Infusion Of AP5 Research Articles

NMDA antagonist AP-5 increase environmentally induced cocaine-conditioned locomotion within the nucleus accumbens

An environment previously associated with cocaine use can elicit cravings, even in the absence of the drug, which may be due to the formation of strong associations between the environment and the drug. These associations can result from motor learning and reinforcing effects of cocaine, and may be mediated in part by ionotropic glutamate receptors in the nucleus accumbens (N.Acc.). To determine whether NMDA receptor activity in the N.Acc. affects the expression of conditioned locomotion, rats were trained using an environment-elicited cocaine-conditioning paradigm. Rats trained to pair a cocaine injection with an environment showed an increased locomotor activity when tested in the drug-paired environment, whereas rats injected with cocaine in their home cages did not exhibit greater locomotion. Significantly greater locomotor activity occurred in trained animals that received an infusion of AP-5, a NMDA receptor antagonist, into the N.Acc. These results suggest that animals trained to associate environmental cues with cocaine become conditioned to this environment. Furthermore, our finding demonstrates that NMDA receptor activation within the N.Acc. modulates cocaine-induced conditioning.

Aversive Learning under Different Training Conditions: Effects of NMDA Receptor Blockade in Area CA1 of the Hippocampus

Adult male Wistar rats were given either a single training trial or one training trial per day during 3 days followed by a retention test trial in an inhibitory avoidance (IA) task. In animals given a single training trial, pretraining, but not pretest bilateral infusion of the NMDA glutamate receptor antagonist d,l-2-amino-5-phosphonopentanoic acid (AP5) (5.0 microg) into the CA1 hippocampal area blocked IA retention. In animals given three training trials, infusions of AP5 given prior to each of the three training trials severely impaired, but did not block retention. The results indicate that NMDA receptors in the hippocampus are involved in the formation, but not in expression, of aversive memory. In addition, rats given repeated training were able to show a mild improvement of performance across training trials, possibly through mechanisms that do not depend on NMDA receptor activation in the dorsal hippocampus.

Effects of AP5 infusion into the lateral ventricle on the activities and hippocampal electrical patterns of sleep episodes in rats

Although N-methyl- d-aspartate (NMDA) receptors of the hippocampus are mainly associated with learning and memory that might occur “on-line” during sharp waves (SPWs) and theta-rhythm, the participation of hippocampal NMDA receptors in sleep-related processes has not been well studied. In this study, the activity of sleep episodes, hippocampal SPWs and theta-rhythm were recorded in rats received a repeated infusion of NMDA receptor antagonist, d, l-2-amino-5-phosphonopentanoic acid (AP5), into the lateral ventricle in a 5-h daytime sleep. The first trial AP5 infusion (30 mM/2 μl) did not change measures of the activity of slow wave sleep (SWS), paradoxical sleep (PS) and awake episodes, but induced a delay in the latency of the first onset of PS; in the hippocampal EEG, it increased the amplitude of SPWs within SWS and shifted the amplitude/spectral power of theta-rhythm from high to low frequency within PS. The repeated AP5 infusion augmented the activity of SWS, and impaired PS and awake episodes; in the EEG-sleep picture, it maintained high scores of SPWs with the complete blockade of theta-rhythm generation. When AP5 rat was woken, the theta-rhythm was seen during exploratory behavior. These findings provide evidence that hippocampal NMDA receptors via SPWs or directly associated with the synaptic events of theta-rhythm generation are critical for the PS activities.

