmacological actions were completely characterized by long-term, chronic intrahippocampal infusion of both agents (WIN and rimonabant) in successive 2-week intervals. Such long-term exposure allowed extraction and confirmation of task-related firing patterns, in which rimonabant reversed the effects of CB1 agonists. This information was then utilized to artificially impose the facilitatory effects of rimonabant and to reverse the effects of WIN on DNMS performance, by delivering multichannel electrical stimulation in the same firing patterns to the same hippocampal regions. Direct comparison of normal and WIN-injected subjects, in which rimonabant injections and ensemble firing facilitated performance, verified reversal of the modulation of hippocampal memory processes by CB1 receptor agonists, including released endocannabinoids.

Pharmacological elevation of anandamide impairs short-term memory by altering the neurophysiology in the hippocampus

In rodents, many exogenous cannabinoid agonists including Δ 9-THC and WIN55,212-2 (WIN-2) have been shown to impair short-term memory (STM) by inhibition of hippocampal neuronal assemblies. However, the mechanisms by which endocannabinoids such as anandamide and 2-arachidonyl glycerol (2-AG) modulate STM processes are not well understood. Here the effects of anandamide on performance of a Delayed-Non-Match-to-Sample (DNMS) task (i.e. STM task) and concomitant hippocampal ensemble activity were assessed following administration of either URB597 (0.3, 3.0 mg/kg), an inhibitor of the Fatty Acid Amide Hydrolase (FAAH), AM404 (1.5, 10.0 mg/kg), a putative anandamide uptake/FAAH inhibitor, or R-methanandamide (3.0, 10.0 mg/kg), a stable analog of anandamide. Principal cells from hippocampal CA3/CA1 were recorded extracellularly by multi-electrode arrays in Long-Evans rats during DNMS task (1–30 s delays) performance and tracked throughout drug administration and recovery. Both R-methanandamide and URB597 caused dose- and delay-dependent deficits in DNMS performance with suppression of hippocampal ensemble activity during the encoding (sample) phase. R-methanandamide-induced effects were not reversed by capsaicin excluding a contribution of TRPV-1 receptors. AM404 produced subtle deficits at longer delay intervals but did not alter hippocampal neuronal activity during task-specific events. Collectively, these data indicate that endocannabinoid levels affect performance in a STM task and their pharmacological elevation beyond normal concentrations is detrimental also for the underlying physiological responses. They also highlight a specific window of memory processing, i.e. encoding, which is sensitive to cannabinoid modulation.

Effects of memantine and donepezil on cortical and hippocampal acetylcholine levels and object recognition memory in rats

This preclinical study investigated the ability of memantine (MEM) to stimulate brain acetylcholine (ACh) release, potentially acting synergistically with donepezil (DON, an acetylcholinesterase inhibitor). Acute systemic administration of either MEM or DON to anesthetized rats caused dose-dependent increases of ACh levels in neocortex and hippocampus, and the combination of MEM (5 mg/kg) and DON (0.5 mg/kg) produced significantly greater increases than either drug alone. To determine whether ACh release correlated with cognitive improvement, rats with partial fimbria-fornix (FF) lesions were treated with acute or chronic MEM or DON. Acute MEM treatment significantly elevated baseline hippocampal ACh release but did not significantly improve task performance on a delayed non-match-to-sample (DNMS) task, whereas chronic MEM treatment significantly improved DNMS performance but only marginally elevated baseline ACh levels. Acute or chronic treatment with DON (in the presence of neostigmine to allow ACh collection) did not significantly improve DNMS performance or alter ACh release. In order to investigate the effect of adding MEM to ongoing DON therapy, lesioned rats pretreated with DON for 3 weeks were given a single intraperitoneal dose of MEM. MEM significantly elevated baseline hippocampal ACh levels, but did not significantly improve DNMS task scores compared to chronic DON-treated animals. These data indicate that MEM, in addition to acting as an NMDA receptor antagonist, can also augment ACh release; however, in this preclinical model, increased ACh levels did not directly correlate with improved cognitive performance.

