Lever-pressing Task Research Articles

Striatal dopamine release in the rat during a cued lever-press task for food reward and the development of changes over time measured using high-speed voltammetry

Substantia nigra dopamine neuronal activity in the primate is thought to be related to the error in predicting reward delivery. Dopamine release in rat nucleus accumbens has been shown to increase in relation to drug/food-seeking behaviour. It is not known how the release of dopamine in the striatum corresponds to the many distinct steps of a rewarded, cued task (e.g. recognizing the cue, executing the behaviour, anticipating the reward, receiving the reward) and how dopamine release then changes over time as task performance improves. To investigate dopamine release during a rewarded, cued task and the development of changes in dopamine release over time, changes in extracellular striatal dopamine concentration during a rewarded, cued lever-press task were measured a few days every week for 5 months using high-speed in vivo voltammetry. Rats were trained to press a lever after a tone to obtain a food reward. The reaction time for the lever press decreased gradually as training continued. Changes in dopamine concentration were measured in the anterior striatum (ventral portion) during the task performance after an initial 6-day familiarization period, in which the animals learned that a lever press yielded food, and a 5-week period for surgery, recovery, and electrode preparation. During the task performance, dopamine concentration started to increase just after the cue, peaked near the time of the lever press, and returned to basal levels 1-2 s after the lever press. This pattern of changes in dopamine concentration was observed over the 5 months of testing, the peak dopamine concentration increasing steadily until peaking at week 7, at which time the task performance had not yet improved significantly from week 2. By week 13, task performance had significantly improved and peak dopamine concentration had begun to subside. Thus, the increase in dopamine concentration after the cue was highest while the task was not yet perfected and subsided toward the end of the learning process. It was concluded that striatal dopamine release during a cued lever-press task is relevant to the novelty of the conditions.

Locomotor Activity Predicts Acquisition of Self-Administration Behavior but Not Cocaine Intake.

The current study investigates locomotor activity in a novel environment and correlates these activity levels with cocaine self-administration in rats that were either trained or untrained on a lever-pressing task prior to cocaine self-administration. The authors report that it is the rate of learning the lever-pressing task, not cocaine self-administration, that correlates with locomotor activity. The results suggest that a correlation between locomotor activity and cocaine self-administration is secondary to a link between locomotor activity and rate of learning to lever press for a reward. The authors conclude that locomotor activity is not necessarily an indicator of propensity to self-administer cocaine and demonstrate that environmental novelty and rate of learning an operant task are important considerations when designing experiments on drug-seeking behaviors.

Fos expression and task-related neuronal activity in rat cerebral cortex after instrumental learning

Learning has been shown to induce changes in neuronal gene expression and to produce development of task-specific neuronal activity. The connection between these two features of neuronal plasticity remains of a great interest. To address this issue we compared distribution of c-Fos expressing and task-related neurons in the rat cerebral cortex following instrumental learning of appetitive lever-press task. The number of Fos-positive neurons was determined immunohistochemically in the retrosplenial and the motor cortex of naive (“control” group), newly trained (“acquisition” group) and overtrained (“performance” group) animals. A significant activation of c-Fos expression was observed in the neurons of the retrosplenial but not motor cortex in the “acquisition” group rats, as compared with the “control” and “performance” groups. In accordance with this c-Fos expression difference, the retrosplenial cortex of the trained animals contained significantly more neurons with lever-press-related activity than the motor cortex. Therefore, the two examined cortical areas showed a parallel between experience-dependent induction of c-Fos and development of task-related neuronal activity. These data support a notion that learning-induced activation of c-Fos is associated with long-term neurophysiological changes produced by training.

1631 Dopamine release in the rat striatum during the cued lever-press task and the effect of serotonin neuron on its release

1631 Dopamine release in the rat striatum during the cued lever-press task and the effect of serotonin neuron on its release

Local Field Potential Oscillations in Primate Cerebellar Cortex: Synchronization With Cerebral Cortex During Active and Passive Expectancy

