Differential effects of post-training muscimol and AP5 infusions into different regions of the cingulate cortex on retention for inhibitory avoidance in rats.

Adult male Wistar rats were bilaterally implanted with indwelling cannulae in four different coordinates of the cingulate cortex: (1) the anterior cingulate (AC), (2) the rostral region of the posterior cingulate (RC), (3) the upper portion of the caudal region of the posterior cingulate (UC), and (4) the lower portion of the caudal region of the posterior cingulate (LC). After recovery, animals were trained in a step-down inhibitory avoidance task (3.0-s, 0.4-mA foot shock). Either immediately, or 90 or 180 min after training, animals received a 0.5-microl infusion of vehicle (phosphate buffer, pH 7.4), of muscimol (0.5 microg), or of AP5 (5.0 microg). Retention testing was carried out 24 h after training. Muscimol was amnestic when given into any of the three coordinates of the posterior cingulate cortex 90 min after training, and when given into LC immediately post-training. In addition, AP5 was amnestic when given into UC 90 min post-training, but not when given into any other region and/or at any other time. None of the treatments had any effect when given into AC. The results suggest that memory processing of the inhibitory avoidance task is regulated by the posterior but not by the anterior cingulate cortex, through muscimol-sensitive synapses, relatively late after training. AP5-sensitive synapses appear to play a very limited role in these processes, restricted to UC.     

Enhancement of inhibitory avoidance and conditioned taste aversion memory with insular cortex infusions of 8-Br-cAMP: involvement of the basolateral amygdala

There is considerable evidence that in rats, the insular cortex (IC) and amygdala are involved in the learning and memory of aversively motivated tasks. The present experiments examined the effects of 8-Br-cAMP, an analog of cAMP, and oxotremorine, a muscarinic agonist, infused into the IC after inhibitory avoidance (IA) training and during the acquisition/consolidation of conditioned taste aversion (CTA). Posttraining infusion into the IC of 0.3 microg oxotremorine and 1.25 microg 8-Br-cAMP enhanced IA retention. Infusions of 8-Br-cAMP, but not oxotremorine, into the IC enhanced taste aversion. The experiments also examined whether noradrenergic activity in the basolateral amygdala (BLA) is critical in enabling the enhancement of CTA and IA memory induced by drug infusions administered into the IC. For both CTA and IA, ipsilateral infusions of beta-adrenergic antagonist propranolol administered into the BLA blocked the retention-enhancing effect of 8-Br-cAMP or oxotremorine infused into the IC. These results indicate that the IC is involved in the consolidation of memory for both IA and CTA, and this effect requires intact noradrenergic activity into the BLA. These findings provide additional evidence that the BLA interacts with other brain regions, including sensory cortex, in modulating memory consolidation.     

Medial prefrontal cortex infusions of bupivacaine or AP-5 block extinction of amphetamine conditioned place preference

The present experiments used reversible lesion techniques and intra-mPFC infusions of the n-methyl d-aspartate (NMDA) receptor antagonist d,l-2-amino-5-phosphonovaleric acid (AP-5) to examine the role of the mPFC in extinction of an amphetamine conditioned place preference (CPP). Following initial training and testing for an amphetamine (2 mg/kg) CPP, adult male Long–Evans rats were given extinction trials that were identical to training, except in the absence of peripheral amphetamine injections. Immediately prior to each extinction trial, rats received intra-mPFC infusions of the anesthetic drug bupivacaine (0.75% solution/0.5 μl), AP-5 (1.25, 2.5, 5.0 μg/0.5 μl), or saline. Following extinction training, rats were given a second CPP test session. Rats receiving intra-mPFC infusions of saline displayed extinction of CPP behavior. In contrast, intra-mPFC infusions of bupivacaine or AP-5 (2.5, 5.0 μg) blocked CPP extinction. The findings indicate (1) the mPFC mediates extinction of approach behavior to drug-associated environmental contexts, and (2) NMDA receptor blockade within the mPFC is sufficient to block extinction of amphetamine CPP behavior.     