Cannabinoid and cholinergic systems interact during performance of a short-term memory task in the rat

It is now well established that cannabinoid agonists such as Δ(9)-tetrahydrocannabinol (THC), anandamide, and WIN 55,212-2 (WIN-2) produce potent and specific deficits in working memory (WM)/short-term memory (STM) tasks in rodents. Although mediated through activation of CB1 receptors located in memory-related brain regions such as the hippocampus and prefrontal cortex, these may, in part, be due to a reduction in acetylcholine release (i.e., cholinergic hypofunction). To determine the interaction between cannabinoid and cholinergic systems, we exposed rats treated with WIN-2 or cholinergic drugs to a hippocampal-dependent delayed nonmatch to sample (DNMS) task to study STM, and recorded hippocampal single-unit activity in vivo. WIN-2 induced significant deficits in DNMS performance and reduced the average firing and bursting rates of hippocampal principal cells through a CB1 receptor-mediated mechanism. Rivastigmine, an acetylcholinesterase inhibitor, reversed these STM deficits and normalized hippocampal discharge rates. Effects were specific to 1 mg/kg WIN-2 as rivastigmine failed to reverse the behavioral and physiological deficits that were observed in the presence of MK-801, an NMDA receptor antagonist. This supports the notion that cannabinoid-modulated cholinergic activity is a mechanism underlying the performance deficits in DNMS. Whether deficits are due to reduced nicotinic or muscarinic receptor activation, or both, awaits further analysis.

Recruitment of hippocampal neurons to encode behavioral events in the rat: alterations in cognitive demand and cannabinoid exposure.

Successful performance by rats of a delayed-nonmatch-to-sample (DNMS) task is hippocampal dependent. We have shown that neurons in hippocampus differentially encode task-relevant events. These responses are critical for correct DNMS performance and are diminished by exogenous cannabinoids. We therefore reasoned that hippocampal neural correlates of behavior are likely shaped during learning; however, to date, no work has examined these correlates during DNMS acquisition training. Consequently, the present study assessed the emergence of hippocampal neural encoding when (i) cognitive task demands were increased through prolongation of delay intervals between sample and nonmatch phase and (ii) when animals are under cannabinoid treatment and performance is compromised. Adult, male Long-Evans rats were trained to perform the DNMS task without delay and then implanted with multielectrode recording arrays directed to CA3 and CA1 subfields of the hippocampus. Following recovery, single units were isolated and animals divided into two treatment groups: vehicle or WIN 55,212-2 (WIN-2, 0.35 mg/kg). Ensemble firing was monitored during retraining in DNMS task at 0 s, and subsequently delay intervals were progressively increased to 1-10 s, 11-20 s, and 21-30 s when animals met criterion (80% correct) at each respective interval. Hippocampal CA3 and CA1 principal cells were isolated and recorded throughout treatment. Extension of the delay led to an increase in the number of task-correlated neurons in controls. This recruitment of novel cells was reduced/prevented in the presence of WIN-2 and was paralleled by impairment in acquisition learning at longer delay intervals. Moreover, WIN-2 suppressed hippocampal ensemble firing during the sample (encoding) but not nonmatch phase of the DNMS task across all delays. These cannabinoid-induced alterations in hippocampal neuronal activity may explain the observed deficits in DNMS performance.

Hippocampal volume is preserved and fails to predict recognition memory impairment in aged rhesus monkeys ( Macaca mulatta)

Aged monkeys exhibit deficits in memory mediated by the medial temporal lobe system, similar to the effects of normal aging in humans. The contribution of structural deterioration to age-associated memory loss was explored using magnetic resonance imaging techniques. We quantified hippocampal, cerebral and ventricular volumes in young ( n = 6, 9–12 years) and aged ( n = 6, 24–29 years) rhesus monkeys. Eleven subjects were tested on a recognition memory task, delayed non-matching-to-sample (DNMS). Compared to young animals, aged monkeys exhibited robust learning deficits and significant memory impairments when challenged with longer retention intervals. Hippocampal volume was statistically equivalent across age groups, differing by less than 6%, and there was no correlation between this measure and DNMS performance. Variability in cerebral volume was greater in the aged compared to young monkeys and this parameter was marginally correlated with DNMS performance with a 10-min delay. These findings confirm and extend the conclusion of recent post-mortem histological analyses demonstrating that normal cognitive aging occurs independently of gross structural deterioration in the primate hippocampus.

Opposite relationship of hippocampal and rhinal cortex damage to delayed nonmatching-to-sample deficits in monkeys.

