Discrimination Reversal Learning Research Articles

Administration of Memantine During Withdrawal Mitigates Overactivity and Spatial Learning Impairments Associated with Neonatal Alcohol Exposure in Rats

Prenatal alcohol exposure can disrupt central nervous system development, manifesting as behavioral deficits that include motor, emotional, and cognitive dysfunction. Both clinical and animal studies have reported binge drinking during development to be highly correlated with an increased risk of fetal alcohol spectrum disorders (FASD). We hypothesized that binge drinking may be especially damaging because it is associated with episodes of alcohol withdrawal. Specifically, we have been investigating the possibility that NMDA receptor-mediated excitotoxicity occurs during alcohol withdrawal and contributes to developmental alcohol-related neuropathology. Consistent with this hypothesis, administration of the NMDA receptor antagonists MK-801 or eliprodil during withdrawal attenuates behavioral alterations associated with early alcohol exposure. In this study, we investigated the effects of memantine, a clinically used NMDA receptor antagonist, on minimizing ethanol-induced overactivity and spatial learning deficits. Sprague-Dawley pups were exposed to 6.0g/kg ethanol via intubation on postnatal day (PD) 6, a period of brain development that models late gestation in humans. Controls were intubated with a calorically matched maltose solution. During withdrawal, 24 and 36hours after ethanol exposure, subjects were injected with a total of either 0, 20, or 30mg/kg memantine. The subjects' locomotor levels were recorded in open field activity monitors on PDs 18 to 21 and on a serial spatial discrimination reversal learning task on PDs 40 to 43. Alcohol exposure induced overactivity and impaired performance in spatial learning. Memantine administration significantly attenuated the ethanol-associated behavioral alterations in a dose-dependent manner. Thus, memantine may be neuroprotective when administered during ethanol withdrawal. These data have important implications for the treatment of EtOH's neurotoxic effects and provide further support that ethanol withdrawal significantly contributes to FASD.

A novel automated test battery reveals enduring behavioural alterations and cognitive impairments in survivors of murine pneumococcal meningitis

Pneumococcal meningitis, caused by Streptococcus pneumoniae infection, is a major form of lethal bacterial meningitis. Survivors are predisposed to developing lifelong disabling sequelae, including cognitive impairment, psychological problems and motor deficits. In our experimental model, ventricular inoculation of 10(5) colony-forming units of S. pneumoniae type 3 caused 90% of mice to develop life-threatening meningitis within 48 h. Antibiotic treatment with ceftriaxone 20 h post infection reduced the incidence of severe meningitis to <10%. At the time of treatment, upregulation of pro-inflammatory cytokines was detected, including interleukin-1β, interleukin-6 and tumour necrosis factor. We evaluated the long-term behavioural and cognitive sequelae in control mice and those surviving meningitis using an automated system (the IntelliCage) in which mice perform a range of behavioural and spatial tasks to obtain water rewards from conditioning units in their home cage. Surviving mice showed a number of altered behaviours relative to controls, including (i) hypoexploration when first exposed to the IntelliCage, (ii) altered activity patterns (fewer visits to conditioning stations during the light phase and more in the dark phase), (iii) avoidance of light (a constant or flashing LED stimulus), (iv) impaired spatial learning (a complex patrolling task), and (v) impaired discrimination reversal learning. Overall these results suggest photophobia and weakened learning ability in post-meningitic mice, particularly on tasks engaging hippocampal and prefrontal neural substrates. This study also demonstrates a standardised and comprehensive battery of tests that can be readily used to investigate neurological sequelae in undisturbed mice residing in a complex home cage environment.

Midsession reversals with pigeons: visual versus spatial discriminations and the intertrial interval

Discrimination reversal learning has been used as a measure of species flexibility in dealing with changes in reinforcement contingency. In the simultaneous-discrimination, midsession-reversal task, one stimulus (S1) is correct for the first half of the session, and the other stimulus (S2) is correct for the second half. After training, pigeons show a curious pattern of choices: They begin to respond to S2 well before the reversal point (i.e., they make anticipatory errors), and they continue to respond to S1 well after the reversal (i.e., they make perseverative errors). That is, pigeons appear to be using the passage of time or the number of trials into the session as a cue to reverse, and are less sensitive to the feedback at the point of reversal. To determine whether the nature of the discrimination or a failure of memory for the stimulus chosen on the preceding trial contributed to the pigeons' less-than-optimal performance, we manipulated the nature of the discrimination (spatial or visual) and the duration of the intertrial interval (5.0 or 1.5 s), in order to determine the conditions under which pigeons would show efficient reversal learning. The major finding was that only when the discrimination was spatial and the intertrial interval was short did the pigeons perform optimally.

