The role of the nucleus accumbens in learned approach behavior diminishes with training.

Nucleus accumbens dopamine plays a key role in reward-directed approach. Past findings suggest that dopamine's role in the expression of learned behavior diminishes with extended training. However, little is known about the central substrates that mediate the shift to dopamine-independent reward approach. In the present study, rats approached and inserted the head into a reward compartment in response to a cue signaling food delivery. On days 4 and 5 of 28-trial-per-day sessions, D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) infused to the NAc core reduced the probability and speed of cued approach. The disruptive effect of D1 receptor blockade was specific to the nucleus accumbens core and not seen with drug infusions to nearby dopamine target regions. In rats that received drug infusions after extended training (days 10 or 11), accumbens core D1 receptor blockade produced little effect on the expression of the same behavior. These results could have been due to a continued accumbens mediation of cued approach even after the behavior had become independent of accumbens D1 receptors. However, accumbens core ionotropic glutamate receptor blockade disrupted cued approach during early but not late stages of training, similar to the effects of D1 antagonist infusions. The results suggest that with extended training, a nucleus accumbens D1-dependent behavior becomes less dependent not only on nucleus accumbens D1 transmission but also on excitatory transmission in the nucleus accumbens. These findings fill an important gap in a growing literature on reorganization of striatal function over the course of training.

Nitric oxide in the dorsal periaqueductal gray mediates the panic-like escape response evoked by exposure to hypoxia.

Exposure of rats to an environment with low O2 levels evokes a panic-like escape behavior and recruits the dorsal periaqueductal gray (dPAG), which is considered to be a key region in the pathophysiology of panic disorder. The neurochemical basis of this response is, however, currently unknown. We here investigated the role played by nitric oxide (NO) within the dPAG in mediation of the escape reaction induced by hypoxia exposure. The results showed that exposure of male Wistar rats to 7% O2 increased nitrite levels, a NO metabolite, in the dPAG but not in the amygdala or hypothalamus. Nitrite levels in the dPAG were correlated with the number of escape attempts during the hypoxia challenge. Injections of the NO synthesis inhibitor NPA, the NO-scavenger c- PTIO, or the NMDA receptor antagonist AP-7 into the dorsolateral column of the periaqueductal gray (dlPAG) inhibited escape expression during hypoxia, without affecting the rats' locomotion. Intra-dlPAG administration of c-PTIO had no effect on the escape response evoked by the elevated-T maze, a defensive behavior that has also been associated with panic attacks. Altogether, our results suggest that NO plays a critical role in mediation of the panic-like defensive response evoked by exposure to low O2 concentrations.

The Nitric Oxide Donor SIN-1-Produced Panic-Like Behaviour And Fear-Induced Antinociception Are Modulated By NMDA Receptors In The Anterior Hypothalamus.

BACKGROUND: An excitatory imbalance in the hypothalamus of rodents caused by local chemical stimulation elicits fear-related defensive reactions such as escape and freezing. In addition, these panic attack-like defensive reactions induced by hypothalamic neurons may cause antinociception. However, there is a shortage of studies showing the participation of the anterior hypothalamic nucleus in these adaptive defensive mechanisms. Nitric oxide (NO) donors have been shown to evoke fear-related defensive responses when microinjected into paralimbic and limbic structures, and this excitatory neuromodulation can recruit the glutamatergic system. AIMS: The aim of this work was to investigate the influence of the glutamatergic system in the nitrergic effects on fear-related defensive responses organised by anterior hypothalamic neurons. METHODS: The present study evaluates the effects of the molsidomine active metabolite SIN-1 NO donor administered into the anterior hypothalamus (AH) of mice at different concentrations (75, 150 and 300 nmol/0.1 µL). Then, we investigated the effects of pre-treatment of the AH with AP-7 (an N-methyl-d-aspartate (NMDA) receptor-selective antagonist; 0.02, 0.2 and 2 nmol/0.1 µL) on the behavioural and antinociceptive effects provoked by AH chemical stimulation with SIN-1 microinjections. RESULTS: The 300 nmol dose of SIN-1 was the most effective at causing panic-like defensive behaviours followed by a significant antinociceptive response. In addition, both of these effects were attenuated or inhibited by AH pre-treatment with AP-7. CONCLUSIONS: These findings suggest that the panicogenic and antinociceptive effects evoked by intra-AH microinjections of SIN-1 depend on NMDA receptor activation.