NMDA Receptors Mediate Consolidation of Contextual Memory in the Hippocampus after Context Preexposure

Male Wistar rats received bilateral infusions of vehicle (VEH) or aminophosphonopentanoic acid (AP5), an N-metil-D-aspartate (NMDA) receptor antagonist, into the dorsal hippocampus immediately after inhibitory avoidance (IA) training. Intrahippocampal infusion of AP5 blocked 24 h IA retention. In the second experiment, animals were preexposed to the IA training context 24 h prior to training and received an infusion of either VEH or AP5 immediately after the preexposure trial and a second infusion of VEH or AP5 immediately after IA training. AP5 did not affect retention in animals preexposed to the IA box and given VEH after preexposure, but blocked retention when given after both preexposure and training. AP5 impaired retention in rats preexposed to an environment distinct from the IA box. These results suggest that NMDA receptors in the dorsal hippocampus mediate the formation of a contextual representation of the task environment.

Hypofunction of the dorsal hippocampal NMDA receptors impairs retrieval of memory to partially presented foreground context in a single-trial fear conditioning in rats

In the present study, the effects of N-methyl- d-aspartate (NMDA) receptor antagonist, d, l-2-amino-5-phosphonopentanoic acid (AP5) bilaterally infused into the dorsal hippocampus (2.0 μl /5 μg), on the retrieval of fear memory to partial and whole foreground cues were evaluated by using a step-through passive avoidance and Pavlovian fear conditioning. In the both conditioning tasks, following a 30-s preshock exposure period to the shock-associated context, rats received a single shock in a foreground manner for fear memory exhibition by freezing. Rats with AP5 infusion 5 min before the retrieval tests showed profound freezing deficits either immediately or 48 h after the shock in the testing section of the passive avoidance chamber where foreground cues was partially presented. In the Pavlovian conditioning chamber where fear conditioning was tested in the whole of the context that was explicitly paired with the shock, AP5 rats in all infusion schedules exhibited robust freezing responses. These results showed that hypofunction of the hippocampal NMDA receptors impaired the retrieval of fear memory to partial, and not whole, foreground cues. This suggests that NMDA receptors of the hippocampus are involved in the formation of background context representations about foreground events when there is a deficit in perceiving certain sensory properties of the foreground retrieval cues.

The contribution of NMDA receptors in the dorsolateral striatum to egocentric response learning.

The present study examined the effects of the N-methyl-D-aspartate (NMDA) competitive antagonist, 2-amino-5-phosphonopentanoic acid (AP-5), injected into the dorsolateral striatum on the acquisition and reversal learning of a response discrimination. Male Long-Evans rats were tested across 2 consecutive days in a modified cross-maze. An infusion of either saline or AP-5 (5 or 25 nM) occurred 5 min prior to testing. In acquisition rats learned to turn left or right. In reversal learning rats learned to turn in the opposite direction. An AP-5 infusion at 25 nmol, but not 5 nmol, impaired response acquisition. Neither AP-5 dose impaired response reversal learning. The results suggest that NMDA receptors in the dorsolateral striatum are critical for the initial learning of an egocentric response discrimination.

Memory consolidation induces N-methyl- d-aspartic acid-receptor- and Ca 2+/calmodulin-dependent protein kinase II-dependent modifications in α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor properties

The N-methyl- d-aspartic acid (NMDA) receptor-dependent activation of Ca 2+/calmodulin-dependent protein kinase II (CaMKII) is necessary for induction of the long-term potentiation of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor-mediated responses in the CA1 region of the hippocampus, a putative model for learning and memory. We analyzed the interplay among NMDA receptor, CaMKII and AMPA receptor during consolidation of the memory for an inhibitory avoidance learning task in the rat. Bilateral intra-CA1 infusion of the NMDA receptor antagonist d-(−)-2-amino-5-phosphonopentanoic acid (AP5) or of the CaMKII inhibitor 2-[ N-(2-hydroxyethyl)]- N-(4-methoxybenzenesulfonyl)] amino- N-(4-chlorocinnamyl)- N-methylbenzylamine) (KN-93) immediately after step-down inhibitory avoidance training hindered memory consolidation. Learning of the avoidance response induced the NMDA receptor-dependent translocation of αCaMKII to a postsynaptic density-enriched fraction isolated from dorsal CA1 and the autophosphorylation of this kinase at Thr-286. Step-down inhibitory avoidance training increased the quantity of GluR1 and GluR2/3 AMPA receptor subunits and the phosphorylation of GluR1 at Ser-831 but not at Ser-845 in CA1 postsynaptic densities. The intra-CA1 infusion of KN-93 and AP5 blocked the increases in GluR1 and GluR2/3 levels and the phosphorylation of GluR1 brought on by step-down inhibitory avoidance training. Our data suggest that step-down inhibitory avoidance learning promotes the learning-specific and NMDA receptor-dependent activation of CaMKII in the CA1 region of the dorsal hippocampus and that this activation is necessary for phosphorylation and translocation of AMPA receptor to the postsynaptic densities, similarly to what happens during long-term potentiation.