Basolateral Amygdala Lesions Facilitate Reward Choices after Negative Feedback in Rats

The orbitofrontal cortex (OFC) and basolateral amygdala (BLA) constitute part of a neural circuit important for adaptive, goal-directed learning. One task measuring flexibility of response to changes in reward is discrimination reversal learning. Damage to OFC produces well documented impairments on various forms of reversal learning in rodents, monkeys, and humans. Recent reports show that BLA, though highly interconnected with OFC, may be differentially involved in reversal learning. In the present experiment, we compared the effects of bilateral, ibotenic acid lesions of OFC or BLA (or SHAM) on visual discrimination and reversal learning. Specifically, we used pairwise visual discrimination methods, as is commonly administered in non-human primate studies, and analyzed how animals use positive and negative trial-by-trial feedback, domains not previously explored in a rat study. As expected, OFC lesions displayed significantly slower reversal learning than SHAM and BLA rats across sessions. Rats with BLA lesions, conversely, showed facilitated reversal learning relative to SHAM and OFC groups. Furthermore, a trial-by-trial analysis of the errors committed showed the BLA group benefited more from incorrectly performed trials (or negative feedback) on future choices than either SHAM or OFC rats. This provides evidence that BLA and OFC are involved in updating responses to changes in reward contingency and that the roles are distinct. Our results are discussed in relation to a competitive framework model for OFC and BLA in reward processing.

Serial discrimination reversal learning in pigeons as a function of signal properties during the delay of reinforcement

Pigeons learned a series of reversals of a simultaneous red-green discrimination with a 6-s delay of reinforcement. The signal properties during the 6-s reinforcement delay were varied across blocks of reversals, such that the delay was either unsignaled (intertrial interval conditions during the delay) or signaled by illumination of the center key. Four different signal conditions were presented: (1) signals only after S+ responses, (2) signals only after S- responses, (3) differential signals after S+ versus S- responding, and (4) the same nondifferential signals after S+ and S- responses. (A zero-delay control condition was also included.) Learning was at a high level in the S+ -only and differential-signal conditions, and learning was at a low level during the unsignaled, nondifferentially signaled, and S- signal conditions. Thus, a differential stimulus contingent on correct choices was necessary for proficient learning-to-learn, even though within-reversal learning occurred in all conditions. During the S+ and differential-signal conditions, improvement in learning continued to occur even after more than 240 reversals (more than 38,000 trials).

Cholecalciferol attenuates perseverative behavior associated with developmental alcohol exposure in rats in a dose-dependent manner

Alcohol is a known teratogen that is estimated to affect 2–5% of the births in the U.S. Prenatal alcohol exposure can produce physical features such as facial dysmorphology, physiological alterations such as cell loss in the central nervous system (CNS), and behavioral changes that include hyperactivity, cognitive deficits, and motor dysfunction. The range of effects associated with prenatal alcohol exposure is referred to as fetal alcohol spectrum disorders (FASD). Despite preventative measures, some women continue to drink while pregnant. Therefore, identifying interventions that reduce the severity of FASD is critical. This study investigated one such potential intervention, vitamin D3, a nutrient that exerts neuroprotective properties. The present study determined whether cholecalciferol, a common vitamin D3 nutritional supplement, could serve as a means of mitigating alcohol-related learning deficits. Using a rat model of FASD, cholecalciferol was given before, during, and after 3rd trimester equivalent alcohol exposure. Three weeks after cholecalciferol treatment, subjects were tested on a serial spatial discrimination reversal learning task. Animals exposed to ethanol committed significantly more errors compared to controls. Cholecalciferol treatment reduced perseverative behavior that is associated with developmental alcohol exposure in a dose-dependent manner. These data have important implications for the treatment of FASD and suggest that cholecalciferol may reduce some aspects of FASD.This article is part of a Special Issue entitled ‘Vitamin D Workshop’.