Roles of N-methyl-d-aspartate receptors during the sensory stimulation-evoked field potential responses in mouse cerebellar cortical molecular layer.

The functions of N-methyl-d-aspartate receptors (NMDARs) in cerebellar cortex have been widely studied under in vitro condition, but their roles during the sensory stimulation-evoked responses in the cerebellar cortical molecular layer in living animals are currently unclear. We here investigated the roles of NMDARs during the air-puff stimulation on ipsilateral whisker pad-evoked field potential responses in cerebellar cortical molecular layer in urethane-anesthetized mice by electrophysiological recording and pharmacological methods. Our results showed that cerebellar surface administration of NMDA induced a dose-dependent decrease in amplitude of the facial stimulation-evoked inhibitory responses (P1) in the molecular layer, accompanied with decreases in decay time, half-width and area under curve (AUC) of P1. The IC50 of NMDA induced inhibition in amplitude of P1 was 46.5µM. In addition, application of NMDA induced significant increases in the decay time, half-width and AUC values of the facial stimulation-evoked excitatory responses (N1) in the molecular layer. Application of an NMDAR blocker, D-APV (250µM) abolished the facial stimulation-evoked P1 in the molecular layer. These results suggested that NMDARs play a critical role during the sensory information processing in cerebellar cortical molecular layer in vivo in mice.

Integration of contextual cues into memory depends on "prefrontal" N-methyl-D-aspartate receptors.

Every learning event is embedded in a context, but not always does the context become an integral part of the memory; however, for extinction learning it usually does, resulting in context-specific conditioned responding. The neuronal mechanisms underlying contextual control have been mainly investigated for Pavlovian fear extinction with a focus on hippocampal structures. However, the initial acquisition of novel responses can be subject to contextual control as well, although the neuronal mechanisms are mostly unknown. Here, we tested the hypothesis that contextual control of acquisition depends on glutamatergic transmission underlying executive functions in forebrain areas, e.g. by shifting attention to critical cues. Thus, we antagonized N-methyl-D-aspartate (NMDA) receptors with 2-amino-5-phosphonovaleric acid (AP5) in the pigeon nidopallium caudolaterale, the functional analogue of mammalian prefrontal cortex, during the concomitant acquisition and extinction of conditioned responding to two different stimuli. This paradigm has previously been shown to lead to contextual control over extinguished as well as non-extinguished responding. NMDA receptor blockade resulted in an impairment of extinction learning, but left the acquisition of responses to a novel stimulus unaffected. Critically, when responses were tested in a different context in the retrieval phase, we observed that NMDA receptor blockade led to the abolishment of contextual control over acquisition performance. This result is predicted by a model describing response inclination as the product of associative strength and contextual gain. In this model, learning under AP5 leads to a change in the contextual gain on the learned association, possibly via the modulation of attentional mechanisms.

Amygdala inputs to prefrontal cortex guide behavior amid conflicting cues of reward and punishment.

Orchestrating appropriate behavioral responses in the face of competing signals that predict either rewards or threats in the environment is crucial for survival. The basolateral nucleus of the amygdala (BLA) and prelimbic (PL) medial prefrontal cortex have been implicated in reward-seeking and fear-related responses, but how information flows between these reciprocally connected structures to coordinate behavior is unknown. We recorded neuronal activity from the BLA and PL while rats performed a task wherein competing shock- and sucrose-predictive cues were simultaneously presented. The correlated firing primarily displayed a BLA→PL directionality during the shock-associated cue. Furthermore, BLA neurons optogenetically identified as projecting to PL more accurately predicted behavioral responses during competition than unidentified BLA neurons. Finally photostimulation of the BLA→PL projection increased freezing, whereas both chemogenetic and optogenetic inhibition reduced freezing. Therefore, the BLA→PL circuit is critical in governing the selection of behavioral responses in the face of competing signals.