The influence of NMDA receptors in the dorsomedial striatum on response reversal learning

In mammals, the dorsomedial striatum is one brain area shown to be critical for the flexible shifting of response patterns. At present, the neurochemical mechanisms that underlie learning during a shift in response patterns are unknown. The present study examined the effects of NMDA competitive antagonist, dl-2-amino-5-phosphonopentanoic acid (AP-5), injected into the dorsomedial striatum on the acquisition and reversal of a response discrimination. Male Long-Evans rats were tested across two consecutive days in a modified cross-maze. Rats received an infusion of either saline or AP-5 (5 or 25 nmol) 5 min prior to each test session. In the acquisition phase rats learned to turn in one direction (right or left) to receive a cereal reinforcement. In the reversal learning phase rats learned to turn in the opposite direction as in the acquisition phase. In both phases, criterion was achieved when a rat made 10 consecutive correct trials. Infusions of AP-5 did not impair acquisition, but impaired reversal learning of a response discrimination in a dose-dependent fashion. The reversal learning deficit induced by AP-5 resulted from reversions back to the originally learned response pattern following the initial shift. These results suggest that activation of NMDA receptors in the dorsomedial striatum are critical for the flexible shifting of response patterns by enhancing the reliable execution of a new response pattern under changing task contingencies.

N-methyl- d-aspartate receptors in the amygdala are necessary for the acquisition and expression of conditioned defeat

Here, we describe a biologically relevant model called conditioned defeat that is used to examine behavioral responses to social defeat in Syrian hamsters. In this model experimental animals that are normally aggressive experience social defeat and consequently display high levels of submissive/defensive behavior even in response to non-threatening conspecifics. N-methyl- d-aspartate (NMDA) receptors within the amygdala play an important role in conditioned fear; therefore, the purpose of this study was to examine whether NMDA receptors within the amygdala are necessary for the acquisition and expression of conditioned defeat. Specifically, the present study examined whether bilateral infusions of the NMDA receptor antagonist dl-2-amino-5-phosphonopentanoic acid (AP5; 0.625, 1.25, 2.5, 5.0, 10.0 μg) into the amygdala would block the acquisition of conditioned defeat. Subsequently, we examined whether bilateral infusions of AP5 (0.625, 1.25, 2.5, 5.0 μg) into the amygdala prior to testing would block the expression of conditioned defeat. Infusions of AP5 into the amygdala immediately before the initial social defeat significantly reduced submissive/defensive behavior when hamsters were tested the following day with a non-aggressive intruder. Similarly, infusions of AP5 into the amygdala immediately before exposure to a non-aggressive intruder significantly attenuated the display of submissive/defensive behavior. These data demonstrate that NMDA receptors are necessary for both the acquisition and expression of conditioned defeat. We believe that conditioned defeat is a unique and valuable animal model with which to investigate the neurobiology of fear-related changes in social behavior.