Reversal learning as a measure of impulsive and compulsive behavior in addictions

Our ability to measure the cognitive components of complex decision-making across species has greatly facilitated our understanding of its neurobiological mechanisms. One task in particular, reversal learning, has proven valuable in assessing the inhibitory processes that are central to executive control. Reversal learning measures the ability to actively suppress reward-related responding and to disengage from ongoing behavior, phenomena that are biologically and descriptively related to impulsivity and compulsivity. Consequently, reversal learning could index vulnerability for disorders characterized by impulsivity such as proclivity for initial substance abuse as well as the compulsive aspects of dependence. Though we describe common variants and similar tasks, we pay particular attention to discrimination reversal learning, its supporting neural circuitry, neuropharmacology and genetic determinants. We also review the utility of this task in measuring impulsivity and compulsivity in addictions. We restrict our review to instrumental, reward-related reversal learning studies as they are most germane to addiction. The research reviewed here suggests that discrimination reversal learning may be used as a diagnostic tool for investigating the neural mechanisms that mediate impulsive and compulsive aspects of pathological reward-seeking and -taking behaviors. Two interrelated mechanisms are posited for the neuroadaptations in addiction that often translate to poor reversal learning: frontocorticostriatal circuitry dysregulation and poor dopamine (D2 receptor) modulation of this circuitry. These data suggest new approaches to targeting inhibitory control mechanisms in addictions.

Discrimination Reversal Learning in Infant Primates Exposed to Low-Dose Thimerosal: A Pilot Study

Discrimination Reversal Learning in Infant Primates Exposed to Low-Dose Thimerosal: A Pilot Study

Schizophrenia-relevant behaviors in a genetic mouse model of constitutive Nurr1 deficiency

Nurr1 (NR4A2) is an orphan nuclear receptor highly essential for the dopaminergic development and survival. Altered expression of Nurr1 has been suggested as a potential genetic risk factor for dopamine-related brain disorders, including schizophrenia. In support of this, recent experimental work in genetically modified mice shows that mice with a heterozygous constitutive deletion of Nurr1 show a facilitation of the development of schizophrenia-related behavioral abnormalities. However, the behavioral characterization of this Nurr1-deficient mouse model remains incomplete. This study therefore used a comprehensive behavioral test battery to evaluate schizophrenia-relevant phenotypes in Nurr1-deficient mice. We found that these mice displayed increased spontaneous locomotor activity and potentiated locomotor reaction to systemic treatment with the non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, dizocilpine (MK-801). In addition, male but not female Nurr1-deficient mice showed significant deficits in the prepulse inhibition and prepulse-elicited reactivity. However, Nurr1 deletion did not induce overt abnormalities in other cardinal behavioral and cognitive functions known to be impaired in schizophrenia, including social interaction and recognition, spatial recognition memory or discrimination reversal learning. Our findings thus suggest that heterozygous constitutive deletion of Nurr1 results in a restricted phenotype characteristic of schizophrenia symptomatology, which primarily relates to motor activity, sensorimotor gating and responsiveness to the psychomimetic drug MK-801. This study further emphasizes a critical role of altered dopaminergic development in the precipitation of specific brain dysfunctions relevant to human psychotic disorder.

Selective cognitive impairment in the YAC128 Huntington's disease mouse

People with HD have a demonstrated early extra-dimensional set-shifting deficit. In the present study, we use a novel water T-maze set-shifting procedure and demonstrate its validity as a set-shifting task in a mouse model of Huntington's disease. Three groups of YAC128 mice of different ages (27, 69 and 117 weeks) were run on the task, which incorporated six distinct stages in which the mice must learn a rule and then switch to a different rule. The six stages were: directional learning, directional learning reversal, light discrimination, light discrimination reversal, return to place learning and a maze rotation spatial learning test. Rule changes from place learning to light discrimination and back constitute extra-dimensional shifts. The results of the study demonstrate robust light/dark discrimination reversal learning deficits in transgenic mice from 27 weeks of age, and a directional learning to light discrimination extra-dimensional set-shifting deficit from 69 weeks of age. The extra-dimensional shift deficit was confirmed with control trials demonstrating the validity of the deficit and the task. The onset of reversal learning and extra-dimensional shift deficits corresponded with the development of mutant huntingtin N-terminal fragment aggregates in neurons of relevant forebrain regions.