Blockade of glutamatergic transmission in the primate basolateral amygdala suppresses active behavior without altering social interaction.

The amygdala is an integrator of affective processing, and a key component of a network regulating social behavior. While decades of lesion studies in nonhuman primates have shown alterations in social interactions after amygdala damage, acute manipulations of the amygdala in primates have been underexplored. We recently reported (Wellman, Forcelli, Aguilar, & Malkova, 2016) that acute pharmacological inhibition of the basolateral complex of the amygdala (BLA) or the central nucleus of the amygdala increased affiliative social interactions in experimental dyads of macaques; this was achieved through microinjection of a GABA-A receptor agonist. Prior studies in rodents have shown similar effects achieved by blocking NMDA receptors or AMPA receptors within the BLA. Here, we sought to determine the role of these receptor systems in the primate BLA in the context of social behavior. In familiar dyads, we microinjected the NMDA receptor antagonist 2-amino-7-phosphonoheptanoic acid (AP7) or the AMPA receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX) and observed behaviors and social interactions in the immediate postinjection period. In striking contrast with our prior report using GABA agonists, and in contrast with prior reports in rodents using glutamate antagonists, we found that neither NMDA nor AMPA blockade increase social interaction. Both treatments, however, were associated with decreases in locomotion and manipulation and increases in passive behavior. These data suggest that local blockade of glutamatergic neurotransmission in BLA is not the functional equivalent of local activation of GABAergic signaling, and raise interesting questions regarding the functional microcircuitry of the nonhuman primate amygdala in the context of social behavior. (PsycINFO Database Record

NMDA receptors in mouse anterior piriform cortex initialize early odor preference learning and L-type calcium channels engage for long-term memory.

The interactions of L-type calcium channels (LTCCs) and NMDA receptors (NMDARs) in memories are poorly understood. Here we investigated the specific roles of anterior piriform cortex (aPC) LTCCs and NMDARs in early odor preference memory in mice. Using calcium imaging in aPC slices, LTCC activation was shown to be dependent on NMDAR activation. Either D-APV (NMDAR antagonist) or nifedipine (LTCC antagonist) reduced somatic calcium transients in pyramidal cells evoked by lateral olfactory tract stimulation. However, nifedipine did not further reduce calcium in the presence of D-APV. In mice that underwent early odor preference training, blocking NMDARs in the aPC prevented short-term (3 hr) and long-term (24 hr) odor preference memory, and both memories were rescued when BayK-8644 (LTCC agonist) was co-infused. However, activating LTCCs in the absence of NMDARs resulted in loss of discrimination between the conditioned odor and a similar odor mixture at 3 hr. Elevated synaptic AMPAR expression at 3 hr was prevented by D-APV infusion but restored when LTCCs were directly activated, mirroring the behavioral outcomes. Blocking LTCCs prevented 24 hr memory and spared 3 hr memory. These results suggest that NMDARs mediate stimulus-specific encoding of odor memory while LTCCs mediate intracellular signaling leading to long-term memory.

Involvement of ventral tegmental area ionotropic glutamate receptors in the expression of ethanol-induced conditioned place preference.

The ventral tegmental area (VTA) is a well-established neural substrate of reward-related processes. Activity within this structure is increased by the primary and conditioned rewarding effects of abused drugs and its engagement is heavily reliant on excitatory input from structures upstream. In the case of drug seeking, it is thought that exposure to drug-associated cues engages glutamatergic VTA afferents that signal directly to dopamine cells, thereby triggering this behavior. It is unclear, however, whether glutamate input to VTA is directly involved in ethanol-associated cue seeking. Here, the role of intra-VTA ionotropic glutamate receptor (iGluR) signaling in ethanol-cue seeking was evaluated in DBA/2J mice using an ethanol conditioned place preference (CPP) procedure. Intra-VTA iGluRs α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)/kainate and N-methyl-d-aspartate (NMDAR) were blocked during ethanol CPP expression by co-infusion of antagonist drugs 6,7-dinitroquinoxaline-2,3-dione (DNQX; AMPA/kainate) and d-(-)-2-Amino-5-phosphonopentanoic acid (AP5; NMDA). Compared to aCSF, bilateral infusion of low (1 DNQX+100 AP5ng/side) and high (5 DNQX+500 AP5ng/side) doses of the AMPAR and NMDAR antagonist cocktail into VTA blocked ethanol CPP expression. This effect was site specific, as DNQX/AP5 infusion proximal to VTA did not significantly impact CPP expression. An increase in activity was found at the high but not low dose of DNQX/AP5. These findings demonstrate that activation of iGluRs within the VTA is necessary for ethanol-associated cue seeking, as measured by CPP.