Effect of a novel experience prior to training or testing on retention of an inhibitory avoidance response in mice: involvement of an opioid system

These experiments examined the effects of a novel experience prior to training or retention testing on 24-h retention of an inhibitory avoidance response in mice. The experiments were based on previous evidence that novel training experiences release hypothalamic beta-endorphin. When given 1 h prior to training, the novel experience (clinging to the wire-mesh ceiling and exploring a small box) attenuated the memory-enhancing effects of post-training administration of naloxone as well as the enhancing effects of beta-endorphin administered prior to the retention test. The novel experience given prior to training did not block the enhancing effects of post-training administration of epinephrine. beta-Endorphin and the novel experience both enhanced retention performance when administered 1 h (as well as 3 but not 6 h) prior to the retention test. The enhancement found with both treatments was blocked by simultaneous administration of naloxone or by administration of propranolol a few minutes prior to the retention test. The findings of these experiments are consistent with the view that the effects of the novel experience are due to a release of endogenous beta-endorphin and provide additional evidence that the effects, on retention, of naloxone given post-training and beta-endorphin given prior to a retention test, are based on training-induced release of beta-endorphin.     

Chronic administration of propranolol impairs inhibitory avoidance retention in mice

Adrenergic systems are importantly involved in memory storage processes. As such, agents that alter adrenergic receptors, such as "beta-blockers," also alter memory storage. However, the anxiety literature cautions that beta-adrenergic receptor antagonists, such as propranolol, may have different behavioral effects with acute vs chronic dosing. The effects of chronic propranolol specifically on memory modulation are unknown. This study was designed to evaluate the effects of chronic propranolol on retention for an aversive task, in which there is endogenous adrenergic activation. Adult male ICR mice were given daily injections of one of four doses of propranolol (2, 4, 8, and 12 mg/kg) or 0.9% NaCl vehicle for 15 days prior to, and continuing during, behavioral tests of exploration and retention. Exploratory behavior, as an index of anxiety level, was measured in a conventional elevated plus-maze, whereas retention of an aversive experience was measured in a step-through inhibitory avoidance apparatus. Sensitivity to aversive footshock was also evaluated. Compared to controls, propranolol-treated mice showed a dose-dependent decrease in retention for the inhibitory avoidance task, but no effect on anxiety on the plus-maze or on footshock sensitivity. Taken together with results from previous studies, it is apparent that propranolol can have different behavioral effects when administered acutely vs chronically, and its chronic effects significantly impair memory storage processes. Since these drugs are typically used chronically, and often in older adults, they could contribute to functional memory impairments.     

Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory

Mammalian target of rapamycin (mTOR), a central regulator of protein synthesis in neurons, has been implicated in synaptic plasticity and memory. Here we show that mTOR inhibition by rapamycin in the basolateral amygdala (BLA) or dorsal hippocampus (DH) impairs both formation and reconsolidation of memory for inhibitory avoidance (IA) in rats. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after IA training or retrieval. Memory retention was tested at different time points after drug infusion. Rapamycin impaired long-term IA retention when given before or immediately after training or retrieval into the BLA. When infused into the DH, rapamycin produced memory impairment when given before training or immediately after retrieval. The impairing effects of post-retrieval rapamycin required memory retrieval and were not reversed by a reminder shock. The results provide the first evidence that mTOR in the BLA and DH might play a role in IA memory reconsolidation.     

Involvement of basolateral amygdala alpha2-adrenoceptors in modulating consolidation of inhibitory avoidance memory

These experiments investigated the role of the alpha(2)-adrenoceptors of the basolateral nucleus of the amygdala (BLA) in modulating the retention of inhibitory avoidance (IA). In Experiment 1, male Sprague Dawley rats implanted with bilateral cannulae in the BLA received microinfusions of a selective alpha(2)-adrenoceptor antagonist idazoxan 20 min either before or immediately after training. Retention was tested 48 h later. Idazoxan induced a dose-dependent enhancement of retention performance and was more effective when administered post-training. In Experiment 2, animals received pre- or post-training intra-BLA infusions of a selective alpha(2)-adrenoceptor agonist UK 14,304. The agonist induced a dose-dependent impairment of retention performance and, as with the antagonist treatments, post-training infusions were more effective. These results provide additional evidence that consolidation of inhibitory avoidance memory depends critically on prolonged activation of the noradrenergic system in the BLA and indicate that this modulatory influence is mediated, in part, by pre-synaptic alpha(2)-adrenoceptors.     

