Latent inhibition disruption by MK-801 in a conditioned taste-aversion paradigm

N-Methyl-D-aspartate (NMDA) receptors appear to be involved in CS processing and memory consolidation. The present paper analyzed the effect of the non-competitive NMDA receptor antagonist Dizocilpine maleate (MK-801) on Latent Inhibition (LI)-retarded learning of a CS-US association after to-be-CS preexposures at time of testing, using Wistar rats as experimental subjects. If NMDA receptors are involved in CS processing, MK-801 administration should affect LI. In fact, previous experiments revealed that a 2.0mg/kg MK-801 dose, administered 20 h before preexposure and conditioning, abolished LI in a conditioned taste-aversion paradigm. In the present paper, MK-801 (0.2 mg/kg) was either injected after preexposure, after conditioning, or after both preexposure and conditioning stages. LI was abolished when MK-801 was injected after preexposure, but not when it was injected after conditioning. These results support the role of NMDA receptors in CS processing and memory consolidation.     

Memory-Enhancing Treatments Do Not Reverse the Impairment of Inhibitory Avoidance Retention Induced by NMDA Receptor Blockade

The aim of the present research was to verify whether the impairment of retention induced by the N-methyl-d-aspartate (NMDA) receptor blocker (+)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cycloheptene-5,10 imine (MK-801) can be reversed by memory-enhancing treatments. Adult female Wistar rats were trained and tested in a step-down inhibitory avoidance task (0.3-mA foot shock, 24-h training-test interval). Animals were given an ip injection of saline (SAL) or MK-801 (0.0625 mg/kg) 30 minutes before training, and an ip injection of SAL, epinephrine (EPI) (25 microg/kg), the opioid receptor antagonist naloxone (NAL) (0.4 mg/kg), the glucocorticoid receptor agonist dexamethasone (DEX) (0.3 mg/kg), or glucose (GLU) (320 mg/kg) immediately after training. There was an impairment of inhibitory avoidance retention in the MK-801-SAL, MK-801-EPI, MK-801-NAL, MK-801-DEX, and MK-801-GLU groups. There was an enhancement of retention in the SAL-EPI, SAL-NAL, SAL-DEX, and SAL-GLU groups. A control experiment showed that the amnestic effects of MK-801 could not be attributed to decreased reactivity to the foot shock. The results suggest that memory-enhancing treatments directed at modulatory mechanisms do not reverse the memory impairment induced by NMDA receptor blockade.     

Activation of nociceptin opioid peptide (NOP) receptor impairs contextual fear learning in mice through glutamatergic mechanisms

The present study investigated whether the selective nociceptin opioid peptide (NOP) receptor agonist, Ro64-6198, impairs acquisition of fear conditioning through glutamatergic mechanisms. Systemic administration of Ro64-6198 (0.3 and 1 mg/kg) or the non-competitive NMDA receptor antagonist, MK-801 (0.03 and 0.1 mg/kg) prior to conditioning severely impaired contextual but not cued fear learning in C57BL/6N mice. When administered together at sub-effective doses, Ro64-6198 (0.5 mg/kg) and MK-801 (0.05 mg/kg), synergistically impaired contextual fear learning, but left cued fear learning intact. We next used the immediate shock deficit paradigm (ISD) to examine the effects of Ro64-6198 and MK-801 on contextual memory formation in the absence of the foot-shock. As expected, naive mice that were shocked briefly after being placed in the training chamber displayed no contextual fear conditioning. This learning deficit was elevated by prior exposure of mice to the training context. Furthermore, administration of Ro64-6198 and MK-801, either separately at amnesic doses (1 mg/kg and 0.1 mg/kg, respectively) or concomitantly at sub-effective doses (0.5 mg/kg and 0.05 mg/kg, respectively) significantly reduced the facilitating effects of context preexposure. These findings demonstrate the existence of functional antagonism between NOP and NMDA receptors that predominantly contributes to modulation of conditioned fear learning which involves spatial-processing demands.     