Three recent studies in macaque monkeys that examined the effects on memory of restricted hippocampal lesions (Murray and Mishkin, J Neurosci 1998;18:6568-6582; Beason-Held et al., Hippocampus 1999;9:562-574; Zola et al., J Neurosci 2000;20:451-463) differed in their conclusions about the involvement of the hippocampus in recognition memory. Because these experiments used a common behavioral procedure, trial-unique visual delayed nonmatching-to-sample (DNMS), a quantitative synthesis ("meta-analysis") was performed to determine whether hippocampal lesions produced a reliable net impairment in DNMS performance, and whether this impairment was related to the magnitude of hippocampal damage. A similar analysis was performed on data from monkeys with perirhinal or rhinal cortex damage (Meunier et al., J Neurosci 1993;13:5418-5432; Buffalo et al., Learn Mem 1999;6:572-599). DNMS performance scores were transformed to d' values to permit comparisons across studies, and a loss in d' score, a measure of the magnitude of the recognition deficit relative to the control group, was calculated for each operated monkey. Two main findings emerged. First, the loss in d' following hippocampal damage was reliably larger than zero, but was smaller than that found after lesions limited to the perirhinal cortex. Second, the correlation of loss in d' with extent of hippocampal damage was large and negative, indicating that greater impairments were associated with smaller hippocampal lesions. This relationship was opposite to that between loss in d' and rhinal cortex damage, for which larger lesions were associated with greater impairment. These findings indicate that damage to the hippocampus and to the rhinal cortex affects recognition memory in different ways. Furthermore, they provide a framework for understanding the seemingly disparate effects of hippocampal damage on recognition memory in monkeys, and by extension, for interpreting the conflicting reports on the effects of such damage on recognition memory abilities in amnesic humans.

Cannabinoids Reveal the Necessity of Hippocampal Neural Encoding for Short-Term Memory in Rats

The memory-disruptive effects of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and the synthetic cannabinoid WIN 55,212-2 (WIN-2) were assessed in rats exposed to varying doses of each drug (Delta(9)-THC, 0.5-2.0 mg/kg; WIN-2, 0.25-0.75 mg/kg) during performance of a delayed nonmatch to sample (DNMS) task. Cannabinoids affected performance in a dose x delay-dependent manner, with WIN-2 showing a potency more than four times that of Delta(9)-THC. These effects on DNMS performance were eliminated if the cannabinoid CB1 receptor antagonist SR141617A (Sanofi Research Inc.) was preadministered, but doses of the antagonist alone had no effect on performance. Simultaneous recording from ensembles of hippocampal neurons revealed that both WIN-2 and Delta(9)-THC produced dose-dependent reductions in the frequency (i.e., "strength") of ensemble firing during the sample phase of the task to the extent that performance was at risk for errors on >70% of trials as a function of delay. This decrease in ensemble firing in the Sample phase resulted from selective interference with the activity of differentiated hippocampal functional cell types, which conjunctively encoded different combinations of task events. A reduction in ensemble firing strength did not occur in the nonmatch phase of the task. The findings indicate that activation of CB1 receptors renders animals at risk for retention of item-specific information in much the same manner as hippocampal removal.

Cognitive processes involved in delayed non-matching-to-sample performance in Parkinson's disease.

Visual recognition memory was assessed in terms of delay duration, memory load and amount of interference(s) in non-demented patients with Parkinson's disease (PD) using an automated delayed non-matching-to-sample (DNMS) task with trial-unique stimuli. Special attention was focused on the different cognitive functions engaged by these patients in solving this recognition memory task. Thirteen patients with PD, carefully selected according to their stable regimen and anticholinergic medication, were compared to 12 controls matched by age and educational level. Besides the DNMS task, a neuropsychological battery that included tasks carefully selected according to processes potentially required to perform the DNMS task (e.g. attention, executive functions, visual discrimination and motor speed) was administered to the subjects. As compared with controls, patients with PD showed a deficit on most DNMS subscores, except those requiring the least cognitive load. The correlative analysis between the DNMS and other neuropsychological tasks suggests involvement of long-term memory mainly in the DNMS performance for the control group, contrasting with a major involvement of executive functions for the patients with PD. These data indicate that visual recognition memory impairment in non-demented patients with PD is largely due to an executive dysfunction, notably in working memory. Several hypotheses are proposed concerning the neuronal substrates underlying the impairment on the visual DNMS task in PD.