Intra-basolateral amygdala infusions of AP-5 impair or enhance retention of inhibitory avoidance depending on training conditions

Previous evidence has suggested that N-methyl- d-aspartate receptors (NMDARs) in the basolateral amygdala (BLA) are critically involved in the acquisition of aversively based learning tasks. However, the role of NMDARs in the BLA in the consolidation of memory of aversive training has not been well elucidated. In the present study, the NMDAR antagonist AP-5 (1 or 3 μg) was infused into the BLA of male Sprague–Dawley rats immediately before, immediately after, or 6 h after training on an inhibitory avoidance task with either a high footshock (HFS; only high dose of AP-5 given) or a low footshock (LFS; both doses of AP-5 given). The 48 h retention of animals given AP-5 (3 μg) immediately before or after HFS training was significantly impaired compared to that of vehicle-controls. In contrast, the retention of rats given AP-5 (3 μg) immediately after LFS training was significantly enhanced compared to that of vehicle-controls. AP-5 (3 μg) infusions administered 6 h after training with either an HFS or LFS did not affect retention. These findings suggest that the NMDARs in the BLA are involved in both the acquisition and consolidation of aversive memory. In addition, the AP-5-induced enhancement of memory obtained with LFS training suggests that NMDARs in the BLA are involved in other mechanisms influencing synaptic transmission, in addition to their well-established role in neuroplasticity.

Differential involvement of hippocampal and amygdalar NMDA receptors in contextual and aversive aspects of inhibitory avoidance memory in rats

Adult male rats bilaterally implanted with guide canullae aimed either at the dorsal hippocampus (dHIP) or the basolateral nucleus of the amygdala (BLA) were trained in a step-down inhibitory avoidance task (IA) and tested for retention 24 h after training. Immediately after training, animals were given a bilateral infusion of the N-methyl- d-aspartate (NMDA) glutamate receptor antagonist d, l-2-amino-5-phosphonopentanoic acid (AP5) (5.0 μg) into the dHIP or the BLA. Both intrahippocampal and intraamygdala infusions of AP5 blocked IA retention. Preexposure to the training box, but not to a different environment 24 h prior to training prevented the impairing effect of intrahippocampal infusion of AP5 on retention. Preexposure did not affect the retention impairment induced by intraamygdala infusion of AP5. These data suggest that hippocampal NMDA receptors might be involved in the contextual and spatial aspects, while amygdalar NMDA receptors might be involved in the aversive aspects of memory for IA.

Dissociable Effects of Antagonism of NMDA and AMPA/KA Receptors in the Nucleus Accumbens Core and Shell on Cocaine-seeking Behavior

The purpose of the present experiment was to investigate the involvement of NMDA and AMPA/KA receptors in the nucleus accumbens core and shell in the control over cocaine-seeking behavior by drug-associated cues. Rats were trained under a second-order schedule of reinforcement for cocaine with five infusions of cocaine being available in each daily session. The NMDA receptor antagonist AP-5 and the AMPA/KA receptor antagonist LY293558 were infused directly into the core or shell. LY293558 infused into the core produced a dose-dependent decrease in responding during both the first, cocaine-unaffected interval and also after cocaine had been self-administered in subsequent intervals. By contrast, AP-5 infused into the core had no effect on responding. Infusion of AP-5 into the shell had the limited effect of decreasing responding during the second interval only. There were no effects of LY293558 infused into the shell. These results indicate that NMDA and AMPA receptor-mediated glutamate transmission in the core and shell are dissociably involved in cocaine-seeking behavior controlled in part by drug-associated cues.

Intra-cerebellar infusion of NMDA receptor antagonist AP5 disrupts classical eyeblink conditioning in rabbits

Rabbits were infused with AP5, an NMDA receptor antagonist, into the region of the cerebellar interpositus nucleus during classical eyeblink conditioning with a tone conditioned stimulus and an air puff unconditioned stimulus. Acquisition of the conditioned eyeblink response was delayed in rabbits infused with AP5 but the NMDA receptor antagonist had little effect on conditioned responses when these same rabbits were infused a second time after reaching asymptotic responding levels. Some rabbits that received AP5 infusions for the first time after the conditioned response was well learned showed temporary alterations in response timing. These data indicate that NMDA receptor activity is involved in the acquisition of classically conditioned eyeblink response and may also be involved in regulating cellular processes involved in response timing and other aspects of conditioned response execution.

