Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions

Considerable evidence indicates that glucocorticoid hormones enhance the consolidation of memory for emotionally arousing events through interactions with the noradrenergic system of the basolateral complex of the amygdala (BLA). We previously reported that intra-BLA administration of a β-adrenoceptor agonist immediately after inhibitory avoidance training enhanced memory consolidation and increased hippocampal expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc). In the present experiments corticosterone (3 mg/kg, i.p.) was administered to male Sprague-Dawley rats immediately after inhibitory avoidance training to examine effects on long-term memory, amygdala norepinephrine levels, and hippocampal Arc expression. Corticosterone increased amygdala norepinephrine levels 15 min after inhibitory avoidance training, as assessed by in vivo microdialysis, and enhanced memory tested at 48 h. Corticosterone treatment also increased expression of Arc protein in hippocampal synaptic tissue. The elevation in BLA norepinephrine appears to participate in corticosterone-influenced modulation of hippocampal Arc expression as intra-BLA blockade of β-adrenoceptors with propranolol (0.5 μg/0.2 μL) attenuated the corticosterone-induced synaptic Arc expression in the hippocampus. These findings indicate that noradrenergic activity at BLA β-adrenoceptors is involved in corticosterone-induced enhancement of memory consolidation and expression of the synaptic-plasticity-related protein Arc in the hippocampus.     

Effects of stress and hippocampal NMDA receptor antagonism on recognition memory in rats

Exposures to uncontrollable stress have been shown to alter ensuing synaptic plasticity in the hippocampus and interfere with hippocampal-dependent spatial memory in rats. The present study examined whether stress, which impairs hippocampal long-term potentiation (LTP), also affects (nonspatial) hippocampal-dependent object-recognition memory, as tested on the visual paired comparison task (VPC) in rats. After undergoing an inescapable restraint–tailshock stress experience, rats exhibited markedly impaired recognition memory at the 3-h (long) familiarization-to-test phase delay but not at the 5-min (short) delay. In contrast, unstressed control animals showed robust recognition memory (i.e., they exhibited reliable preferences for novel over familiar objects) at both short- and long-delay periods. The impairing effect of stress on long-delay recognition memory was transient because 48 h after undergoing stress experience, animals performed normally at the long delay. Similar to stress, microinfusions of DL-2-amino-5-phosphonovaleric acid (APV), a competitive N-methyl-D-aspartate receptor (NMDAR) antagonist that blocks LTP, into the dorsal hippocampus selectively impaired object-recognition memory at the long-delay period. Together, these results suggest that stress and intrahippocampal administration of APV affect recognition memory by influencing synaptic plasticity in the hippocampus.

[The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper H. Blair.]

     

Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats

Metabotropic glutamate receptor 5 (mGlu5) has been implicated in a variety of learning processes and is important for inhibitory avoidance and conditioned taste aversion learning. MGlu5 receptors are physically connected with NMDA receptors and they interact with, and modulate, the function of one another in several brain regions. The present studies used systemic co-administration of an mGlu5 receptor positive allosteric modulator, 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and an NMDA receptor antagonist dizocilpine maleate (MK-801) to characterize the interactions of these receptors in two aversive learning tasks. Male Sprague-Dawley rats were trained in a single-trial step-down inhibitory avoidance or conditioned taste aversion task. CDPPB (3 or 10mg/kg, s.c.), delivered by itself prior to the conditioning trial, did not have any effect on performance in either task 48 h after training. However, CDPPB (at 3mg/kg) attenuated the MK-801 (0.2mg/kg, i.p.) induced learning deficit in both tasks. CDPPB also reduced MK-801-induced hyperactivity. These results underlie the importance of mGlu5 and NMDA receptor interactions in modulating memory processing, and are consistent with findings showing the efficacy of positive allosteric modulators of mGlu5 receptors in reversing the negative effects of NMDA receptor antagonists on other behaviors such as stereotypy, sensorimotor gating, or working, spatial and recognition memory.     

Testosterone increases analgesia,anxiolysis, and cognitive performance of male rats