Many brain regions, such as the cerebellum, primary somatosensory cortex (SI), and primary motor cortex (MI), interact to produce coordinated actions. Synchronization of local field potentials (LFPs) in sensorimotor cerebral areas has been related to motor performance, often through 10- to 25-Hz oscillatory LFPs. The macaque cerebellar paramedian lobule (PM) also shows 10- to 25-Hz LFP oscillations, which are modulated in a stimulus-response lever press task to get reward (active condition), but also, albeit differently, in a similarly timed stimulus-reward relation (passive condition). This study focuses on simultaneous LFP activity in primate SI or MI and the PM cerebellum during the active (left- or right-hand lever presses) and passive conditions. Results show a similar modulation pattern of 10- to 25-Hz oscillations in the cerebellum, MI, and SI during the active condition (left or right hand), decreasing after stimulus onset, returning, and again decreasing after movement onset. In the passive condition, when the monkey did not move but got reward, all 3 areas show an oscillatory profile where oscillations increase after stimulus onset and last until reward, denoting a role for these oscillations in passive expectancy. However, synchronization between cerebellar LFPs and SI LFPs is higher during the active condition than during the passive condition, and highest for the interested hand. This greater PM-SI synchronization, when the monkey had to press the lever, could represent a form of cerebro-cerebellar communication, perhaps to serve somatosensory processing to accomplish the task; PM-MI synchronization was less selective for the hand used and might carry a more general type of information.

Long-term memory for instrumental responses does not undergo protein synthesis-dependent reconsolidation upon retrieval

Recent evidence indicates that certain forms of memory, upon recall, may return to a labile state requiring the synthesis of new proteins in order to preserve or reconsolidate the original memory trace. While the initial consolidation of "instrumental memories" has been shown to require de novo protein synthesis in the nucleus accumbens, it is not known whether memories of this type undergo protein synthesis-dependent reconsolidation. Here we show that low doses of the protein synthesis inhibitor anisomycin (ANI; 5 or 20 mg/kg) administered systemically in rats immediately after recall of a lever-pressing task potently impaired performance on the following daily test sessions. We determined that the nature of this impairment was attributable to conditioned taste aversion (CTA) to the sugar reinforcer used in the task rather than to mnemonic or motoric impairments. However, by substituting a novel flavored reinforcer (chocolate pellets) prior to the administration of doses of ANI (150 or 210 mg/kg) previously shown to cause amnesia, a strong CTA to chocolate was induced sparing any aversion to sugar. Importantly, when sugar was reintroduced on the following session, we found that memory for the task was not significantly affected by ANI. Thus, these data suggest that memory for a well-learned instrumental response does not require protein synthesis-dependent reconsolidation as a means of long-term maintenance.

Experience-Dependent Regulation of the Immediate-Early Gene Arc Differs across Brain Regions

Previously, we demonstrated that initial acquisition of a lever-press task resulted in higher levels of activity-regulated cytoskeleton-associated protein (Arc) mRNA induction than did overtrained performance (Kelly and Deadwyler, 2002). The present study extends this finding by characterizing (1) the behavioral regulation of Arc protein expression, (2) the time course of decay of Arc mRNA signal in different brain regions immediately after the initial acquisition session, and (3) the persistence of Arc mRNA induction in those same brain regions across sessions. Rats killed after initial acquisition of a simple lever-press response demonstrated significantly elevated levels of Arc protein. Interestingly, of the brain regions that demonstrated Arc mRNA induction 30 min after the acquisition session, there was a differential rate in signal decay, with only half of the regions continuing to demonstrate elevated levels of Arc at 60 min. Similarly, the extent to which Arc mRNA induction persisted across days also varied across brain regions. An unexpected outcome was that areas such as CA1 and CA3 that showed the least persistence in Arc activation immediately after the initial acquisition session showed the greatest perseverance of induction across days of training. Finally, animals less proficient at the task expressed higher levels of Arc mRNA than animals that acquired the task more quickly. Taken together, the results show that Arc mRNA and protein were regulated in an experience-dependent manner; however, the fact that the time course of Arc mRNA expression differed across brain structures suggests a differential rate of consolidation of the newly acquired behavior across specific brain regions.

Reinforcement value of sucrose measured by progressive ratio operant licking in the rat

Progressive ratio (PR) schedules, which require increasing numbers of responses for successive reinforcements, are widely used to measure the reward value of foods, fluids, and drugs in operant lever-pressing tasks. The present study evaluated a PR operant licking task as a measure of sweet taste reward. In Experiment 1, food deprived rats were offered sucrose to drink on PR lick or fixed ratio (FR) lick schedules (30 min/day). In Experiment 2, nondeprived rats were offered sucrose to drink on PR or FR schedules and free access to water and food 23 h/day. In both experiments, the FR rats increased and then decreased their sucrose solution intake as concentration increased from 1% to 32% or 64%. The PR rats, in contrast, showed a near-linear increase in sucrose solution intake, lick rates, and break points (highest ratio completed) as a function of sucrose concentration. The PR rats drank less sucrose than did the FR rats although they emitted more total licks at the highest concentration tested. These results are similar to those reported with PR lever-pressing tasks. Thus, PR operant licking, which requires minimal training and equipment, is a useful alternate measure of fluid reward in rodents.