Acquisition of specific response-outcome associations requires NMDA receptor activation in the basolateral amygdala but not in the insular cortex.

The basolateral amygdala (BLA) and the gustatory region of the insular cortex (IC) are required for the encoding and retrieval of outcome value. Here, we examined if these regions are also necessary to learn associations between actions and their outcomes. Hungry rats were first trained to press two levers for a common outcome. Next, specific response-outcome (R-O) associations were introduced such that each response now earned a distinct food outcome. Prior to each specific R-O training session, rats received a bilateral infusion of the N-methyl-D-aspartate (NMDA) receptor antagonist, DL-APV, into either the BLA or the IC. One of the two outcomes was then devalued immediately prior to a choice test. Inhibition of NMDA receptor activity in the BLA, but not the IC, during the acquisition of specific R-O associations abolished selective devaluation. These results indicate that the BLA is critical for learning the association between actions and their specific consequences.

The role of NMDA receptors of the medial septum and dorsal hippocampus on memory acquisition.

The glutamatergic neurons in the medial septal/diagonal band of broca (MS/DB) affect the hippocampal functions by modulating the septo-hippocampal neurons. Our study investigated the possible role of NMDA receptors of the medial septum nucleus (MS) and dorsal hippocampus (CA1) on memory acquisition in male Wistar rats. Animals were bilaterally implanted with chronic cannulae in the MS and CA1. Rats were trained in a step-through type inhibitory avoidance task, and tested 24h after training to measure step-through latency as memory retrieval. Our results indicated that pre-training intra-MS or intra-CA1 infusions of NMDA (0.125 µg/rat) and D-AP7 (0.012 µg/rat) increased and decreased memory acquisition, respectively when compared to saline control group. Also, pre-training intra-CA1 and intra-MS injection of an effect dose of D-AP7 (0.012 µg/rat) along with an effect dose of NMDA (0.125 µg/rat) impaired memory acquisition. Interestingly, pre-training intra-CA1/MS infusion of D-AP7 (0.012 µg/rat) diminished memory response produced by pre-training injection of NMDA (0.125 µg/rat) in the MS/CA1, respectively (cross injection or bilateral injection). Also, all above doses of drugs did not alter locomotor activity. These results suggest that the glutamatergic pathway between the MS and CA1 regions is involved in memory acquisition process.

Differential frequency-dependent antidromic resonance of the Schaffer collaterals and mossy fibers.

To better understand information transfer along the hippocampal pathways and its plasticity, here we studied the antidromic responses of the dentate gyrus (DG) and CA3 to activation of the mossy fibers and Schaffer collaterals, respectively, in hippocampal slices from naïve and epileptic rats. We applied trains of 600 electrical stimuli at functionally meaningful frequencies (θ, ß/γ and γ). The responses of the DG to θ frequency trains underwent rapid potentiation that lasted about 400 stimuli, after which they progressively returned to control value. At ß/γ and γ frequencies, however, the initial potentiation was followed by a strong frequency-dependent depression within the first 50 stimuli. In kindled animals, the initial potentiation was stronger than in control preparations and the resonant phase at θ frequency lasted longer. In contrast, CA3 responses were exponentially depressed at all frequencies, but depression was significantly less intense at θ frequency in epileptic preparations. Failure of fibers to fire action potentials could account for some of the aforementioned characteristics, but waveforms of the intracellular action potentials also changed as the field responses did, i.e., half-duration and time-to-peak increased in both structures along the stimulation trains. Noteworthy, block of glutamate and GABA ionotropic receptors prevented resonance and reduced the depression of antidromic responses to ß/γ and γ stimulation recorded in the DG, but not in CA3. We show that the different behavior in the information transfer along these pathways depends on the frequency at which action potentials are generated, excitability history and anatomical features, including myelination and tortuosity. In addition, the mossy fibers are endowed with ionotropic receptors and terminal active properties conferring them their sui generis non-passive antidromic responses.