Calcium channel antagonists enhance retention of passive avoidance and maze learning in mice

Although a number of studies have shown that treatment with calcium channel antagonists (CCAs) can ameliorate impairments in learning and memory in aged animals, evidence for a general nootropic effect of CCAs in neurologically normal young adult animals is ambiguous. This study attempts to resolve some of this ambiguity by comparing the effects of several CCAs on retention of passive avoidance learning and acquisition and retention of appetitively motivated spatial discrimination learning in young adult mice. Animals were trained in a step through passive avoidance apparatus and, immediately after training, injected subcutaneously with different doses of nimodipine, nifedipine, amlodipine, flunarazine, diltiazem, or verapamil. Retention was tested 24 h after training. In the maze-learning task mice were treated with the same doses of the aforementioned CCAs immediately after a brief training session in a linear maze and retention was tested 24 h after training. The most effective dose of each agent in the maze-retention experiment was administered to additional groups of animals 1 h prior to training to determine the effects of CCAs on acquisition processes. The effects of central administration of CCAs were examined by intracerebroventricular injection of different doses of amlodipine immediately after passive avoidance training. Results showed (1) all peripherally administered drugs except verapamil facilitated retention of passive avoidance training in a dose-dependent manner, (2) all drugs dose dependently facilitated retention of linear maze learning, (3) all doses of the drugs (except verapamil) which facilitated maze retention also facilitated maze learning, and (4) central administration of the dihydropyridine amlodipine produced a dose-dependent facilitation of the retention of passive avoidance learning. These data indicate that drugs which block calcium channels can enhance retention of two different types of learning in mice.     

Psychoneurogenic stress influences upon retention of an inhibitory avoidance response in the rat

Hormones and peptides involved in the response of an organism to stress play a modulating role in learning and memory processes. We studied whether psychoneurogenic stressors such as sound stimulation or novelty influence retention of an inhibitory avoidance response. An impairing effect on retention was observed when these stressors were applied shortly after the acquisition trial, but not after a 3-h delay. However, sound stimulation and novelty applied shortly before the retention test may facilitate retention behavior. It is suggested that the effect of psychoneurogenic stressors on retention behavior may be linked to influences on consolidation and retrieval processes mediated through the neurohumoral response of the organism to stress.     

Factors that influence test session performance measured 0, 3, or 6 h after inhibitory avoidance training

Rats were trained in a step-down inhibitory avoidance task using a 0.3-mA, 60-Hz footshock, and were tested at 0, 3, and 6 h from training. Retrieval scores (test session minus training session step-down latencies) were higher in control groups at 0 than at 3 or 6 h. Test session performance at 0 h was unaffected by the pretraining ip injection of ACTH1-24 (0.2 microgram/kg), epinephrine-HCl (5.0 micrograms/kg), human beta-endorphin (1.0 microgram/kg), or naloxone-HCl (0.4 mg/kg); or by a pretreatment with dexamethasone phosphate (2.0 mg/kg in divided doses 24 and 12 h before training); or by anterior or posterior hypothalamic deafferentation. Test session performance at 0 h was depressed by prior bilateral transection of the fornix, which suggests it depends on hippocampal function. The effect of the fornix lesion on test session performance at 0 h was not counteracted by ACTH, epinephrine, or beta-endorphin administration. When animals were tested 3 h after training, the post-training administration of ACTH and epinephrine caused an enhancement of test session performance; neither post-training beta-endorphin or naloxone, nor pretest ACTH, epinephrine, or beta-endorphin administration, had any effect in these animals. At 6 h from training, the post-training facilitatory action of ACTH and epinephrine was still present and the post-training depressant effect of beta-endorphin and the post-training facilitatory effect of naloxone became manifest, and so did the naloxone-reversible pretest facilitation induced by ACTH, epinephrine, or beta-endorphin. The influence of post-training naloxone or pretest beta-endorphin on retrieval scores at 6 h was not observed in the fornix-lesioned animals. In conclusion: Test session performance of this task at 0 h from training is regulated by different mechanisms than those which regulate test session performance at 3 or 6 h; in particular, it is less susceptible to modulation by the drugs used in the present study and it depends on the fornix; At least two major classes of modulatory factors influence retrieval scores at later times: consolidation-enhancing effects of ACTH and epinephrine, which become manifest at 3 h, and mechanisms related to beta-endorphin, which involve a form of state dependency and only become manifest at 6 h from training.     