Equine utilization of a previously learned visual stimulus to solve a novel task

Forty-four horses were used to determine if a learned stimulus could be used to increase acquisition of a response unrelated to the original learned task. Horses were paired by age, breed and sex. One randomly chosen horse from each pair served as the control while the remaining horse was trained to respond to a visual stimulus by pushing a lever to obtain a food reward. In Experiment I ( n=28), the food reward was delivered in a feed box located equidistant between two levers located 2.7 m apart on one wall of the test stall. Trained horses were given 30 training trials daily until they achieved at least 85% correct responses in three nonconsecutive days. After each trained horse reached criterion, both horses in the pair were tested in 30 trials daily for five consecutive days in a modified Y maze. The stimulus that indicated the correct lever in the initial training task was used to signify the correct arm of the maze for both the control and trained horses. The correct arm of the maze was changed randomly during each daily session, and correct choices resulted in a food reward. In Experiment II ( n=16), levers were located on opposite walls (11 m apart) of the test stall, and the stimulus and modified Y maze were simplified. Trained horses received 15 training trials daily until they reached at least 85% correct responses on three consecutive days. As each trained horse achieved this criterion, both horses in the pair were tested in a maze for 15 trials daily for 7 days. Again, the stimulus from initial lever-pressing task was used to signify the rewarded arm of the maze. Correct choices of trained and control horses in both experiments were compared using a paired t-test. In Experiment I, no differences ( P>0.34) in mean correct responses were detected between trained and control horses on the first day in the maze (15.3 and 16.8, respectively) or after 5 days in the maze (84.0 and 82.1, respectively). Similarly, in Experiment II, trained and control horses did not differ ( P>0.50) in mean correct responses on the first day (6.9 and 7.4, respectively) or after 7 days in the maze (63.6 and 61.6, respectively). These results indicate that the stimuli used to solve the lever-pressing task were not utilized by horses in the maze task, and that horses may have difficulty transferring learned visual stimuli to new tasks.

Local Field Potential Oscillations in Primate Cerebellar Cortex: Modulation During Active and Passive Expectancy

Cerebellar local field potential (LFP) oscillations were recorded in the paramedian lobule of one hemisphere, while monkeys were in two behavioral conditions: actively performing an elbow flexion-extension or a lever-press task in response to an auditory or visual stimulus to get reward (active condition), or waiting quietly for the reward to come in the same time window after the appearance of the stimulus (passive condition). The oscillations in the paramedian lobule were first characterized in four monkeys, and they showed an idiosyncratic frequency for each monkey, between 13 and 25 Hz. The granule cell layer multi-unit activity was phase-locked with the negative phase of the LFP oscillations, while Purkinje cell simple spikes were also sometimes phase-locked with the LFP. Three monkeys were trained to perform the motor tasks: the LFP oscillations were modulated, in the active condition, in a systematic manner in relation to the lever-press or elbow flexion-extension tasks. During periods when the monkey was waiting to initiate movement, LFP oscillations appeared and then stopped with movement initiation. This modulation was valid for the task being executed with either hand. Surprisingly, the LFP oscillations were also systematically modulated during the passive condition; as the monkey was waiting for the usual time to get a reward passively, oscillations appeared stronger and were stopped by the end of the usual delay, whether the monkey was rewarded or not. This type of modulation was not affected by the length of the stimulus, as long as the reward window was known to the monkey. If the monkey had not been previously trained to the active condition, the modulation appeared in the passive condition. These results show that cerebellar LFP oscillations in the paramedian lobule are reliably present when the monkey is involved in a waiting period, whether this period ends with an active or passive event. This study provides electrophysiological evidence for a specific pattern of activity in the cerebellum for the expectancy of events that are known to be bound to happen, either externally, or from voluntary action.