GABA-Mediated Inactivation of Medial Prefrontal and Agranular Insular Cortex in the Rat: Contrasting Effects on Hunger- and Palatability-Driven Feeding.

A microanalysis of hunger-driven and palatability-driven feeding was carried out after muscimol-mediated inactivation of two frontal regions in rats, the agranular/dysgranular insular cortex (AIC) and the ventromedial prefrontal cortex (vmPFC). Food and water intake, feeding microstructure, and general motor activity were measured under two motivational conditions: food-deprived rats given standard chow or ad libitum-fed rats given a palatable chocolate shake. Muscimol infusions into the AIC diminished intake, total feeding duration, and average feeding bout duration for the palatable-food condition only but failed to alter exploratory-like behavior (ambulation or rearing). In contrast, intra-vmPFC muscimol infusions did not alter the overall intake of chow or chocolate shake. However, these infusions markedly increased mean feeding bout duration for both food types and produced a modest but significant reduction of exploratory-like behavior. The lengthening of feeding-bout duration and reduction in rearing were mimicked by intra-vmPFC blockade of AMPA-type but not NMDA-type glutamate receptors. Neither water consumption nor the microstructure of water drinking was affected by inactivation of either site. These results indicate a regional heterogeneity in frontal control of feeding behavior. Neural processing in AIC supports palatability-driven feeding but is not necessary for intake of a standard food under a food-restriction condition, whereas ventromedial prefrontal cortex, and AMPA signaling therein, modulates the duration of individual feeding bouts regardless of motivational context. Results are discussed in the context of regionally heterogeneous frontal modulation of two distinct components of feeding behavior: reward valuation based upon taste perception (AIC) vs switching between ingestive and non-ingestive (eg, exploratory-like) behavioral repertoires (vmPFC).

N-methyl-D-aspartate receptors in the ventral tegmental area mediate the excitatory influence of Pavlovian stimuli on instrumental performance.

Pavlovian stimuli predictive of food can markedly amplify instrumental responding for food. This effect is termed Pavlovian-instrumental transfer (PIT). The ventral tegmental area (VTA) plays a key role in mediating PIT, however, it is yet unknown whether N-methyl-D-aspartate (NMDA)-type glutamate receptors in the VTA are involved in PIT. Here, we examined the effects of an NMDA-receptor blockade in the VTA on PIT. Immediately prior to PIT testing, rats were subjected to intra-VTA infusions of vehicle or of the NMDA-receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) (1, 5 µg/side). In rats that received AP-5 at the lower dose, the PIT effect was intact, i.e. presentation of the Pavlovian stimulus enhanced instrumental responding. By contrast, in rats that received AP-5 at the higher dose, the PIT effect was blocked. The data suggest that NMDA receptors in the VTA mediate the activating effects of Pavlovian stimuli on instrumental responding.

Hippocampal AP5 treatment impairs both spatial working and reference memory in radial maze performance in rats.

The possible involvement of hippocampal N-methyl-d-aspartate (NMDA) receptors in spatial reference and working memory was investigated. Rats were first trained in a four-baited/four-unbaited version of the eight-arm radial maze task in which only predetermined four arms for each rat were baited with a food pellet. After rats reached the learning criterion, their performance was tested under the treatment of a NMDA antagonist, AP5 (d,l-2-amino-5-phosphonopentanoic acid, 20-40nmol), or vehicle into the dorsal hippocampus through the bilaterally implanted guide cannulae. AP5 produced dose-dependent increments on both reference and working memory errors, but did not have any effect on the running speed. Additionally, there were significant correlations between the number of trials to criterion in acquisition and the number of reference and working memory errors induced by AP5 treatment. The results suggest that hippocampal NMDA receptors are involved in both spatial reference and working memory.