Preliminary evidence suggests that testosterone (T) may have anxiety-reducing and cognitive-enhancing properties in animals and people. Performance in a number of affective and cognitive behavioral tasks was examined in intact, T-depleted, and T-depleted and T-replaced male rats. Rats that were gonadally intact (n = 33), gonadectomized (GDX; n = 30), or GDX with silastic capsules of T implanted (n = 28) were tested through a battery of affective tasks (horizontal crossing, open field, elevated plus-maze, emergence, holeboard, social interaction, tailflick, pawlick, and defensive burying) and in the inhibitory avoidance task for cognitive performance. An additional 6 rats per group had plasma androgen concentrations measured and were determined to be physiological for intact rats, supraphysiological for T-implanted rats, and near the nadir for GDX rats. Testosterone implants produced analgesia as shown by the increased tailflick latencies of the GDX rats with silastic capsules of T implanted, relative to intact or GDX rats. Testosterone also produced anxiolysis. Intact rats spent more time interacting with a conspecific and less time burying an electrified prod than did the GDX or T-implanted rats. Intact rats or GDX rats with T implants also spent more time on the open arms of the elevated plus-maze than did GDX rats. Testosterone also enhanced cognitive performance in the inhibitory avoidance task. Intact rats had longer crossover latencies in the inhibitory avoidance task relative to GDX rats; GDX rats with T implants had longer crossover latencies relative to GDX or intact rats. Together, these data demonstrate that endogenous T or administration of T produced analgesia and enhanced affect and cognitive performance of adult male rats.     

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.     

Ritanserin and voluntary alcohol intake in rats

In a previous study (Rammsayer & Vogel, 1991), rats selectively bred for high and low catecholamine responses to stress showed a selective response to the 5-HT2 receptor blocker ritanserin. However, it remained unclear whether selective breeding resulted in a decrease in 5-HT responsivity, as suggested by the lack of an effect in high stress responding rats, or in an increase in 5-HT responsivity, as suggested by ritanserin-induced reduction in alcohol intake in low-responding rats. To answer this question, nonselectively bred rats were forced to drink a 5% alcohol solution for 10 days. For the subsequent six days, animals were injected subcutaneously with 2.5 mg/kg/2 ml ritanserin or vehicle only, and both a 5% solution of alcohol and water were presented to the animals. Ritanserin neither affected alcohol nor total fluid intake suggesting that in the general population of N/NIH (Hansen) rats as well as in rats of the same strain selectively bred for high catecholamine responses, mesolimbic dopaminergic activity is not effectively modulated by specific blockade of 5-HT2 receptors. However, a very pronounced ritanserin induced difference in daily water intake between nonbred male and female rats became evident.     

Self-control in male and female rats

Eight male and 8 female Wistar rats were exposed to a discrete-trial procedure in which they chose between the presentation of a small (one pellet) or a large (three pellets) reinforcer. The delay to the small and large reinforcer was 6.0 s in the first condition of Experiment 1. Subjects consistently chose the large reinforcer. When the delay to the small reinforcer was decreased to 0.1 s in the next experimental condition, all subjects continued to choose the large 6.0-s delayed reinforcer. When the contingencies correlated with the two levers were reversed in the next experimental condition, the majority of subjects (5 males and 6 females) still chose the large delayed reinforcer over the small immediately presented reinforcer. The delay to the small reinforcer was maintained at 6.0 s, but the delay to the large reinforcer was varied among 9.0, 15.0, 24.0, and 36.0 s in Experiment 2, in which 4 males and 4 females participated. Most subjects consistently chose the large increasingly delayed reinforcer, although choice for the small 6.0-s delayed reinforcer developed in some females when the large reinforcer was delayed for 24.0 or 36.0 s. These choice patterns were not predicted from a literal application of a model that says choice should favor the alternative correlated with the higher (amount/delay) ratio.     

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.     

Effects of NMDA receptor channel blockade on aggression in isolated male mice

N‐Methyl‐D ‐aspartate (NMDA) receptor antagonists are perspective candidates for medication development for a number of diseases/states that are associated with increased aggressiveness (e.g., opioid withdrawal). The prototypic NMDA receptor antagonist phencyclidine (PCP) itself is a widely abused substance and is known to elevate levels of aggression in drug users. The present study was aimed at testing several drugs that share with PCP the ability to block NMDA receptor–associated channel. The resident‐intruder procedure was used to assess drug effects on aggressive behavior in isolated male mice. Resident aggressive mice were administered NMDA channel blockers (PCP; 0.3–10 mg/kg), dizocilpine (MK‐801; 0.01–0.3 mg/kg), memantine (1–30 mg/kg), and MRZ 2/579 (0.1–5.6 mg/kg). The competitive NMDA receptor antagonist D CPPene (0.1–5.6 mg/kg) was also tested as a compound representing an alternative approach to reduce activity of NMDA receptor complex. PCP, dizocilpine, and memantine inhibited expression of aggressive behaviors only at doses that produced ataxia. The novel channel blocker MRZ 2/579 also produced ataxia at the highest dose level but failed to affect aggressiveness. Reduction in aggression with a corresponding increase in sociability was observed after administration of D ‐CPPene. Overall, the present results suggest that NMDA receptor channel blockers do not exert selective effects on aggressive behavior. Aggr. Behav. 25:381–396, 1999. © 1999 Wiley‐Liss, Inc.     