On the requirement of nitric oxide signaling in the amygdala for consolidation of inhibitory avoidance memory

Evidence suggests that the NO/sGC/PKG pathway plays a key role in memory processing but the actual participation of this signaling cascade in the amygdala during memory consolidation remains unknown. Here, we show that when infused in the amygdala immediately after inhibitory avoidance training, but not later, the NO synthase inhibitor L-NNA hindered long-term memory retention without affecting locomotion, exploratory behavior, anxiety state or retrieval of the avoidance response. The amnesic effect of L-NNA was not state-dependent and was mimicked by the soluble guanylyl cyclase inhibitor LY83583 and the PKG inhibitor KT-5823. On the contrary, post-training intra-amygdala infusion of the NOS substrate L-Arg, the NO-releasing compound SNAP or the non-hydrolysable analog of cGMP 8Br-cGMP increased memory retention in a dose-dependent manner. Co-infusion of 8Br-cGMP reversed the amnesic effect of L-NNA and LY83583 but not that of KT-5823. Our data indicate that the NO-induced activation of PKG in the amygdala is a necessary step for consolidation of inhibitory avoidance memory.     

Effect of novel experiences on retention of inhibitory avoidance behavior in mice: the influence of previous exposure to the same or another experience

Mice were trained and tested in a step-through inhibitory avoidance task with a 24-h interval between training and testing. At one of several intervals prior to the test session (9 h, 6 h, 3 h, or 6 min), they were given one of the following novel experiences: 4 min in a small Plexiglas box containing an empty water bottle, or 4 min hanging from the wire mesh ceiling of a large Plexiglas box. When given 3 h or 6 min before testing, both novel experiences enhanced retention test performance. The effect was antagonized by naltrexone and mimicked by an administration of beta-endorphin 6 min prior to testing. Thus, the findings are consistent with previous evidence suggesting that the effects of novel experiences on retention test performance are due to an activation of the brain beta-endorphin system. When one of the novel experiences given 3 h or 6 min prior to testing was preceded by the same experience given 6 h earlier retention test performance was not enhanced. Thus, the enhancing effect is obtained only if the experience is novel. Further, an experience given prior to retention testing did not affect performance if either the same or a different experience was given 3 h earlier. This finding is consistent with previous evidence indicating that following a novel experience, the brain beta-endorphin remains unresponsive for several hours. These results provide additional evidence that novel experiences prior to retention testing affect retention performance and provide additional support for the view that the effect may involve the release of beta-endorphin.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Involvement of the rostral anterior cingulate cortex in consolidation of inhibitory avoidance memory: interaction with the basolateral amygdala

Previous findings suggest that the rostral anterior cingulate cortex (rACC) is involved in memory for emotionally arousing training. There is also extensive evidence that the basolateral amygdala (BLA) modulates the consolidation of emotional arousing training experiences via interactions with other brain regions. The present experiments examined the effects of posttraining intra-rACC infusions of the cholinergic agonist oxotremorine (OXO) on inhibitory avoidance (IA) retention and investigated whether the BLA and rACC interact in enabling OXO effects on memory. In the first experiment, male Sprague-Dawley rats were implanted with bilateral cannulae above the rACC and given immediate posttraining OXO infusions. OXO (0.5 or 3 ng) induced significant enhancement of retention performance on a 48-h test. In the second experiment, unilateral posttraining OXO infusions (0.5, 3.0 or 10 ng) enhanced retention when infused into rACC, but not caudal ACC, consistent with previous evidence that ACC is composed of functionally distinct regions. A third experiment investigated the effects of posttraining intra-rACC OXO infusions (0.5 or 10 ng) in rats with bilateral sham or NMDA-induced lesions of the BLA. The BLA lesions did not impair IA retention, but blocked the enhancement induced by posttraining intra-rACC OXO infusions. Lastly, unilateral NMDA lesions of rACC blocked the enhancement of IA retention induced by posttraining ipsilateral OXO infusions into the BLA. These findings support the hypothesis that the rACC is involved in modulating the storage of emotional events and provide additional evidence that the BLA modulates memory consolidation through interactions with efferent brain regions, including the cortex.     