Full-gestational exposure to nicotine and ethanol augments nicotine self-administration by altering ventral tegmental dopaminergic function due to NMDA receptors in adolescent rats.

In adult rats, we have shown full-gestational exposure to nicotine and ethanol (Nic + EtOH) augmented nicotine self-administration (SA) (increased nicotine intake) compared to pair-fed (PF) offspring. Therefore, we hypothesized that full-gestational exposure to Nic + EtOH disrupts control of dopaminergic (DA) circuitry by ventral tegmental area (VTA) NMDA receptors, augmenting nicotine SA and DA release in nucleus accumbens (NAcc) of adolescents. Both NAcc DA and VTA glutamate release were hyper-responsive to intra-VTA NMDA in Nic + EtOH offspring versus PF (p = 0.03 and 0.02, respectively). Similarly, DA release was more responsive to i.v. nicotine in Nic + EtOH offspring (p = 0.02). Local DL-2-Amino-5-phosphonopentanoic acid sodium salt (AP5) (NMDA receptor antagonist) infusion into the VTA inhibited nicotine-stimulated DA release in Nic + EtOH and PF offspring. Nicotine SA was augmented in adolescent Nic + EtOH versus PF offspring (p = 0.000001). Daily VTA microinjections of AP5 reduced nicotine SA by Nic + EtOH offspring, without affecting PF (p = 0.000032). Indeed, nicotine SA in Nic + EtOH offspring receiving AP5 was not different from PF offspring. Both VTA mRNA transcripts and NMDA receptor subunit proteins were not altered in Nic + EtOH offspring. In summary, adolescent offspring exposed to gestational Nic + EtOH show markedly increased vulnerability to become dependent on nicotine. This reflects the enhanced function of a subpopulation of VTA NMDA receptors that confer greater nicotine-induced DA release in NAcc. We hypothesized that concurrent gestational exposure to nicotine and ethanol would disrupt the control of VTA dopaminergic circuitry by NMDA receptors. Resulting in the augmented nicotine self-administration (SA) in adolescent offspring.

Local NMDA receptor blockade attenuates chronic tinnitus and associated brain activity in an animal model.

Chronic tinnitus has no broadly effective treatment. Identification of specific markers for tinnitus should facilitate the development of effective therapeutics. Recently it was shown that glutamatergic blockade in the cerebellar paraflocculus, using an antagonist cocktail was successful in reducing chronic tinnitus. The present experiment examined the effect of selective N-methyl d-aspartate (NMDA) receptor blockade on tinnitus and associated spontaneous brain activity in a rat model. The NMDA antagonist, D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (0.5 mM), was continuously infused for 2 weeks directly to the ipsilateral paraflocculus of rats with tinnitus induced months prior by unilateral noise exposure. Treated rats were compared to untreated normal controls without tinnitus, and to untreated positive controls with tinnitus. D-AP5 significantly decreased tinnitus within three days of beginning treatment, and continued to significantly reduce tinnitus throughout the course of treatment and for 23 days thereafter, at which time testing was halted. At the conclusion of psychophysical testing, neural activity was assessed using manganese enhanced magnetic resonance imaging (MEMRI). In agreement with previous research, untreated animals with chronic tinnitus showed significantly elevated bilateral activity in their paraflocculus and brainstem cochlear nuclei, but not in mid or forebrain structures. In contrast, D-AP5-treated-tinnitus animals showed significantly less bilateral parafloccular and dorsal cochlear nucleus activity, as well as significantly less contralateral ventral cochlear nucleus activity. It was concluded that NMDA-mediated glutamatergic transmission in the paraflocculus appears to be a necessary component of chronic noise-induced tinnitus in a rat model. Additionally, it was confirmed that in this model, elevated spontaneous activity in the cerebellar paraflocculus and auditory brainstem is associated with tinnitus.

Investigations into the involvement of NMDA mechanisms in recognition memory.