The effects of a single memantine treatment on behavioral alterations associated with binge alcohol exposure in neonatal rats

BackgroundThe third trimester in human fetal development represents a critical time of brain maturation referred to as the “brain growth spurt”. This period occurs in rats postnatally, and exposure to ethanol during this time can increase the risk of impairments on a variety of cognitive and motor tasks. It has been proposed that one potential mechanism for the teratogenic effects of ethanol is NMDA receptor-mediated excitotoxicity during periods of ethanol withdrawal. In neonatal rats, antagonism of NMDA receptors during ethanol withdrawal, with drugs such as MK-801 and eliprodil, has been shown to mitigate some of the behavioral deficits induced by developmental ethanol exposure. The current study examined whether memantine, an NMDA receptor antagonist and a drug used clinically in Alzheimer's patients, would attenuate impairments associated with binge ethanol exposure in neonatal rats. MethodsOn postnatal day 6, rats were exposed to 6g/kg ethanol via intubation with controls receiving an isocaloric maltose dextrin solution. Twenty-one hours following the ethanol binge, rats received intraperitoneal injections of memantine at 0, 10, 15, or 20mg/kg. Ethanol's teratogenic effects were assessed using multiple behavioral tasks: open field activity, parallel bars and spatial discrimination reversal learning. ResultsEthanol-treated rats were overactive in the open field and were impaired on both reversal learning and motor performance. Administration of 15 or 20mg/kg memantine during withdrawal significantly attenuated ethanol's adverse effects on motor coordination, but did not significantly alter activity levels or improve the spatial learning deficits associated with neonatal alcohol exposure. ConclusionThese results indicate that a single memantine administration during ethanol withdrawal can mitigate motor impairments but not spatial learning impairments or overactivity observed following a binge ethanol exposure during development in the rat.

Dopamine, but not serotonin, regulates reversal learning in the marmoset caudate nucleus.

Studies of visual discrimination reversal learning have revealed striking neurochemical dissociations at the level of the orbitofrontal cortex (OFC) with serotoninergic, but not dopaminergic, integrity being important for successful reversal learning. These findings have considerable implications for disorders such as obsessive compulsive disorder and schizophrenia, in which reversal learning is impaired, and which are primarily treated with drugs targeting the dopaminergic and serotoninergic systems. Dysfunction in such disorders however, is not limited to the OFC and extends subcortically to other structures implicated in reversal learning, such as the medial caudate nucleus. Therefore, because the roles of the serotonin and dopamine within the caudate nucleus are poorly understood, this study compared the effects of selective serotoninergic or selective dopaminergic depletions of the marmoset medial caudate nucleus on serial discrimination reversal learning. All monkeys were able to learn novel stimulus-reward associations but, unlike control monkeys and monkeys with selective serotoninergic medial caudate depletions, dopamine-depleted monkeys were markedly impaired in their ability to reverse this association. This impairment was not perseverative in nature. These findings are the opposite of those seen in the OFC and provide evidence for a neurochemical double dissociation between the OFC and medial caudate in the regulation of reversal learning. Although the specific contributions of these monoamines within the OFC-striatal circuit remain to be elucidated, these findings have profound implications for the development of drugs designed to remediate some of the cognitive processes underlying impaired reversal learning.

Simultaneous discrimination reversal learning in pigeons and humans: anticipatory and perseverative errors

Pigeons were trained on a two-choice simultaneous discrimination (red vs. green) that reversed midway through each session. After considerable training, they consistently made both anticipatory errors prior to the reversal and perseverative errors after the reversal, suggesting that time (or number of trials) into the session served as a cue for reversal. In Experiment 2, to discourage the use of time as a cue, we varied the location of the reversal point within the session such that it occurred semirandomly after Trial 10, 25, 40, 55, or 70. Pigeons still tended both to anticipate and to perseverate. In Experiment 3, we required 20 pecks to a stimulus on each trial to facilitate memory for the preceding response and sensitivity to local reinforcement contingencies, but the results were similar to those of Experiment 2. We then tested humans on a similar task with a constant (Experiment 4) or variable (Experiment 5) reversal location. When the reversal occurred consistently at the midpoint of the session, humans, like pigeons, showed a tendency to anticipate the reversal; however, they did not show perseverative errors. When the reversal location varied between sessions, unlike pigeons, humans adopted a win-stay/lose-shift strategy, making only a single error on the first trial of the reversal.