Acquisition of a novel behavior induces higher levels of Arc mRNA than does overtrained performance

Arc (also termed activity-regulated cytoskeleton-associated protein or Arg3.1), is an effector immediate early gene whose upregulation has been demonstrated during events of synaptic plasticity. In the present study, the possibility that Arc would be specifically upregulated in rats during the acquisition of a quickly learned behavioral task but not in overtrained animals was investigated. Three groups of rats, pseudotrained, newly trained and overtrained, were examined with respect to Arc expression following training on a simple operant lever-pressing task. Newly trained animals were killed 30 min following the session in which they demonstrated acquisition of the task, and overtrained animals were trained on the same task for 13–14 days and then killed. Relative to base level measures taken 6 h following the session, all three groups demonstrated significant levels of induction of Arc mRNA; however, newly trained animals exhibited heightened induction of Arc mRNA relative to both pseudotrained and overtrained animals. The increased levels of Arc mRNA in newly trained animals were located in the CA1 and CA3 fields of hippocampus, the subiculum, and the anterior cingulate, piriform, infra/prelimbic, perirhinal and entorhinal cortical areas. Additionally, Arc mRNA was expressed differentially across the above anatomic structures in a relative pattern that was the same in all three groups. Finally, levels of Arc mRNA in specific brain regions of newly trained animals correlated negatively with the rate of task acquisition, such that slow learners exhibited higher levels of Arc mRNA than fast learners. From these results we suggest that Arc is upregulated in an experience-dependent manner, with higher levels of induction occurring during the initial stage of learning. Furthermore, the finding of increased Arc levels in slow versus fast learners indicates that Arc expression may be associated with the length of time required to: (1) form new associations or (2) remodel existing connections. These results confirm other reports that Arc is a critical substrate for the synaptic plasticity underlying the acquisition of new behaviors.

The combined effects of pyridostigmine and chronic stress on brain cortical and blood acetylcholinesterase, corticosterone, prolactin and alternation performance in rats

Thousands of soldiers who served in the Gulf War have symptoms that have been collectively termed Gulf War Illness (GWI). It has been suggested that a combination of operational stress and pyridostigmine, a drug given as a pretreatment to protect soldiers against the effects of exposure to nerve agents, might have had unexpected adverse health effects causing these symptoms. Our laboratory has previously modeled operational stress in rats using a paradigm of around-the-clock intermittent signalled footshock. In the present studies, this model was used to investigate the potential synergistic effects of chronic stress and pyridostigmine on physiology and behavior. Seventy-two rats were trained to perform an alternation leverpressing task to earn their entire daily food intake. The rats were then implanted with osmotic minipumps containing vehicle, pyridostigmine (25 mg/ml pyridostigmine bromide) or physostigmine (20 mg/ml eserine hemisulfate). The pumps delivered 1 μl/h, which resulted in a cumulative dosing of approximately 1.5 mg/kg/day of pyridostigmine or 1.2 mg/kg/day of physostigmine, equimolar doses of the two drugs. The rats were then returned to their home cages where performance continued to be measured 24 h/day. After 4 days, 24 of the 72 rats were trained to escape signalled footshock (avoidance-escape group) and 24 other rats (yoked-stressed group) were each paired to a rat in the avoidance-escape group. The remaining 24 rats were not subjected to footshock (unstressed group). Shock trials were intermittently presented in the home cage 24 h/day for 3 days, while alternation performance continued to be measured. Since only 12 test cages were available, each condition was repeated to achieve a final n of six rats per group. Pyridostigmine and physostigmine each decreased blood acetylcholinesterase levels by approximately 50%. Physostigmine also decreased brain cortical acetylcholinesterase levels by approximately 50%, while pyridostigmine had no effect on cortical acetylcholinesterase activity. Alternation performance was impaired on the first day of stress and then recovered. Neither pyridostigmine nor physostigmine affected performance in the absence of stress or increased the effects of stress alone. Corticosterone was significantly increased in the yoked stress group compared to unstressed controls. These data suggest that pyridostigmine does not exacerbate the effects of stress on performance or levels of stress hormones. Furthermore, these data do not suggest that stress enables pyridostigmine to cross the blood brain barrier.

N-methyl-D-aspartate receptor-dependent plasticity within a distributed corticostriatal network mediates appetitive instrumental learning.