This review will focus on evidence showing that NMDA receptor neurotransmission is critical for synaptic plasticity processes within brain regions known to be necessary for the formation of object recognition memories. The aim will be to provide evidence concerning NMDA mechanisms related to recognition memory processes and show that recognition memory for objects, places or associations between objects and places depends on NMDA neurotransmission within the perirhinal cortex, temporal association cortex medial prefrontal cortex and hippocampus. Administration of the NMDA antagonist AP5, selectively into each of these brain regions has revealed that the extent of the involvement NMDA receptors appears dependent on the type of information required to solve the recognition memory task; thus NMDA receptors in the perirhinal cortex are crucial for the encoding of long-term recognition memory for objects, and object-in-place associations, but not for short-term recognition memory or for retrieval. In contrast the hippocampus and medial prefrontal cortex are required for both long-term and short-term recognition memory for places or associations between objects and places, or for recognition memory tasks that have a temporal component. Such studies have therefore confirmed that the multiple brain regions make distinct contributions to recognition memory but in addition that more than one synaptic plasticity process must be involved. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.

Impairing effect of amphetamine and concomitant ionotropic glutamate receptors blockade in the ventral striatum on spatial learning in mice.

RATIONALE: Accumulating evidence supports the involvement of the ventral striatum (VS) in spatial information processing. The multiple cortical glutamatergic and mesolimbic dopaminergic (DAergic) afferences on the same neurons in the ventral striatum provide the neuroanatomical substrate for glutamate and dopamine functional interaction. However, there is little evidence in the literature on how this interaction affects the ability to encode spatial information. OBJECTIVE: First, we evaluated the effect of intra-VS bilateral infusion of different doses of amphetamine (0.3, 0.75, and 1.5 µg/side) on the ability to detect spatial novelty in mice. Next, we examined the impact produced on the same abilities by intra-VS infusion of ineffective doses of amphetamine (0.3 µg/side) in association with N-methyl-D-aspartate (NMDA) (3.125 ng/side) or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) (0.25 ng/side) receptor antagonist. RESULTS: The results show that infusion of amphetamine impairs detection of spatial novelty, affecting also exploratory activity and marginally the detection of nonspatial novelty. In contrast, an association of subthreshold doses of amphetamine with NMDA or AMPA receptor antagonists exerted a selective effect on reactivity to a spatial change. CONCLUSIONS: These findings demonstrate that enhanced DAergic activity in the VS enhances glutamate receptor antagonist-induced impairment in learning and memory.

N-methyl-d-aspartate receptors, learning and memory: chronic intraventricular infusion of the NMDA receptor antagonist d-AP5 interacts directly with the neural mechanisms of spatial learning.

Three experiments were conducted to contrast the hypothesis that hippocampal N-methyl-d-aspartate (NMDA) receptors participate directly in the mechanisms of hippocampus-dependent learning with an alternative view that apparent impairments of learning induced by NMDA receptor antagonists arise because of drug-induced neuropathological and/or sensorimotor disturbances. In experiment 1, rats given a chronic i.c.v. infusion of d-AP5 (30 mm) at 0.5 µL/h were selectively impaired, relative to aCSF-infused animals, in place but not cued navigation learning when they were trained during the 14-day drug infusion period, but were unimpaired on both tasks if trained 11 days after the minipumps were exhausted. d-AP5 caused sensorimotor disturbances in the spatial task, but these gradually worsened as the animals failed to learn. Histological assessment of potential neuropathological changes revealed no abnormalities in d-AP5-treated rats whether killed during or after chronic drug infusion. In experiment 2, a deficit in spatial learning was also apparent in d-AP5-treated rats trained on a spatial reference memory task involving two identical but visible platforms, a task chosen and shown to minimise sensorimotor disturbances. HPLC was used to identify the presence of d-AP5 in selected brain areas. In Experiment 3, rats treated with d-AP5 showed a delay-dependent deficit in spatial memory in the delayed matching-to-place protocol for the water maze. These data are discussed with respect to the learning mechanism and sensorimotor accounts of the impact of NMDA receptor antagonists on brain function. We argue that NMDA receptor mechanisms participate directly in spatial learning.