Does dizocilpine (MK-801) inhibit the development of morphine-induced behavioural sensitization in rats?

Intermittent morphine pretreatment (10 mg/kg/day for 14 days) induced long-lasting (one month post-treatment) sensitization to the locomotor effects of morphine and amphetamine in rats. Co-administration of the non-competitive NMDA-receptor antagonist dizocilpine (MK-801) (0.1 mg/kg) with morphine did not prevent the development of long-term behavioural sensitization. However, this dose of MK-801 did cause long-term sensitization to its own locomotor effects. Co-administration of 0.25 mg/kg MK-801 with morphine caused death in 60% of the animals. In the animals that survived MK-801 plus morphine pretreatment, neither short-term (3 days) nor long-term morphine-induced sensitization was observed. MK-801 alone (0.25 mg/kg/day for 14 days) induced short-term cross-sensitization to morphine. Thus, the development of long-term morphine-induced locomotor sensitization could only be prevented by a dose of MK-801 that yields a lethal combination with morphine. In addition, MK-801 induced sensitization to its own locomotor effects and cross-sensitization to morphine. These findings seriously question whether MK-801 can be used to study the development of morphine-induced behavioural sensitization.     

Does dizocilpine (MK-801) selectively block the enhanced responsiveness to repeated amphetamine administration?

In order to examine the hypothesis that N-methyl-{d}-aspartate (NMDA) receptors are selectively involved in the development of stimulant sensitization, we characterized the interaction between acute and chronic dizocilpine (MK-801)?+?amphetamine using a detailed behavioral analysis, including concurrent assessment of the locomotor and stereotypy components of the stimulant response and continuous monitoring of all the various phases of the emergent sensitization. The results showed that MK-801 (0.125 mg/kg) significantly affected the acute response to amphetamine (0.5, 1.75, 4.0 mg/kg), increasing or decreasing locomotor activity depending on dose. Repeated administration of MK-801?+?amphetamine resulted in a suppression of stereotyped behaviors and a potentiated locomotor sensitization. These findings suggest that rather than blocking the development of sensitization, MK-801 pretreatment may produce a unique behavioral augmentation that is apparent during coadministration and that persists for up to 48 hr in the response to amphetamine challenge. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Selective absorption of radio frequency energy due to collective motion of charged domains: case of lysozyme crystal

The role of the N-methyl-D-aspartate (NMDA) receptors in cocaine conditioning and sensitization of locomotor activity was studied in four groups of Sprague-Dawley rats. A sub-motoric dose of the NMDA antagonist MK-801 (0.1 mg/kg, i.p.) was employed using a novel dual-compartment Pavlovian drug conditioning paradigm. The animals were placed sequentially in two different test environments in which locomotor activity was monitored. In the first compartment, the animals always received a non-drug test for 20 min. Upon completion of this test, the animals received either saline, cocaine (10 mg/kg i.p.), MK-801 or MK-801 plus cocaine depending on group assignment and were then placed immediately into the second compartment and again tested for 20 min. A total of six non-drug and six drug tests were conducted every other day over a 12-day period. Across all drug/saline treatment and post-treatment tests for conditioning, there were no statistical differences in locomotor activity among the saline and drug treatment groups in the non-drug test environment. In the drug/saline associated environment, however, cocaine had a reliable stimulant effect on locomotion when administered alone or in combination with MK-801. Following a 1-day and again after 21-days of withdrawal, all animals were administered a non-drug test for conditioning in which no injections were administered. On both tests, all groups had equivalent activity levels in the non-drug environment. In the drug/saline environment, only the cocaine group of the three drug treatment groups exhibited conditioned hyperlocomotion. Importantly, MK-801 blocked conditioned hyperlocomotion in the combined cocaine+MK-801 group. MK-801 did not alter serum or brain cocaine concentration or the cocaine effects on dopamine metabolism in limbic brain tissue. The co-administration of MK-801 with cocaine, however, blocked the corticosterone release effect of cocaine. Thus, the NMDA receptor site appears critical for cocaine induced conditioning and for corticosterone release.     