The effect of microinfusion of the N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic acid (AP-5) into the amygdala, medial prefrontal cortex, and dorsal and ventral subiculum on acquisition of a lever-pressing task for food in rats was examined. Serial transmission between the basolateral amygdala and nucleus accumbens core was also examined in an asymmetric infusion design. AP-5 administered bilaterally into either the amygdala or medial prefrontal cortex markedly impaired learning, whereas administration into the dorsal or ventral subiculum had no effect. Unilateral infusion of AP-5 into either the nucleus accumbens core or amygdala was also sufficient to impair learning. These data provide novel evidence for NMDA receptor-dependent plasticity within corticostriatal networks in the acquisition of appetitive instrumental learning.

GF 109203X, a selective inhibitor of protein kinase C, impairs retention performance in an operant task.

The effects of post-training administration of GF 109203X (5 and 50 ng i.c.v.), a selective inhibitor of protein kinase C, on retention performance were investigated in a positively reinforced lever press task, in male Swiss mice. Both doses of GF 109203X suppressed the spontaneous improvement of performance observed in control animals between the last 5 min of the acquisition session and the first 5 min of the retention session 24 h later. GF 109203X had no effect on food intake and locomotor activity. These data suggest that GF 109203X selectively interferes with mechanisms underlying post-training organization of information and that protein kinase C is involved in this memory process.

Response-reinforcement learning is dependent on N-methyl-D-aspartate receptor activation in the nucleus accumbens core.

The nucleus accumbens, a site within the ventral striatum, is best known for its prominent role in mediating the reinforcing effects of drugs of abuse such as cocaine, alcohol, and nicotine. Indeed, it is generally believed that this structure subserves motivated behaviors, such as feeding, drinking, sexual behavior, and exploratory locomotion, which are elicited by natural rewards or incentive stimuli. A basic rule of positive reinforcement is that motor responses will increase in magnitude and vigor if followed by a rewarding event. It is likely, therefore, that the nucleus accumbens may serve as a substrate for reinforcement learning. However, there is surprisingly little information concerning the neural mechanisms by which appetitive responses are learned. In the present study, we report that treatment of the nucleus accumbens core with the selective competitive N-methyl-D-aspartate (NMDA) antagonist 2-amino-5-phosphonopentanoic acid (AP-5; 5 nmol/0.5 microl bilaterally) impairs response-reinforcement learning in the acquisition of a simple lever-press task to obtain food. Once the rats learned the task, AP-5 had no effect, demonstrating the requirement of NMDA receptor-dependent plasticity in the early stages of learning. Infusion of AP-5 into the accumbens shell produced a much smaller impairment of learning. Additional experiments showed that AP-5 core-treated rats had normal feeding and locomotor responses and were capable of acquiring stimulus-reward associations. We hypothesize that stimulation of NMDA receptors within the accumbens core is a key process through which motor responses become established in response to reinforcing stimuli. Further, this mechanism, may also play a critical role in the motivational and addictive properties of drugs of abuse.

Effects of α 1-Adrenoceptor and Ca 2+ Channel Inhibition on Norepinephrine-Induced Thermoregulatory Behavior in the Cold

This experiment examined whether paradoxical temperature-dependent effects of norepinephrine (NE) can be blocked by the α 1-adrenoceptor antagonist WB 4101 (WB) and the Ca 2+-channel blocker nifedipine. An operant lever-pressing task was used to measure the demand for heat in a cold environment. As noted previously, NE alone (250 μg/kg) produced a substantial and significant increase in the demand for heat, and yet post-test colonic temperature (Tc) fell. When tested alone, WB and nifedipine also increased the demand for heat, but this was sufficient to maintain Tc. When combined with NE, WB and nifedipine reduced the demand for heat and the fall in Tc such that there were no differences between the effects of the blockers given alone or with NE. These results indicate that paradoxical thermoregulatory effects of NE in the cold can be antagonized effectively by either an α 1-adrenoceptor antagonist or a Ca 2+-channel blocker.

Blockade of Spontaneous Posttraining Performance Improvement in Mice by NMDA Antagonists

We investigated the effects of immediate post-training systemic administration of γ- l-glutamyl- l-aspartate (γ-LGLA) and 3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonate (CPP), antagonists at the N-methyl- d-aspartate receptor, in a lever-press task in two inbred strains of mice. When retention performance was tested in control animals 24 h after partial acquisition of the task, BALB/c mice exhibited a spontaneous performance improvement whereas C57BL/6J mice did not. γ-LGLA at doses of 2.5 and 25 μmol/kg and CPP at doses ranging between 0.025 and 2.5 μmol/kg blocked the spontaneous performance improvement found in BALB/c mice but had no apparent effects on the retention performance of C57BL/6J mice. These data suggest that retention impairment induced by CPP and γ-LGLA in BALB/c mice results from an interference with posttraining memory processes.