Appetitive memory reconsolidation depends upon NMDA receptor-mediated neurotransmission

Memory persistence is a dynamic process involving the reconsolidation of memories after their reactivation. Reconsolidation impairments have been demonstrated for many types of memories in rats, and signaling at N-methyl-d-aspartate (NMDA) receptors appears often to be a critical pharmacological mechanism. Here we investigated the reconsolidation of appetitive pavlovian memories reinforced by natural rewards. In male Lister Hooded rats, systemic administration of the NMDA receptor antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo{a,d}cyclohepten-5,10-imine maleate (MK-801, 0.1 mg/kg i.p.) either before or immediately following a brief memory reactivation session abolished the subsequent acquisition of a new instrumental response with sucrose conditioned reinforcement. However, only when injected prior to memory reactivation was MK-801 effective in disrupting the maintenance of a previously-acquired instrumental response with conditioned reinforcement. These results demonstrate that NMDA receptor-mediated signaling is required for appetitive pavlovian memory reconsolidation.     

Strain-dependent interactions between MK-801 and cocaine on retention of C57BL/6 and DBA/2 mice tested in a one-trial inhibitory avoidance task: involvement of dopaminergic mechanisms

Two sets of experiments were carried out with C57BL/6 (C57) and DBA/2 (DBA) mice tested in a one-trial inhibitory avoidance task. In the first set C57 and DBA mice were injected posttraining with saline or with the D1 DA receptor antagonist SCH 23390 and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Cocaine enhanced retention in the C57 strain and impaired it in the DBA strain, and MK-801 potentiated the effects of cocaine in both strains. Furthermore, pretreatment with SCH 23390 completely antagonized the potentiation of the effects of cocaine exerted by MK-801. In the second set of experiments mice belonging to these same two strains were injected posttraining with vehicle or with the D2 DA receptor antagonist (-)-sulpiride and then with saline, cocaine (5 mg/kg), MK-801 (0.1 mg/kg), or with a combination of these two drugs. Pretreatment with the D2 DA receptor antagonist completely antagonized in both strains the potentiation of the effect of cocaine exerted by MK-801. The results of the present research show that the noncompetitive NMDA receptor antagonist MK-801 enhances the effect of cocaine on retention performance in C57 and DBA mice and that dopaminergic mechanisms are involved in this potentiation.     

MK-801与环境线索交互作用对吗啡行为敏感化的影响

为探讨MK-801与环境线索交互作用对吗啡诱导行为敏感化的影响,将42只大鼠随机分为对照组,MK-801组,吗啡组（匹配和非匹配）和MK-801+吗啡组（匹配和非匹配）。行为敏感化模型建立分为发展期,戒断期和表达期三个阶段。实验结果发现：同时给予MK-801（0.1mg·kg-1）会促进吗啡（5mg·kg-1）诱导大鼠行为敏感化的发展,而且会使MK-801成为大鼠行为敏感化表达所必需的条件性刺激。MK-801的内部线索作用过强,从而削弱了环境的外部线索作用。研究结果表明：MK-801对吗啡诱导行为敏感化的影响存在状态依赖（state-dependency）现象,提示在NMDA受体与行为敏感化关系的研究中应考虑选择刺激特性更小的药物     

NMDA and muscarinic receptors of the nucleus accumbens have differential effects on taste memory formation

Animals recognize a taste cue as aversive when it has been associated with post-ingestive malaise; this associative learning is known as conditioned taste aversion (CTA). When an animal consumes a new taste and no negative consequences follow, it becomes recognized as a safe signal, leading to an increase in its consumption in subsequent presentations (attenuation of neophobia, AN). It has been shown that the nucleus accumbens (NAcc) has an important role in taste learning. To elucidate the involvement of N-methyl-D-aspartate (NMDA) and muscarinic receptors in the NAcc during safe and aversive taste memory formation, we administrated bilateral infusions of DL-2-amino-5-phosphonopentanoic acid (APV) or scopolamine in the NAcc shell or core respectively. Our results showed that pre-training injections of APV in the NAcc core and shell disrupted aversive but not safe taste memory formation, whereas pre-training injections of scopolamine in the NAcc shell, but not core, disrupted both CTA and AN. These results suggest that muscarinic receptors seem to be necessary for processing taste stimuli for either safe or aversive taste memory, whereas NMDA receptors are only involved in the aversive taste memory trace formation.     