Blockade of NMDA receptors in the amygdala prevents latent inhibition of fear-conditioning

The association between a conditioned stimulus (CS) and an unconditioned stimulus (US) in fear-conditioning depends on N-methyl-D-aspartate (NMDA) receptors in the basolateral amygdala complex (BLA). Latent inhibition (LI) is the retardation in learning due to nonreinforced presentation of the prospective CS before conditioning. Disruption of LI in rats is an animal model of schizophrenia, reflecting the deficits of schizophrenic patients in neglecting irrelevant information. We investigated whether the BLA is involved in LI of fear-potentiated startle. Infusions of the NMDA receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5; 12.5 nmoles) into the BLA before preexposure of rats to the neutral stimulus prevent LI of fear-conditioning. We also demonstrated by the same method that a complex of thalamic nuclei, comprising the medial part of the medial geniculate nucleus, the posterior intralaminar nucleus, and the suprageniculate nucleus, is involved in fear-conditioning, but not in LI. This suggests that the presentation of an innocuous stimulus during preexposure leads to an NMDA receptor-dependent change of neurotransmission in the BLA, but not in the thalamus. Our data show that the BLA but not the thalamus regulates in LI of fear-potentiated startle. Furthermore, it supports the hypothesis that the inability of schizophrenic patients to ignore irrelevant stimuli may be caused by hypofunction of the glutamatergic transmission in the brain and suggests an involvement of the amygdala in the neuropathology of schizophrenia.     

Visual discrimination learning and transfer in rats with hippocampal lesions

Two experiments were performed on rats with hippocampal brain damage and on a control group with neocortical lesions. In the first experiment the hippocampal group learned a difficult visual discrimination as promptly as the controls, and neither group was subsequently impaired by adding relevant or irrelevant background cues to the original stimuli. In the second experiment the animals learned a simultaneous visual discrimination in which the stimuli differed in both brightness and orientation. The hippocampal group was impaired relative to the controls on acquisition, and showed poorer transfer to stimuli differing only in brightness or orientation. The results are incompatible with the hypothesis which attempts to explain the effects of hippocampal damage by a widespread reduction in sensory gating, but they are consistent with a more restricted version of the same hypothesis.     

Activation of cannabinoid CB1 receptors in the central amygdala impairs inhibitory avoidance memory consolidation via NMDA receptors

In the present study, we investigated the influence of bilateral intra-central amygdala (intra-CeA) microinjections of N-methyl-d-aspartate (NMDA) receptor agents on amnesia induced by a cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA). This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that intra-CeA administration of ACPA (2 ng/rat) immediately after training decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-CeA microinjections of NMDA (0.0001, 0.001 and 0.01 μg/rat) did not affect IA memory consolidation. However co-administration of NMDA with ACPA (2 ng/rat) prevented the impairment of IA memory consolidation that was induced by ACPA. Although post-training intra-CeA administration of the NMDA receptor antagonist, d-(−)-2-amino-5-phosphonopentanoic acid (d-AP5; 0.01, 0.05 and 0.1 μg/rat) alone had no effect, its co-administration with an ineffective dose of ACPA (1 ng/rat) impaired IA memory consolidation. Post-training intra-CeA microinjection of an ineffective dose of d-AP5 (0.01 μg/rat) prevented an NMDA response to the impaired effect of ACPA. These results suggest that amnesia induced by intra-CeA administration of ACPA is at least partly mediated through an NMDA receptor mechanism in the Ce-A.     

Neonatal testosterone augmentation increases juvenile play fighting but does not influence the adult dominance relationships of male rats

Neonatal male rats were either injected subcutaneously with testosterone propionate (TP) or oil vehicle. When weaned, each treated pup was paired with an untreated male sibling. The play fighting of TP-and oil-treated rats were compared at the juvenile phase (30–36 days), and in adulthood (84–90 days). In the juvenile phase, the rate of initiating playful attacks was significantly greater for TP-treated rats. Playful defense in response to such attacks did not differ between TP- and oil-treated rats. At the completion of the study, cortical thickness was measured for all the groups of rats. Oil treatment decreased overall cortical thickness relative to untreated pairmates, whereas TP treatment did not. Both oil and TP treatment abolished the asymmetry in hemispheric thickness, which was present in the untreated pairmates. The reversal of at least one of these injectioninduced changes in the cortex by TP provided independent evidence for the effectiveness of the TP treatment. As adults, neither the TP treatment nor the oil treatment influenced which pairmate became dominant. Dominance was judged by which pairmate initiated less playful attacks. Therefore, it is concluded that the early neonatal testosterone surge is not likely to be a factor in influencing the behaviors that lead to adult dominance. In contrast, play fighting is influenced by hormonal events in this early neonatal phase. It thus appears that play fighting and the aggressive systems subserving dominance relationships are differentially controlled. © 1992 Wiley-Liss, Inc.     

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.