CHRONOMERGE: an application for the merging and display of multiple time-stamped data streams

Neonatal excitotoxic damage of the ventral hippocampus (VH) is a heuristic model of schizophrenia. We investigated whether: (1) neonatal damage of the medial prefrontal cortex (mPFC) has effects similar to the neonatal VH lesion; and (2) intrinsic mPFC neurons contribute to the abnormal behaviors associated with VH lesions. Neonatal rats were lesioned in the mPFC. In adulthood, they showed attenuated locomotion in response to novelty, amphetamine, and MK-801, and enhanced apomorphine-induced stereotypies as compared to controls. Striatal D1 and D2 receptor mRNAs were unaltered. Another group was lesioned in the VH and additionally in the mPFC in adulthood. Destroying mPFC neurons normalized hyperlocomotion to novelty and amphetamine of the neonatally VH lesioned rats. Thus, neonatal damage of the mPFC does not provide a heuristic model of schizophrenia-like phenomena, in contrast to analogous damage of the VH. However, mPFC intrinsic neurons that have developed in the context of abnormal hippocampal connectivity may be responsible for abnormal behaviors in the neonatally VH lesioned rats.     

Cocaine-induced expression of striatal c-fos in the rat is inhibited by NMDA receptor antagonists

To assess the possible involvement of NMDA receptors in mediating the expression of striatal c-fos by cocaine injection, we investigated the effects of the noncompetitive NMDA receptor antagonists, ketamine and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine hydrogen maleate (MK-801), as well as the competitive NMDA receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), in the perikarya of cocaine-treated rat brains. As previously shown by our group, administration of 20 mg/kg cocaine (IP) resulted in the immunocytochemical expression of the protooncogene in numerous cells of the caudate putamen (dorsal/sensorimotor striatum). A ketamine mixture anesthetic (2 mg/kg), however, administered 30 min prior to cocaine exposure completely blocked such genomic expression. Pretreatment with MK-801 (1 mg/kg) or CPP (5 mg/kg) also interfered, albeit to a lesser extent, with the expression of c-fos by cocaine in awake animals. These results indicate that cocaine induction of cellular c-fos in the caudate putamen is mediated at least in part by NMDA-sensitive receptors.     

Effects of amphetamine, morphine and dizocilpine (MK-801) on spontaneous alternation in the 8-arm radial maze

The induction of psychomotor activation, behavioural sensitization and of perseverative behaviours, resulting in reduced behavioural variability, have been proposed to be common properties of drugs of abuse. The present investigation tested whether these drug effects could be measured using spontaneous alternation in an 8-arm radial maze. Behavioural effects of repeated treatment with amphetamine (2 and 4 mg/kg, i.p.), morphine (1.25 and 10 mg/kg, i.p.) and the non-competitive NMDA receptor antagonist, MK-801 (0.1 and 0.2 mg/kg, i.p.), on spontaneous alternation were evaluated in this paradigm. All drugs induced psychomotor activation. Sensitized as well as reduced locomotor activity could be observed after repeated treatment depending on drug and dose. Analysis of the sequences of arm entries revealed that all drugs induced perseverative locomotor patterns, but the pattern induced by amphetamine and morphine differed qualitatively from the pattern induced by MK-801.     

The NMDA receptor antagonist MK-801 elicits conditioned place preference in rats

(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate, (MK-801) a potent noncompetitive antagonist of central NMDA receptors, has been hypothesized to have rewarding properties indicative of abuse potential. To test this hypothesis, the effects of MK-801 on the acquisition of a conditioned place preference and on locomotor activity were assessed and compared with d-amphetamine. Both MK-801 (0.03 and 0.1 mg/kg, SC) and d-amphetamine (1.0 mg/kg, SC) administration resulted in the acquisition of a conditioned place preference. However, while both amphetamine and the higher dose of MK-801 produced a behavioral activation during the training period the lower dose of MK-801 did not. These results suggest that MK-801, at doses that produce behavioral activation and below, is rewarding and therefore may have abuse potential.     