The NMDA receptor antagonist MK-801 blocks acquisition and extinction of conditioned hypoalgesic responses in the rat

The role of the N-methyl-D-aspartate (NMDA) receptor in Pavlovian conditioning of hypoalgesic responses in the hotplate apparatus was examined using the non-competitive NMDA antagonist MK-801. Either MK-801 or saline were administered before the training phase, test phase, or both, and MK-801 disrupted the acquisition and extinction but not the expression of conditioned hypoalgesic responses. All rats received counterbalanced injections of both MK-801 and saline after the training phase, therefore the learning decrements could not be attributed to a delayed, non-specific action of the drug. MK-801 did not augment paw-lick latencies on either the training or test days, indicating that its behavioural effects are not due to alterations in nociceptive sensitivity or motor performance. Similarly, MK-801's effects upon acquisition and extinction could not be attributed to state-dependent generalization decrement or impairments in processing of the hot-plate apparatus cues during training, as rats displayed normal hypoalgesic responses when tested with MK-801, and MK-801-treated animals displayed normal habituation of novelty-induced hypoalgesia in the hot-plate apparatus. These data suggest that the NMDA receptor system is involved in the acquisition and extinction, but not the expression of conditioned hypoalgesia and parallels the effects of NMDA receptor antagonists on the acquisition and expression of long-term potentiation (LTP) both in vitro and in vivo. It is plausible that an endogenous NMDA-mediated form of LTP plays a vital role in the acquisition and storage of aversive representations mediating conditioned hypoalgesic responses.     

Effects of MK-801 and ethanol combinations on memory consolidation in CD1 mice: involvement of GABAergic mechanisms

In the present research the effect of the noncompetitive N-methyl-d-aspartate receptor antagonist MK-801 and ethanol combinations on memory consolidation and the involvement of GABAergic mechanisms in this effect were investigated in CD1 mice injected intraperitoneally with the drugs immediately or 120 min after training in a one-trial inhibitory avoidance apparatus and tested for retention 24 h later. The results showed that (a) the retention performances of mice were impaired in a dose-dependent manner by immediate posttraining MK-801 (0.2 and 0.3, but not 0.1 mg/kg) and ethanol (1 and 2, but not 0.5 g/kg) administrations; (b) an otherwise ineffective dose of MK-801 (0.1 mg/kg) enhanced the deleterious effect exerted by ethanol (1 and 2 g/kg); (c) an otherwise ineffective dose of muscimol (0.5 mg/kg) enhanced, while otherwise ineffective doses of picrotoxin (0.25 mg/kg) or bicuculline (0.1 mg/kg) antagonized, this effect; and (d) no effect was observed when the treatments were carried out 120 min after training, suggesting that the effects observed following immediate posttraining administrations were due to the influence on the consolidation of memory. From these experiments it is evident that (a) MK-801 enhances ethanol's effects on memory consolidation and (b) GABAergic mechanisms are involved in this effect.     

Relationship between vomiting and taste aversion learning in the ferret: studies with ionizing radiation, lithium chloride, and amphetamine.