Loss of Lever Press-Related Firing of Rat Striatal Forelimb Neurons after Repeated Sessions in a Lever Pressing Task

Lateral striatal neurons that fire phasically in relation to active movement of the contralateral forelimb (determined via daily sensorimotor examination) were studied during acquisition of cued lever pressing. Rats were trained to lift the contralateral forepaw from the floor to press a lever in the presence of a tone. The tone was presented 70 times per day (session) for 18 consecutive days. All animals acquired the task, evidenced by gradual improvements across sessions and eventual asymptotic levels in tone discrimination, reaction time, and efficiency of the lever press. Forelimb neurons fired in relation to the lever press during early sessions of acquisition but not after repeated sessions on the task. This difference in firing could not be attributed to differences in forelimb movements during lever pressing or to sampling from different populations of neurons in early versus late sessions. In view of evidence that striatal damage impairs acquisition of motor skills, the change in firing suggests that the striatal activity present in early sessions may be necessary for the acquisition of, but not the automatic performance of, learned motor responses.

Differential Efficacy of Prior Cuing with CS, US, and Context in Enhancing Long-Term Retention of a Conditioned Emotional Response in Rats

This study investigates the relative efficacy of the conditioned stimulus (CS), the unconditioned stimulus (US), and a discrete feature of the experimental context to act as retrieval cues on long-term retention of a CS–US association in a conditioned suppression paradigm. Rats pretrained to press a lever for food reward were then given a single session of five trials of classical conditioning in a different chamber. A tone acted as CS and was paired with a footshock as an US. Control rats were given explicitly unpaired tones and footshocks. Conditioning and retention were tested (1 and 50 days later) by presenting the CS alone (extinction procedure) while animals were engaged in the food-motivated lever-pressing task. Long-term retention was measured after an interval of 50 days in independent groups of rats exposed to one of three prior-cuing treatments: the CS, the US, and a specific element of the conditioning context (the pattern of the walls). Noncued rats served as conditioned controls. Conditioned suppression to the CS in noncued rats showed that five CS–US pairings produced reliable conditioning, tested at 1 day, with almost no forgetting after 50 days. Noncued rats demonstrated rapid extinction with repeated presentation of the CS alone. Prior cuing with information related to the CS or the US were ineffective in mediating resistance to extinction, whereas pretest exposure to the context enhanced retention performance, as indicated by the slowing down of the rate of extinction during testing. These results suggest the prevalence of context over the CS and US in promoting retrieval from long-term memory in classical conditioning, even when contextual information is limited to a single discrete feature of the conditioning experience and when no performance deterioration is observed after a long retention interval. They suggest the context may gain control over the CS–US association after a long-term retention interval.

The neurosteroid pregnenolone sulfate blocks deficits induced by a competitive NMDA antagonist in active avoidance and lever-press learning tasks in mice

The neurosteroid pregnenolone sulfate (PREG-S) has been shown to modulate positively NMDA receptor activity and to have memory enhancing properties in mice. The present study was designed to evaluate the effects of post-training administration of PREG-S, alone or in combination with D-2-amino-5-phosphonovalerate (D-AP5), a competitive NMDA receptor antagonist, in Y-maze avoidance and appetitively motivated lever-press learning tasks and in a traction reflex test in mice. Intracerebroventricular (i.c.v.) administration of PREG-S (0.01–0.1 nmol/mouse) blocked the selective retention deficits induced by 0.02 nmol D-AP5 in the Y-maze avoidance task. PREG-S (0.1 nmol, i.c.v.) also blocked the retention deficits induced by 0.02 nmol D-AP5 in the lever-press task. Post-training administration of PREG-S alone (0.001–0.1 nmol, i.c.v.) had no effect on retention performance in the Y-maze and the lever-press tasks. PREG-S (1–10 nmol, i.c.v.) significantly reduced the impairment of the traction reflex induced by 2 nmol D-AP5. The ability of PREG-S to block retention performance deficits as well as motor impairment induced by D-AP5 is in agreement with its positive modulatory action at NMDA receptors.