Abnormal strategies during visual discrimination reversal learning in ephrin-A2−/− mice

Eph receptors and ephrins are involved in establishing topographic connectivity in primary sensory brain regions, but also in higher order structures including the cortex and hippocampus. Ephrin-A2 −/− mice have abnormal topography in the primary visual system but have normal visual and learning performance on a simple visual discrimination task. Here we use signal detection theory to analyse learning behaviour of these mice. Wild-type (WT) and ephrin-A2 −/− (KO) mice performed equally well in a two-stimulus visual discrimination task, with similar learning rates and response latencies. However, during reversal learning, when the rewarded stimulus was switched, the two genotypes exhibited differences in response strategies: while WTs favoured a win-stay strategy, KOs remained relatively neutral. KOs also exhibited a stronger lateralization bias in the initial stages of learning, choosing the same arm of the maze with high probability. In addition, use of a Bayesian “optimal observer” revealed that compared to WT, KO mice adapted their decisions less rapidly to a change in stimulus-reward relationship. We suggest that the misexpression of ephrin-A2 may lead to abnormal connectivity in regions known for their involvement in reversal learning and perseverative behaviours, including thalamic–prefrontal cortical–striatal circuitry and particularly orbitofrontal cortex. The implication is that topographic organisation of higher order brain regions may play an important role in learning and decision making.

Serial discrimination reversal learning in pigeons as a function of intertrial interval and delay of reinforcement

Pigeons learned a series of reversals of a simultaneous red-green visual discrimination. Delay of reinforcement (0 vs. 2 sec) and intertrial interval (ITI; 4 vs. 40 sec) were varied across blocks of reversals. Learning was faster with 0-sec than with 2-sec delays for both ITI values and faster with 4-sec ITIs than with 40-sec ITIs for both delays. Improvement in learning across successive reversals was evident throughout the experiment, furthermore, even after more than 120 reversals. The potent effects of small differences in reinforcement delay provide evidence for associative accounts and appear to be incompatible with accounts of choice that attempt to encompass the effects of temporal parameters in terms of animals' timing of temporal intervals.

A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning.

M(1) muscarinic acetylcholine receptors (mAChRs) may represent a viable target for treatment of disorders involving impaired cognitive function. However, a major limitation to testing this hypothesis has been a lack of highly selective ligands for individual mAChR subtypes. We now report the rigorous molecular characterization of a novel compound, benzylquinolone carboxylic acid (BQCA), which acts as a potent, highly selective positive allosteric modulator (PAM) of the rat M(1) receptor. This compound does not directly activate the receptor, but acts at an allosteric site to increase functional responses to orthosteric agonists. Radioligand binding studies revealed that BQCA increases M(1) receptor affinity for acetylcholine. We found that activation of the M(1) receptor by BQCA induces a robust inward current and increases spontaneous EPSCs in medial prefrontal cortex (mPFC) pyramidal cells, effects which are absent in acute slices from M(1) receptor knock-out mice. Furthermore, to determine the effect of BQCA on intact and functioning brain circuits, multiple single-unit recordings were obtained from the mPFC of rats that showed BQCA increases firing of mPFC pyramidal cells in vivo. BQCA also restored discrimination reversal learning in a transgenic mouse model of Alzheimer's disease and was found to regulate non-amyloidogenic APP processing in vitro, suggesting that M(1) receptor PAMs have the potential to provide both symptomatic and disease modifying effects in Alzheimer's disease patients. Together, these studies provide compelling evidence that M(1) receptor activation induces a dramatic excitation of PFC neurons and suggest that selectively activating the M(1) mAChR subtype may ameliorate impairments in cognitive function.

Reversal-specific learning impairments after a binge regimen of methamphetamine in rats: possible involvement of striatal dopamine.

A growing body of evidence indicates that protracted use of methamphetamine (mAMPH) causes long-term impairments in cognitive function in humans. Aside from the widely reported problems with attention, mAMPH users exhibit learning and memory deficits, particularly on tasks requiring response control. Although binge mAMPH administration to animals results in cognitive deficits, few studies have attempted to test behavioral flexibility in animals after mAMPH exposure. The aim of this study was to evaluate whether mAMPH would produce impairments in two tasks assessing flexible responding in rats: a touchscreen-based discrimination-reversal learning task and an attentional set shift task (ASST) based on a hallmark test of executive function in humans, the Wisconsin Card Sort. We treated male Long-Evans rats with a regimen of four injections of 2 mg/kg mAMPH (or vehicle) within a single day, a dosing regimen shown earlier to produce object recognition impairments. We then tested them on (1) reversal learning after pretreatment discrimination learning or (2) the ASST. Early reversal learning accuracy was impaired in mAMPH-treated rats. MAMPH pretreatment also selectively impaired reversal performance during ASST testing, leaving set-shifting performance intact. Postmortem analysis of [(125)I]RTI-55 binding revealed small (10-20%) but significant reductions in striatal dopamine transporters produced by this mAMPH regimen. Together, these results lend new information to the growing field documenting impaired cognition after mAMPH exposure, and constitute a rat model of the widely reported decision-making deficits resulting from mAMPH abuse seen in humans.