The relationship between emesis and taste aversion learning was studied in ferrets (Mustela putorius furo) following exposure to ionizing radiation (50-200 cGy) or injection of lithium chloride (1.5-3.0 mEq/kg, ip). When 10% sucrose or 0.1% saccharin was used as the conditioned stimulus, neither unconditioned stimulus produced a taste aversion, even when vomiting was produced by the stimulus (Experiments 1 and 2). When a canned cat food was used as the conditioned stimulus, lithium chloride, but not ionizing radiation, produced a taste aversion (Experiment 3). Lithium chloride was effective in producing a conditioned taste aversion when administration of the toxin was delayed by up to 90 min following the ingestion of the canned cat food, indicating that the ferrets are capable of showing long-delay learning (Experiment 4). Experiment 5 examined the capacity of amphetamine, which is a qualitatively different stimulus than lithium chloride or ionizing radiation, to produce taste aversion learning in rats and cats as well as in ferrets. Injection of amphetamine (3 mg/kg, ip) produced a taste aversion in rats and cats but not in ferrets which required a higher dose (> 5 mg/kg). The results of these experiments are interpreted as indicating that, at least for the ferret, there is no necessary relationship between toxin-induced illness and the acquisition of a CTA and that gastrointestinal distress is not a sufficient condition for CTA learning.     

Differential roles of hippocampal metabotropic glutamate receptors 1 and 5 in inhibitory avoidance learning

Group I metabotropic glutamate receptors (mGlu1 and 5) have been implicated in synaptic plasticity and learning and memory. However, much of our understanding of how these receptors in different brain regions contribute to distinct memory stages in different learning tasks remains incomplete. The present study investigated the effects of the mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), and mGlu1 receptor antagonist, (S)-(+)-alpha-amino-4-carboxy-2-methylbenzene-acetic acid (LY 367385) in the dorsal hippocampus on the consolidation and extinction of memory for inhibitory avoidance learning. Male, Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance task. MPEP, LY 367385 or saline were infused bilaterally into the CA1 region immediately after training or immediately after the first retention test which was given 24h after training. Rats receiving MPEP (1.5 or 5.0 microg/side) or LY 367385 (0.7 or 2.0 microg/side) infusion exhibited a dose-dependent decrease in retention when tested 24h later. MPEP was ineffective while LY 367385 significantly attenuated extinction when injected after the first retention test using an extinction procedure. These findings indicate a selective participation of hippocampal group I mGlu receptors in memory processing in this task.     

Blockade of NMDA Receptors in the Anterior Forebrain Impairs Sensory Acquisition in the Zebra Finch (Poephila guttata)

Juvenile zebra finches (Poephila guttata) learn song in two stages: during sensory acquisition, they memorize the song of an adult tutor, and during sensorimotor learning, they alter their vocalizations to match the stored song model. Like many other forms of neural plasticity and memory formation, vocal learning in zebra finches is impaired by pharmacological blockade of NMDA receptors, but the relevant NMDA receptors have not yet been localized. During song development, one neural region that has been implicated specifically in song learning, the lMAN, exhibits an increased density of NMDA receptors as well as decreased binding affinity for the NMDA antagonist MK-801. To test the hypothesis that sensory acquisition requires activation of NMDA receptors in or near the lMAN we infused the NMDA receptor antagonist amino-5-phosphonopentanoic acid (AP5; 2.5 μg in 0.1 μl) directly into the anterior forebrain. Birds receiving AP5 infusions prior to each of 10 tutoring sessions copied significantly less of their tutor's song than did sham-operated birds, saline-infused birds, birds that received AP5 infusions on nontutoring days, or birds that received AP5 infusions into the cerebellum. Furthermore, infusions of AP5 in the anterior forebrain did not impair young birds’ ability to discriminate zebra finch from canary song. These findings are consistent with the hypothesis that NMDA receptor activation in the anterior forebrain is necessary for the memorization of song material during avian vocal learning. This is also the first report that song-related regions of the anterior forebrain contribute to sensory acquisition specifically.     