YM796, a novel muscarinic agonist, improves the impairment of learning behavior in a rat model of chronic focal cerebral ischemia

Four-layered microgyria is associated with many developmental disorders, including mental retardation, epilepsy, and developmental dyslexia. Freezing lesions to the newborn rodent neocortex result in the formation of four-layered microgyria. Previous research had suggested this type of injury acts as an hypoxic/ischemic event to the developing cortical plate. The current study examines the effectiveness of the non-competitive N-methyl-D-aspartate receptor antagonist dizocilpine (MK-801) in protecting against freezing injury to the newborn rat cortical plate. Three groups of rats received freezing injury to the cortical plate on the first day of life (postnatal day 1). Two groups were treated with MK-801 (1 or 2 mg/kg) 0.5 h before the lesion and 6 and 14 h after, while one group received saline injections. A fourth group received MK-801 injections, but did not have a freezing lesion. The volume of neocortical abnormality was determined for all three groups in rats killed after postnatal day 7. Treatment with the higher dose of MK-801 (3 x 2 mg/kg) dramatically reduced the effects of freezing injury but also resulted in over 50% mortality in both lesioned and unlesioned groups. Animals in the lesioned group, however, had a decreased volume of abnormal cortex, and there were fewer animals with microsulci than in the untreated group. This is the first demonstration of a significant anatomical neuroprotective effect in newborns leading to a reduction of cortical malformation.     

Sensitization to the rewarding effects of the specific dopamine uptake inhibitor GBR12783

The conditioned place preference (CPP) induced by increasing doses (1.25-40 mg/kg) of cocaine or the specific dopamine uptake inhibitor GBR12783 was investigated in rats previously treated with cocaine (10 or 20 mg/kg), GBR12783 (10 mg/kg) or morphine (10 mg/kg) for 15 days. In solvent-pretreated rats, cocaine- and GBR12783-induced CPPs were biphasic, with the highest scores observed at 20 mg/kg. Prior exposure to GBR12783 sensitized the rats to the rewarding effects of low doses of either GBR12783 or cocaine. Pretreatment with cocaine 20 mg/kg, but not 10 mg/kg, sensitized the rats to its own rewarding effects. Furthermore, it was less efficient than GBR12783 in sensitizing the animals to the rewarding effects of both drugs. These data confirm the major role of dopamine uptake inhibition in the sensitization process. On the other hand, the magnitude of CPP induced by a high dose of both drugs (20 mg/kg) was decreased after pretreatment with either GBR12783 or cocaine, reaching the lower scores observed at 40 mg/kg. This decrease was unrelated to altered anxiety level but was associated with sensitization to stereotypies. Morphine pretreatment modified neither the CPP induced by high doses of cocaine or GBR12783 nor cocaine- or GBR12783-induced stereotypies. However, prior exposure to morphine sensitized the rats to the rewarding effects of cocaine (2.5 mg/kg) but not to those of GBR12783, suggesting that other mechanisms working in concert with dopamine may facilitate the rewarding effect of cocaine without affecting that of GBR12783.     

Evaluation of enterolithiasis in equids: 900 cases (1973-1996)

In this study we investigated the effect of lesioning the noradrenergic systems on the behavioral effects of (5R, 10S)-(+)-5-Methyl-10,11-dihydro-5H-dibenzo [a, d] cyclohepten-5,10-imine hydrogen maleate--MK-801, in rats. The noradrenergic system was lesioned with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride--DSP4 (60 mg/kg IP). MK-801 increased the locomotor activity and rearing. DSP4 significantly further increased the hyperlocomotor activity, circling (especially to the left side), sniffing, rolling, and falling that were induced by MK-801. These results showed that destruction of the noradrenergic system increased MK-801-hyperlocomotor activity, ataxia and stereotypy.     

Dizocilpine (MK-801) blocks tolerance to the analgesic but not to the hyperthermic effect of morphine in the rat

The effect of dizocilpine (MK-801), an N-methyl-D-aspartate receptor antagonist, on the development of tolerance to the analgesic and hyperthermic effects of morphine was determined in the rat. Tolerance to morphine in male Sprague-Dawley rats was induced by implanting subcutaneously 6 morphine pellets during a 7-day period. Two schedules of intraperitoneal injections of MK-801 were used. In one, the drug was injected once a day, and in the other it was injected twice a day. The doses of MK-801 were 0.03, 0.1 and 0.3 mg/kg. In the treatment once a day, MK-801 blocked the development of tolerance to the analgesic effect of morphine, but there was no dose-dependent effect. In the treatment twice a day, MK-801 produced a dose-dependent inhibition of tolerance to the analgesic effect of morphine. Higher doses of MK-801 produced high mortality. MK-801 given once a day or twice a day failed to affect the tolerance to the hyperthermic effect of morphine. In both schedules of MK-801 treatment, the highest dose of MK-801 resulted in high mortality. It is concluded that MK-801 is selective in blocking the tolerance to the analgesic effect of morphine in the rat.     