Opposite effects of a single versus repeated doses of gabapentin on retention performance of an inhibitory avoidance response in mice

CF-1 male mice were trained in an inhibitory avoidance (IA) task. A single gabapentin (GBP) administration (50mg/kg, ip) immediately after training enhanced retention performance when mice were tested 8 days after training. On the contrary, when the same dose of the anticonvulsant drug was given twice a day for 7 days (repeated treatment), a significant impairment on retention performance 12h after the last injection of GBP was observed. When the retention test was delayed 7 days after the end of the repeated treatment, the retention performance was not significant different from the control group, whereas if the retention test was delayed 14 days, retention performance was higher than control group but similar to that observed when GBP was administered once immediately after training. The impairment on retention performance was correlated with a significant decrease in the high affinity choline uptake in the hippocampus at the end of the retention test. The pretest administration of the direct muscarinic cholinergic agonist oxotremorine (50 microg/kg, ip) reversed the impairment on retention performance. This reversion was prevented by the muscarinic cholinergic antagonist scopolamine (0.5 mg/kg, ip). Taken together, these results suggest that the impairment on retention performance of an IA task in mice induced by repeated administration of GBP affected memory retrieval but not memory consolidation and that this impairment may be attributable to a reduction on central cholinergic activity.     

Lesions of the ventral hippocampus, but not the dorsal hippocampus, impair conditioned fear expression and inhibitory avoidance on the elevated T-maze

The hippocampus has been suggested to be involved in spatial (or configural) memory and also in the inhibition of certain response or goal alternatives. An increasing number of anatomical, physiological, and behavioral studies indicate that the hippocampus is functionally heterogeneous along the dorsal-ventral axis. Identification of distinct behavioral roles for the dorsal (DH) and ventral (VH) hippocampus may resolve differences between the various theoretical accounts of hippocampal function. The present study examined the effects of electrolytic lesions restricted to the DH or VH on fear-conditioned freezing, passive avoidance on the elevated T-maze (ETM) test of anxiety, and general activity in male Sprague-Dawley (Charles-River derived) albino rats. We found that rats with lesions of the VH, but not DH showed reduced freezing to both context and tone conditioned stimuli (CS). Rats with VH lesions also showed a reduced latency to emerge from the enclosed arm on trials 2 and 3 of the ETM (indicating reduced anxious behavior), while having no effect on the latency to escape from the open arms on trial 4. There were no differences in activity between the groups. These results indicate that the VH and DH are differentially involved in passive avoidance on the ETM and conditioned freezing to context and tone CS. We suggest that the VH may be specifically involved in modulating goal-oriented, defensive behavior expression through hypothalamic and amygdaloid connections.     

Reversible inactivation of the nucleus of the solitary tract impairs retention performance in an inhibitory avoidance task.

Several peripherally acting hormones and drugs are known to modulate memory storage processes, yet the mechanisms which permit these agents to influence memory is not well understood since they do not freely enter the brain. The nucleus of the solitary tract (NTS) is one brainstem structure which receives important neural input from the periphery. Therefore, the objective of this experiment was to determine whether the NTS is involved in modulating processes contributing to memory formation. Male Sprague-Dawley rats were trained in a one-trial inhibitory avoidance task (0.35 mA, 0.5 s footshock). Immediately or 2 h after training microinjections of 2% lidocaine hydrochloride (20 mg/kg) or a phosphate buffer solution were administered bilaterally into the NTS. Two other groups received microinjections of lidocaine into the fourth ventricle or cerebellum. On retention tests given 48 h after training the latency to reenter the dark compartment of the apparatus was recorded. The retention latencies of rats receiving bilateral microinjections of 0.5 microliter of lidocaine hydrochloride into the NTS were significantly shorter than those of animals given injections of a buffer solution (0.5 microliter), delayed injections of buffer or lidocaine, or control injections of lidocaine into the cerebellum or fourth ventricle. These findings suggest that memory storage processes are impaired by reversible inactivation of the NTS after training. The implications of these findings in terms of a possible role of the NTS in modulating brain processes involved in memory storage are discussed.