Spatial discrimination reversal learning in weanling rats is impaired by striatal administration of an NMDA-receptor antagonist

The striatum plays a major role in both motor control and learning and memory, including executive function and "behavioral flexibility." Lesion, temporary inactivation, and infusion of an N-methyl-d-aspartate (NMDA)-receptor antagonist into the dorsomedial striatum (dmSTR) impair reversal learning in adult rats. Systemic administration of MK-801 disrupts reversal learning in developing rats, as reported in an earlier work by Chadman et al., but it is not known whether NMDA-receptor function within the dmSTR plays a role in this effect. In Experiment 1, reversal learning was dose-dependently impaired following bilateral dmSTR administration of MK-801 (either 2.5 or 5.0 microg) only during the reversal phase relative to saline in postnatal day (P) 26 rats. In Experiment 2, separate groups of P26 rats were trained on the same reversal learning task, but were administered bilateral dmSTR infusions during acquisition only (MK-SAL), reversal only (SAL-MK), both phases (MK-MK), or neither phase (SAL-SAL). The MK-801 effect was specific to the reversal training phase. The drug did not alter acquisition of the initial discrimination. Analysis of the pattern of errors indicates that dmSTR MK-801 treatment increased perseveration of the choice response trained in acquisition. NMDA receptors in the dmSTR play a role in reversal learning in the weanling rat.

Medial prefrontal administration of MK-801 impairs T-maze discrimination reversal learning in weanling rats

Several executive functions rely on the medial prefrontal cortex (mPFC) in the rat. Aspiration and neurotoxic lesions of the mPFC impair reversal learning in adult rats. Systemic administration of MK-801, an NMDA-receptor antagonist, impairs T-maze reversal learning in weanling rats but the role of mPFC NMDA-receptor antagonism in this effect is not known in either adult or young animals. This set of studies showed that mPFC NMDA receptors are specifically involved in T-maze discrimination reversal in weanling rats. In Experiment 1, 26-day-old rats (P26) demonstrated a dose-dependent impairment following bilateral mPFC administration of either 2.5 or 5.0 μg MK-801 or saline (vehicle) during the reversal training phase only. In Experiment 2, P26 rats were trained on the same task, but four groups of rats received bilateral mPFC infusions during acquisition only (MK–SAL), reversal only (SAL–MK), both phases (MK–MK), or neither phase (SAL–SAL). MK-801 impaired performance only when infused during reversal. This suggests that NMDA-receptor antagonism in the mPFC is selectively involved in reversal learning during development and this may account for the previously reported effects of systemic MK-801 on T-maze discrimination reversal in weanling rats.

Intrahippocampal administration of an NMDA-receptor antagonist impairs spatial discrimination reversal learning in weanling rats

Systemic administration of MK-801, an NMDA-receptor antagonist, impairs reversal learning in weanling rats [Chadman, K.K., Watson, D.J., & Stanton, M.E. (2006). NMDA-receptor antagonism impairs reversal learning in developing rats. Behavioral Neuroscience, 120(5), 1071–1083]. The brain systems responsible for this effect are not known in either adult or young animals. This study tested the hypothesis that hippocampal NMDA receptors are engaged in weanling-age rats during spatial discrimination reversal training in a T-maze. In Experiment 1, 26-day-old Long-Evans rats (P26) showed a dose-related impairment on this task following bilateral intrahippocampal administration of either 2.5 or 5.0 μg MK-801 or saline vehicle during the reversal training phase only. In Experiment 2, P26 rats were trained on the same task, but received intrahippocampal MK-801 (2.5 μg) during acquisition, reversal, both, or neither. MK-801 failed to impair acquisition, ruling out nonspecific “performance effects” of the drug. MK-801 impaired reversal irrespective of drug treatment during acquisition. NMDA-receptor antagonism in the hippocampus is sufficient to account for the previously reported effects of systemic MK-801 on reversal of T-maze position discrimination.