Induction of locomotor sensitization by amphetamine requires the activation of NMDA receptors in the rat ventral tegmental area.

The activation of NMDA receptors in the rat ventral tegmental area has been proposed to be necessary for the induction of locomotor sensitization by amphetamine, yet there has been no direct assessment of this view. The present study examined the ability of the competitive NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (AP-5) to block this effect when infused either into the ventral tegmental area or, for comparison, into the nucleus accumbens. These sites are known to be important for the induction and expression, respectively, of locomotor sensitization by amphetamine. Rats in different groups received four pairs of injections (one IC and one IP), one pair given every third day. The IC injection (0, 1 or 5 nmol/side AP-5) was administered immediately before the IP injection (saline or amphetamine, 1 mg/kg). Locomotor activity was measured following each pair of injections and again 2 weeks later when all rats were tested for sensitization following a challenge injection of amphetamine (1 mg/kg, IP). AP-5 was not administered on this test. As expected, rats previously exposed to amphetamine alone showed higher levels of horizontal locomotion and rearing on the test for sensitization when compared to saline pre-exposed rats. Preceding the amphetamine pre-exposure injections with infusions of AP-5 into the ventral tegmental area, but not the nucleus accumbens, dose-dependently blocked the induction of this effect. Rats previously exposed to AP-5 alone in either site did not differ significantly from saline preexposed rats on the test for sensitization. The results indicate that NMDA receptor activation in the ventral tegmental area, but not the nucleus accumbens, is necessary for the induction of locomotor sensitization by amphetamine.

Infusions of AP5 into the basolateral amygdala impair the formation, but not the expression, of step-down inhibitory avoidance.

We evaluated the effects of infusions of the NMDA receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP5) into the basolateral nucleus of the amygdala (BLA) on the formation and expression of memory for inhibitory avoidance. Adult male Wistar rats (215-300 g) were implanted under thionembutal anesthesia (30 mg/kg, ip) with 9.0-mm guide cannulae aimed 1.0 mm above the BLA. Bilateral infusions of AP5 (5.0 microg) were given 10 min prior to training, immediately after training, or 10 min prior to testing in a step-down inhibitory avoidance task (0.3 mA footshock, 24-h interval between training and the retention test session). Both pre- and post-training infusions of AP5 blocked retention test performance. When given prior to the test, AP5 did not affect retention. AP5 did not affect training performance, and a control experiment showed that the impairing effects were not due to alterations in footshock sensitivity. The results suggest that NMDA receptor activation in the BLA is involved in the formation, but not the expression, of memory for inhibitory avoidance in rats. However, the results do not necessarily imply that the role of NMDA receptors in the BLA is to mediate long-term storage of fear-motivated memory within the amygdala.

Involvement of the Medial Precentral Prefrontal Cortex in Memory Consolidation for Inhibitory Avoidance Learning in Rats