Effects of Ibotenate Hippocampal and Extrahippocampal Destruction on Delayed-Match and -Nonmatch-to-Sample Behavior in Rats

The effects of ibotenate lesions of the hippocampus (HIPP) or hippocampus plus collateral damage to extrahippocampal structures (HCX) were investigated in rats trained to criterion on spatial versions of either a delayed-match (DMS) or delayed-nonmatch-to-sample (DNMS) task. After recovery from surgery, animals were retrained at "0" sec delays, then assessed at 0-30 sec delays for 15 d, retrained again at 0 sec delays, and retested for another 25 d on 0-30 sec delays. Pretrained HIPP-lesioned animals showed marked delay-dependent deficits in both tasks that never recovered. Detailed examination of within- and between-trial performance factors, including changes in response preferences, length of previous trial delay, and sequential dependencies, revealed important factors operating in lesioned animals that were either absent or insignificant before the lesion. Pretrained HCX-lesioned animals showed deficits similar to those of HIPP animals, with the noticeable exception of a strong "recency" influence of the previous trial. Another group of HIPP- and HCX-lesioned animals trained on the tasks after the lesion showed reduced impairments of the type described above, suggesting that extrahippocampal structures trained after the lesion can assume the role of the hippocampus to some degree. The findings indicate that both the type of lesion and the previous history of the animal determine the postlesion DMS and DNMS performance of animals suffering damage to the hippocampus and/or related structures.

Facilitative Effects of the Ampakine CX516 on Short-Term Memory in Rats: Correlations with Hippocampal Neuronal Activity

In the companion article (Hampson et al., 1998), the ampakine CX516 (Cortex Pharmaceuticals) was shown to produce a marked facilitation of performance of a spatial delayed-nonmatch-to-sample (DNMS) task in rats. Injections of the drug before each daily session produced a marked and progressive improvement in performance at longer delays (>5 sec) that persisted for 7 d after drug treatment was terminated. In most animals (n = 9) the increase in performance carried over to the intervening vehicle for days, whereas in others (n = 3) the effects dissipated within the session according to the pharmacological half-life of CX516. In this article we report firing correlates of simultaneously recorded cells in the CA1 and CA3 fields of the hippocampus over the period in which DNMS performance was facilitated by CX516. Sample and Delay period firing was enhanced by 100-350% under CX516 and increased progressively over days as did DNMS performance. The firing increases were restricted to correct trials only and were largest on trials with long delays. Firing in the intertrial interval was also altered, but in a manner consistent with a previously demonstrated reduction in between-trial proactive interference by CX516. Finally, in animals in which the effects of CX516 were restricted to when the drug was actually present (i.e., no carryover effects), increased cell firing also paralleled the time course of the performance increase. Results are discussed with respect to the actions of ampakines on hippocampal cellular and synaptic processes that underlie DNMS performance.

Facilitative Effects of the Ampakine CX516 on Short-Term Memory in Rats: Enhancement of Delayed-Nonmatch-to-Sample Performance

Ampakines are a family of drugs that selectively increase AMPA receptor-gated currents and improve performance on several behavioral tasks. This report describes evidence that ampakines cause a cumulative enhancement of performance in a spatial short-term memory task (Deadwyler et al., 1996). Two groups of rats were trained on a spatial variant of the delayed-nonmatch-to-sample (DNMS) paradigm. One group (n = 12) received the ampakine CX516 (Cortex Pharmaceuticals) alternated with vehicle for 17 consecutive days and then only vehicle for an additional 7 d. The second group (n = 6) received only vehicle injections over the same number of days. CX516 improved performance within sessions, particularly on trials with delays of 6-35 sec. In 9 of 12 rats, the positive effect of the drug was also present on nondrug days between CX516 administration and after cessation of CX516 injections. The animals that received only vehicle injections showed no improvement in DNMS performance over the entire 32 d of testing. Three of the 12 animals given CX516 did not exhibit "carryover" effects of the drug to the intervening (vehicle only) test sessions, but nonetheless exhibited superior performance during the first half of the session on days in which the ampakine was administered. Evaluation of errors suggests that the ampakine eliminated the necessity for a shift in response strategy that produced proactive interference on the following trial. Hippocampal involvement in these ampakine effects is discussed as a prelude to the second article in the series (Hampson et al., 1998).