Blood lead of intravenous drug users

Ethanol, morphine, cocaine and amphetamine were examined in place conditioning. After determination of initial preferences, animals were conditioned with ethanol (1 g/kg), morphine (5 mg/kg), cocaine (5 mg/kg) and amphetamine (5 mg/kg) alone or with combinations of these drugs plus naloxone (1 mg/kg). Naloxone prevented the ability of all drugs used to produce a place preference. The reinforcing properties of ethanol and morphine were reduced by sodium nitroprusside at a dose equal to 1/10 of LD50 given before preference testing. Molsidomine (1/10 LD50 and 1/20 LD50) altered the expression of the conditioned place preference produced by ethanol but not by morphine. Results of the present study suggest the involvement of endogenous opioids and probably of nitric oxide in the rewarding actions of drugs of abuse.     

Drug-induced reinstatement of heroin- and cocaine-seeking behaviour following long-term extinction is associated with expression of behavioural sensitization

The present study was designed to evaluate the relationship between reinstatement of drug-seeking behaviour following long-term extinction of intravenous (i.v.) drug self-administration (an animal model for craving) and long-term behavioural sensitization. Rats were allowed to self-administer heroin (50 microg/kg per inj., 14 daily sessions), cocaine (500 microg/kg per inj., 10 daily sessions) or saline. Following a 3-week extinction period, reinstatement tests were performed to evaluate priming effects of amphetamine, cocaine and heroin on nonreinforced drug-seeking behaviour. In addition, the occurrence of long-term behavioural sensitization in rats with a history of heroin or cocaine self-administration was determined. Heroin-seeking behaviour was reinstated by heroin (0.25 mg/kg), amphetamine (1.0 mg/kg) and cocaine (10 mg/kg). In addition, animals with a history of heroin self-administration displayed locomotor sensitization to both heroin and amphetamine. Cocaine-seeking behaviour was reinstated by cocaine and amphetamine, but not by heroin. Interestingly, locomotor sensitization to amphetamine, but not heroin, was observed in animals with a history of cocaine self-administration. In other words, the induction of drug-seeking behaviour following a prolonged drug-free period was found to be associated with the expression of long-term behavioural sensitization. These data provide experimental evidence for a role of behavioural sensitization in the incentive motivation underlying drug-seeking behaviour. If drug hyperresponsiveness would indeed be a crucial factor in drug-induced craving in human addicts, pharmacological readjustment of the neuroadaptations underlying drug sensitization may prevent relapse to drug use long after detoxification.     

Promoter/repressor system of Lactobacillus plantarum phage og1e: characterization of the promoters pR49-pR-pL and overproduction of the cro-like protein cng in Escherichia coli

Previous studies have shown that extensive damage to the medial prefrontal cortex (mPFC) of rats causes reversal learning deficits. The mPFC of rats, however, consists of several subareas that are different from each other in both cytoarchitecture and neural connectivity, suggesting a functional dissociation among the mPFC subareas. In the present study, selective lesions of the mPFC of rats were made with a specially designed microknife whose intracranial placement could be controlled stereotaxically. Restricted lesions were made to each of the 3 parts of the mPFC: the anterior cingulate area (AC) (including the medial precentral area, PrCm), the prelimbic area (PL), and the infralimbic area (IL). One week after surgery, rats were trained in an aversively motivated visual discrimination task in a novel rotating T-maze. After reaching the acquisition criterion, rats were trained in a reversal task in the same maze. No difference was found in acquisition between control and mPFC lesioned rats. However, lesions of either the PL or the IL produced a marked deficit in the reversal task. This behavioral deficit was not found in rats with lesions of the AC. The results indicate that the mPFC of rats is not essential for discrimination learning, but that each of the 2 ventral subareas of the mPFC, PL, and IL, plays a critical role in reversal learning.     

Effects of calcium channel entry blockers on cocaine and amphetamine-induced motor activities and toxicities

The effects of calcium channel entry blockers on cocaine and amphetamine-induced behavioral responses were investigated. Cocaine and amphetamine produced dose-dependent increases in locomotor activity and stereotyped behavior with a maximum response at 40 and 1.2 mg/kg, respectively. The 1,4-dihydropyridine nimodipine and the benzothiazepine diltiazem were more effective in inhibiting cocaine (20 mg/kg)-induced responses than amphetamine (0.6 mg/kg)-induced responses. At doses of cocaine and amphetamine that caused seizures and death, nimodipine, nitrendipine and diltiazem did not offer any protection; rather, they potentiated the toxicities produced by these psychomotor stimulants.     