N-Methyl-D-aspartate receptors in the ventral tegmental area are involved in retrieval of inhibitory avoidance memory by nicotine

The interaction of opiate, cholinergic, glutamatergic and (possibly) dopaminergic inputs in the ventral tegmental area (VTA) influencing a learned behavior is certainly a topic of great interest. In the present study, the effect of intra-VTA administration of N-methyl-d-aspartate (NMDA) receptor agents on nicotine's effect in morphine state-dependent learning was investigated. An inhibitory avoidance (IA) task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 7.5mg/kg) immediately after training decreased IA response on the test day, which was reinstated by pre-test administration of the same doses of the opioid; this is known as state-dependency. Moreover, pre-test administration of nicotine (0.2, 0.4 and 0.6 mg/kg, s.c.) also reversed the decrease in IA response because of post-training morphine (5mg/kg). Here, we also show that when infused into the VTA before testing, NMDA (0.01 and 0.1 microg/rat) reverse the post-training morphine effect on memory. In addition, the sub-effective doses of NMDA (0.0001 and 0.001 microg/rat) in combination with a low dose of nicotine (0.1mg/kg) which had no effects by themselves, synergistically improved retrieval of IA memory on the test day. In contrast, pre-test administration of a competitive NMDA receptor antagonist D-AP5 (0.5, 1 and 2 microg/rat) which had no effect alone prevented the nicotine reversal of morphine effect on memory. Our data indicate that NMDA receptors in the VTA are involved in the reversing effect of nicotine on morphine induced state-dependency.     

Reactivation-dependent amnesia for appetitive memories is determined by the contingency of stimulus presentation

Previously acquired aversive and appetitive memories are not stable and permanent. The reactivation of such memories by re-exposure to training stimuli renders them vulnerable to disruption by amnestic agents such as the noncompetitive N-methyl-D-aspartate receptor antagonist (+)-5-methyl-10,11-dihydro-SH-dibenzo{a,d}cyclohepten-5,10-imine maleate (MK-801). However, relatively little is known about the parameters that influence the reactivation process. Here, we show that the method of stimulus presentation during memory reactivation is of great importance. Male Lister Hooded rats were trained to acquire a lever press response that delivered a sucrose reward paired with a light conditioned stimulus (CS). The CS-sucrose association was then reactivated through re-exposure to the CS, either contingently upon the lever press response, or noncontingently in the absence of instrumental responding. Systemic administration of MK-801 (0.1 mg/kg) at the time of memory reactivation resulted in amnesia, and hence a reduction in subsequent sucrose seeking induced by, and dependent upon, presentation of the CS, only when the memory was reactivated contingently. Therefore, stimuli may have to be presented in the same manner at memory reactivation as during learning in order to render a previously acquired memory vulnerable to disruption. These results have important implications for the potential translational use of glutamatergic treatments in conjunction with targeted memory reactivation.     

Glycine(B) receptor antagonists and partial agonists prevent memory deficits in inhibitory avoidance learning

Activation of N-methyl-d-aspartate (NMDA) receptors has been hypothesized to mediate certain forms of learning and memory. This hypothesis is based on the ability of competitive and uncompetitive NMDA receptor antagonists to disrupt learning. We investigated the effects of glycine site antagonists and partial agonists on deficits of acquisition (learning) and consolidation (memory) in a single trial inhibitory avoidance learning paradigm. Posttraining administration of either hypoxia (exposure to 7% oxygen) or the convulsant drug pentylenetetrazole (PTZ) (45 mg/kg) to mice impaired consolidation without producing neuronal cell death. Pretreatment with the competitive glycine antagonist 7-chlorokynurenic acid (7KYN) and the glycine partial agonists 1-aminocyclopropanecarboxylic acid (ACPC) and (+)HA-966 prevented memory deficits induced by hypoxia and PTZ, but did not affect scopolamine-induced learning impairment. In addition, ACPC prevented consolidation deficits evoked by a nonexcitotoxic concentration of l-trans-pyrrolidine-2, 4-dicarboxylate, a competitive inhibitor of glutamate transport that increases extracellular levels of glutamate. Moreover, (+)HA-966, 7KYN, and ACPC facilitated both acquisition and consolidation of inhibitory avoidance training, an effect that was dose-dependent and reversed by glycine. These results indicate that memory deficits induced by both hypoxia and PTZ involve NMDA receptor activation. Furthermore, the present findings demonstrate that glycine site antagonists and partial agonists prevent memory deficits of inhibitory avoidance learning by affecting consolidation, but not acquisition processes.     