Disruption of spatial but not object-recognition memory by neurotoxic lesions of the dorsal hippocampus in rats.

Ischemia-induced cell loss in the CA1 region of the dorsal hippocampus results in severe deficits on delayed non-matching-to-sample (DNMS), whereas hippocampectomy produces little or no impairment, suggesting that partial hippocampal damage is more detrimental to DNMS performance than total ablation. To test this hypothesis, rats with or without preoperative DNMS training were given partial cytotoxic lesions of the dorsal hippocampus. When tested, neither group displayed any DNMS deficits despite widespread cell loss in the CA1 and other regions of the dorsal hippocampus. In the final experiments, rats tested previously on DNMS were found to be impaired on the Morris water maze. The finding that partial hippocampal lesions disrupt spatial memory while leaving object-recognition memory intact indicates a specialized role for the hippocampus in mnemonic processes.

The glycine/NMDA receptor antagonist HA-966 impairs visual recognition memory in rhesus monkeys

Recent studies have shown that strychnine-insensitive glycine binding sites positively modulate the N -methyl- d -aspartate (NMDA) subclass of glutamate receptors, which are important in neural pathways involved in cognitive function. We examined the effect of (±)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), a highly specific antagonist of this glycine modulatory site on the NMDA receptor, on visual recognition memory in four rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trial-unique graphic symbols. In addition, the effect of HA-966 was compared with that of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine; MK-801), a noncompetitive NMDA channel blocker. Administration of HA-966 (0.1–10 mg/kg, i.m.) 30 min before testing impaired DNMS performance dose-dependently, starting at doses of 3.2 mg/kg; the memory deficit following the highest dose (10 mg/kg) was associated with prolonged response latencies. Similar impairments in recognition memory were observed following treatment with MK-801, though at much lower doses (3.2–32 μg/kg) than those at which HA-966 was effective. Administration of low doses of HA-966 (1 mg/kg) and MK-801 (10 μg/kg), each of which had no significant effect on performance when given alone, also failed to impair performance when given concurrently. Combined administration of both drugs, each at amnesia-producing doses (3.2 mg/kg of HA-966 plus 32 μg/kg of MK-801), markedly impaired performance in an additive, not a synergistic, manner. From these results, we propose that the recognition memory impairment observed in our monkeys following HA-966 administration is via an action on the glycine modulatory site of the NMDA receptor complex.

The glycine/NMDA receptor antagonist HA-966 impairs visual recognition memory in rhesus monkeys

Recent studies have shown that strychnine-insensitive glycine binding sites positively modulate the N-methyl- d-aspartate (NMDA) subclass of glutamate receptors, which are important in neural pathways involved in cognitive function. We examined the effect of (±)-3-amino-1-hydroxy-2-pyrrolidone (HA-966), a highly specific antagonist of this glycine modulatory site on the NMDA receptor, on visual recognition memory in four rhesus monkeys performing a computer-automated version of delayed nonmatching-to-sample (DNMS) with a list length of 20 trial-unique graphic symbols. In addition, the effect of HA-966 was compared with that of (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine; MK-801), a noncompetitive NMDA channel blocker. Administration of HA-966 (0.1–10 mg/kg, i.m.) 30 min before testing impaired DNMS performance dose-dependently, starting at doses of 3.2 mg/kg; the memory deficit following the highest dose (10 mg/kg) was associated with prolonged response latencies. Similar impairments in recognition memory were observed following treatment with MK-801, though at much lower doses (3.2–32 μg/kg) than those at which HA-966 was effective. Administration of low doses of HA-966 (1 mg/kg) and MK-801 (10 μg/kg), each of which had no significant effect on performance when given alone, also failed to impair performance when given concurrently. Combined administration of both drugs, each at amnesia-producing doses (3.2 mg/kg of HA-966 plus 32 μg/kg of MK-801), markedly impaired performance in an additive, not a synergistic, manner. From these results, we propose that the recognition memory impairment observed in our monkeys following HA-966 administration is via an action on the glycine modulatory site of the NMDA receptor complex.