Increased sensitivity to the locomotor depressant effect of a dopamine receptor antagonist during cocaine withdrawal in the rat

The effect of a dopamine receptor antagonist on locomotor activity was examined during withdrawal from either self-administered or experimenter-administered cocaine. In the self-administration experiment, the locomotor response to a challenge injection of cis-flupenthixol was assessed in photocell cages at 4 h after the cessation of a 12-h cocaine self-administration session. Rats which had self-administered cocaine, and were challenged with cis-flupenthixol (0.05 mg/kg), were found to be hypoactive relative to controls. In the experimenter-administered cocaine experiment, animals were given eight IP injections of 15 mg/kg cocaine over a 9.5-h period, for a total of 120 mg/kg. At 4, 8, and 24 h (tested in three separate groups of rats) after cessation of the eight injections, the locomotor response to a challenge injection of saline or cis-flupenthixol was tested. Cocaine-treated animals displayed a dose-dependent, heightened sensitivity to the locomotor depressant effects of 0.05 mg/kg and 0.2 mg/kg cis-flupenthixol 4 h post-cocaine, whereas they did not show increased sensitivity to 0.05 mg/kg cis-flupenthixol 8 or 24 h post-cocaine. However, cocaine-treated animals displayed a mild hypoactivity 8 h post-cocaine. In a separate group of animals, a dose-response experiment was performed which indicated that a dose of cis-flupenthixol as high as 0.2 mg/kg was required to produce locomotor depression in cocaine-naive rats. The results of this study support clinical observations of dopamine antagonist-precipitated motor dysfunction in abstinent cocaine abusers, and lend further support to the hypothesis that alterations in dopaminergic neurotransmission consequent to prolonged cocaine exposure are partly responsible for some of the symptoms of cocaine withdrawal.     

Differences in NMDA receptor antagonist-induced locomotor activity and [3H]MK-801 binding sites in short-sleep and long-sleep mice

Short-Sleep (SS) and Long-Sleep (LS) mice differ in initial sensitivity to ethanol. Ethanol acts as an antagonist at N-methyl D-aspartate receptors (NMDARs). Therefore, we tested whether SS and LS mice also differ in initial sensitivity to NMDAR antagonists. Systemic injection (intraperitoneal) of either the noncompetitive NMDAR antagonist MK-801 (dizocilpine) or the competitive NMDAR antagonist 2-carboxypiperazin-4-yl-propyl-1-phosphonic acid (CPP) produced similar results. At lower drug doses, SS mice showed greater locomotor activation than LS mice; and at higher doses, SS mice continued to be activated whereas LS mice became sedated. Brain levels of [3H]MK-801 were 40% higher in SS, compared with LS, mice. However, blood levels of [3H]MK-801 and [3H]CPP and brain levels of [3H]CPP were similar in the two lines. NMDARs were measured using quantitative autoradiographic analysis of in vitro [3H]MK-801 binding to SS and LS mouse brains. Significantly higher (20 to 30%) receptor densities were observed in the hippocampus and cerebral cortex of SS mice. Our results support the hypothesis that SS and LS mice differ in initial sensitivity to NMDAR antagonists and suggest that the line differences in the dose-response relationships for MK-801- and CPP-induced locomotor activity are qualitatively similar to those reported for ethanol. Differences in pharmacokinetics and number of NMDARs may contribute to, but are unlikely to entirely account for, the differential behavioral responsiveness of SS and LS mice to MK-801 and CPP.     

Spontaneous and drug-stimulated locomotor activity after the administration of pertussis toxin into the ventral tegmental area