Extinction of conditioned taste aversion depends on functional protein synthesis but not on NMDA receptor activation in the ventromedial prefrontal cortex

We investigated the role of the ventromedial prefrontal cortex (vmPFC) in extinction of conditioned taste aversion (CTA) by microinfusing a protein synthesis inhibitor or N-methyl-d-asparate (NMDA) receptors antagonist into the vmPFC immediately following a non-reinforced extinction session. We found that the protein synthesis blocker anisomycin, but not the NMDA receptors antagonist D,L-2-amino-5-phosphonovaleric acid, impaired CTA extinction in the vmPFC. Anisomycin microinfusion into vmPFC had no effect on CTA acquisition and by itself did not induce CTA. These findings show the necessary role functional protein synthesis is playing in the vmPFC during the learning of CTA extinction.     

MK-801-Induced Disruptions of One-Trial Inhibitory Avoidance Are Potentiated by Stress and Reversed by Naltrexone

Five experiments were carried out to investigate opioid and NMDA receptor-mediated responses to one-trial inhibitory avoidance training in CD1 mice. In the first experiment immediate posttraining intraperitoneal administration of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 impaired the performance of mice. The effects of MK-801 were time-dependent (they were absent in mice injected with the drug starting 120 min after training). No effect was evident in no-foot-shock groups, showing lack of proactive influence of the treatment on performance. In the second experiment preexposure of the mice to the testing apparatus decreased the effects of MK-801. In the the third experiment naltrexone antagonized the effects of MK-801, suggesting an involvement of opioid neurons. In the fourth experiment immediate posttraining immobilization stress exerted a potentiating effect on the performance of MK-801-injected animals. In the fifth experiment the potentiation of the impairing effect of MK-801 induced by immobilization stress was antagonized by naltrexone.     

Spatial learning and goldfish telencephalon NMDA receptors

Recent results have demonstrated that the mammalian hippocampus and the dorso-lateral telencephalon of ray-finned fishes share functional similarities in relation to spatial memory systems. In the present study, we investigated whether the physiological mechanisms of this hippocampus-dependent spatial memory system were also similar in mammals and ray-finned fishes, and therefore possibly conserved through evolution in vertebrates. In Experiment 1, we studied the effects of the intracranial administration of the noncompetitive NMDA receptor antagonist MK-801 during the acquisition of a spatial task. The results indicated dose-dependent drug-induced impairment of spatial memory. Experiment 2 evaluated if the MK-801 produced disruption of retrieval of a learned spatial response. Data showed that the administration of MK-801 did not impair the retrieval of the information previously stored. The last experiment analyzed the involvement of the telencephalic NMDA receptors in a spatial and in a cue task. Results showed a clear impairment in spatial learning but not in cue learning when NMDA receptors were blocked. As a whole, these results indicate that physiological mechanisms of this hippocampus-dependent system could be a general feature in vertebrate, and therefore phylogenetically conserved.     

Differential interaction of platelet-activating factor and NMDA receptor function in hippocampal and dorsal striatal memory processes

The interaction between platelet activating factor (PAF) and NMDA receptor function in hippocampal and dorsal striatal memory processes was examined. In both a hidden and a visible platform water maze task, peripheral post-training injection of MK-801 (0.05 mg/kg) impaired memory. Post-training intrahippocampal infusions of PAF (1.0 microg/0.5 microl) enhanced memory in the hidden platform task, while intradorsal striatal infusion of PAF (1.0 microg/0.5 microl) enhanced memory in the visible platform task. The memory impairing effects of post-training injection of MK-801 was blocked by concurrent intrahippocampal infusion of PAF. In contrast, post-training injection of MK-801 blocked the memory enhancing effects of concurrent intradorsal striatal infusion of PAF. The results suggest that (1) the memory enhancing effects of intracerebral PAF infusion involve an interaction with NMDA receptor function, and (2) the nature of this interaction may represent a differential mechanism mediating the distinct roles of the hippocampus and dorsal striatum in cognitive memory and stimulus-response habit formation, respectively.