MELLO E SOUZA, T., M. R. M. VIANNA, C. RODRIGUES, J. QUEVEDO, B. A. MOLETA AND I. IZQUIERDO. Involvement of the medial precentral prefrontal cortex in memory consolidation for inhibitory avoidance learning in rats. PHARMACOL BIOCHEM BEHAV 66(3) 615–622, 2000.—Adult male Wistar rats were trained in a step-down inhibitory avoidance learning task (3.0-s, 0.4-mA foot shock), received a 0.5-μl infusion of muscimol (0.02, 0.1, or 0.5 μg), AP5 (0.16, 0.34, 0.5, 1.6, or 5.0 μg), SCH 23390 (0.05, 0.34, 0.5, or 1.75 μg), saline, or vehicle (DMSO 20%) into the anterior medial precentral area (Fr2) (CI) immediately after training, and were tested 24 h later. Muscimol (0.02, 0.1, or 0.5 μg), AP5 (0.34 or 0.5 μg), or SCH (0.5 or 1.75 μg) were amnesic. Then, animals were infused with muscimol (0.1 or 0.5 μg), AP5 (0.34, 0.5, or 5.0 μg), or SCH (0.5 μg) at other posttraining times and/or into the junction of Fr1–Fr2 (CII). Muscimol (0.1 and 0.5 μg) or SCH into CI were amnesic when given 90 or 180 min after training, but not when given 270 min after training. Muscimol (0.5 μg, but not 0.1 μg) or SCH into CII were amnesic when given 90 min after training, but not when given 0 or 180 min after training. AP5 (0.5, but not 5.0 μg) was amnesic when given into CI, but not into CII, at 0 or 180 min posttraining, and a trend toward an amnesic effect was seen at 90 min posttraining. The results suggest that 1) the glutamatergic, GABAergic, and dopaminergic systems in Fr2 are involved in the consolidation of memory for inhibitory avoidance learning, either directly or as parts of modulatory systems; and 2) timing of involvement of anterior Fr2 (CI) is different from that of posterior Fr2 (CII).

NMDA receptor antagonism in the basolateral amygdala blocks enhancement of inhibitory avoidance learning in previously trained rats

Extensive evidence suggests that N-methyl- d-aspartate (NMDA) glutamate receptor channels in the amygdala are involved in fear-motivated learning, and infusion of NMDA receptor antagonists into the amygdala blocks memory of fear-motivated tasks. Recent studies have shown that previous training can prevent the amnestic effects of NMDA receptor antagonists on spatial learning. In the present study, we evaluated whether infusion of the NMDA antagonist d,l-2-amino-5-phosphonopentanoic acid (AP5) into the basolateral nucleus of the amygdala (BLA) impairs reinforcement of inhibitory avoidance learning in rats given previous training. Adult male Wistar rats (220–310 g) were bilaterally implanted under thionembutal anesthesia (30 mg/kg, i.p.) with 9.0-mm guide cannulae aimed 1.0 mm above the BLA. Infusion of AP5 (5.0 μg) 10 min prior to training in a step-down inhibitory avoidance task (0.4 mA footshock) blocked retention measured 24 h after training. When infused 10 min prior to a second training session in animals given previous training (0.2 mA footshock), AP5 blocked the enhancement of retention induced by the second training. Control experiments showed that the effects were not due to alterations in motor activity or footshock sensitivity. The results suggest that NMDA receptors in the basolateral amygdala are involved in both formation of memory for inhibitory avoidance and enhancement of retention in rats given previous training.

Regulation of serotonin release by GABA and excitatory amino acids.

Regulation of serotonin release by gamma-aminobutyric acid (GABA) and glutamate was examined by microdialysis in unanaesthetized rats. The GABA(A) receptor agonist muscimol, or the glutamate receptor agonists kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxazolaproprionate or N-methyl-D-aspartate were infused into the dorsal raphe nucleus (DRN) while extracellular serotonin was measured in the DRN and nucleus accumbens. Muscimol produced decreases, and the glutamate receptor agonists produced increases in serotonin. To determine if these receptors have a tonic influence on serotonergic neurons, glutamate or GABA(A) receptor antagonists were infused into the DRN. Kynurenate, a nonselective glutamate receptor blocker, produced a small, 30% decrease in serotonin. A similar decrease was obtained with combined infusion of AP-5 and DNQX into the DRN. The GABAA receptor blocker bicuculline produced an approximately three-fold increase in DRN serotonin. In conclusion, glutamate neurotransmitters have a weak tonic excitatory influence on serotonergic neurons in the rat DRN. However, the predominate influence is mediated by GABA(A) receptors.

Effect of intrabulbar infusion of the NMDA receptor antagonist AP5 on olfactory learning in young rats

Effect of intrabulbar infusion of the NMDA receptor antagonist AP5 on olfactory learning in young rats

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.