Pertussis toxin (PTX) injected into the ventral tegmental area (VTA) produces an enhanced locomotor response to amphetamine. In the present study, we have evaluated the role of dopamine receptors on spontaneous locomotor activity and the enhanced locomotor response to dopaminergic agonists after the administration of PTX into the VTA. PTX injected into the VTA of rats produced a delayed increase in spontaneous locomotor activity with a latency of 4 d. This activity was markedly increased by day 6 and remained elevated for at least 28 d after PTX treatment. This increased spontaneous locomotor activity of PTX-treated animals was antagonized by the administration of the D1 receptor antagonist SCH23390 (0.03 and 0.1 mg/kg sc), but not by the D2 receptor antagonist eticlopride (0.1 and 0.3 mg/kg sc). After adaptation to the locomotor cages, the animals showed a markedly enhanced motor response to amphetamine (0.5 mg/kg ip) and apomorphine (5 mg/kg sc). The heightened locomotor responses to these dopaminergic agonists could be elicited for at least 2 mo after PTX administration. The enhanced response to amphetamine was antagonized by the administration of SCH23390 (0.03 and 0.1 mg/kg sc), but not by eticlopride (0.1 mg/kg). The increased response to apomorphine in PTX-treated animals was inhibited by SCH23390 (0.1 mg/kg sc) and partially inhibited by eticlopride (0.1 mg/kg sc). Both of these antagonists inhibited the spontaneous and the drug-induced locomotor responses in vehicle-treated control animals. These results suggest that the administration of PTX into the VTA leads to an increase in spontaneous and drug-induced locomotor activity in which D1 receptors seem to play an important role.     

The influence of nimodipine and MK-801 on the brain free arachidonic acid level and the learning ability in hypoxia-exposed rats

1. The influence of voltage dependent calcium channel blocker (VDCC), nimodipine and N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 on the brain free arachidonic acid (FAA) level and on the learning ability in hypoxia-exposed rats was examined. 2. Some animals were decapitated after cerebral hypoxia had been obtained and the brain FAA level was determined by gas chromatography. The other animals were trained in a passive avoidance procedure and were exposed to hypoxic conditions immediately after the learning trial response had been acquired. A passive avoidance retention test was performed 24 hours later. 3. Various doses of nimodipine (0.03; 0.1; 0.3 and 1.0 mg/kg) and MK-801 (0.03; 0.1 and 0.3 mg/kg) had been injected 30 minutes before biochemical or behavioral procedures started. 4. It was found that hypoxia strongly increased the brain FAA level and impaired the retention of the passive avoidance response. 5. Pretreatment with 0.3 mg/kg and 1.0 mg/kg of nimodipine prevented the brain FAA accumulation. It has also been shown that all tested doses of nimodipine significantly improved the retention deficit in the animals exposed to hypoxia. 6. Neither the one of tested doses of MK-801 influenced significantly the increase of the brain FAA level and/or passive avoidance behavior in hypoxic animals. 7. These results confirm the hypothesis that the brain FAA accumulation and cognitive impairment, caused by hypoxia, are maybe associated with disturbances in calcium homeostasis and that nimodipine may be useful in ameliorating the hypoxia-induced brain tissue damage. Blocade of NMDA receptor-channel complex by MK-801 was not sufficient to prevent hypoxia-induced neuronal damage.     

NMDA receptors modulate long-term habituation to spatial novelty: dose- and genotype-dependent differential effects of posttrial MK-801 and CPP in rats

To investigate the role N-methyl-D-aspartate (NMDA) receptors play in behavioral plasticity, adult male rats of the Naples high-(NHE) and low-excitability (NLE) lines, and of a random-bred Sprague-Dawley strain (NRB) received, the noncompetitive (MK-801:0.01 or 2.5 mg/kg) or the competitive (CPP: 0.01 or 5 mg/kg) NMDA receptor antagonists, or vehicle IP soon after a 10-min test in a Làt-maze. Retention was tested 1 week later. Habituation of activity and defecation score was monitored by the between-test decrement (LTH) in the frequency of corner-crossings (HA) and rearings (VA), with prevailing cognitive and noncognitive meaning, respectively, and of fecal boli. (i) In the NLE-rats, low and high doses of MK-801 facilitate LTH of HA, and a high dose of CPP facilitates LTH of HA. (ii) In the NRB-rats, MK-801 facilitates LTH of HA at a low dose and inhibits LTH of VA at a high dose, whereas CPP inhibits LTH of HA at a high dose only. In contrast, (iii) in the NHE-rats, high doses of MK-801 impair LTH of HA, and low doses of CPP facilitate LTH of HA. In conclusion, the dose- and genotype-dependent differential effects of allosteric and isosteric receptor blockade support the hypothesized modulatory role of NMDA receptors in behavioral plasticity; and the dissociation between retention of cognitive and noncognitive behavioral components suggests that NMDA receptors are involved in their parallel processing.