D-Cycloserine enhances memory consolidation of hippocampus-dependent latent extinction

Adult male Long-Evans rats were trained to run in a straight-alley maze for food reward and subsequently received hippocampus-dependent latent extinction training. Immediately following latent extinction, rats received peripheral injections of the NMDA receptor partial agonist D-cycloserine (DCS, 15 mg/kg), or saline. Twenty-four hours later, rats received four extinction "probe" trials. Relative to saline controls, latencies to reach the goal box on probe trials were significantly higher in rats that had received DCS. These findings indicate that memory consolidation underlying hippocampus-dependent latent extinction, a cognitive form of learning in which the previously rewarded response is not made during extinction training, can be enhanced by NMDA-receptor agonism.     

Apparent Incentive Contrast Effects in Autoshaping with Rats

The effects of shifts in reward quality and quantity on Pavlovian acquisition were studied in rats. In Experiment 1, animals preexposed to unsignaled food pellets, 10% sucrose solution, or home cage controls subsequently received autoshaping training (response-independent lever-pellet or lever-solution pairings, in three groups each). Unsignaled preexposure to sucrose solution facilitated autoshaping for pellets (relative to unshifted controls), whereas unsignaled preexposure to pellets retarded autoshaping for sucrose solution. In Experiment 2, unsignaled preexposure to 30% sucrose solution impaired acquisition reinforced by food pellets, relative to 2% solution. Using a choice procedure, Experiment 3 demonstrated that rats prefer pellets to either 2 or 10% sucrose solutions, but they prefer the 30% solution to the pellets. Experiment 4 demonstrated the facilitatory effect after an upward shift in reward magnitude rather than quality (from 1 to 12 pellets), but provided weaker evidence for retardation following a downward magnitude shift. Experiment 5 was similar to Experiment 4, except that animals received autoshaping training from the outset. No evidence of successive positive contrast was obtained, but there was a significant successive negative contrast effect. Moreover, extinction was faster after acquisition with 12 pellets rather than 1. These results suggest the presence of incentive contrast effects under Pavlovian training conditions.     

Positive contrast following gradual and abrupt increases in reward magnitude using delay of reinforcement

In Experiment 1, rats were given a 1-pellet reward for 48 preshift trials. During a subsequent 20-trial postshift phase, one group was shifted to a 12-pellet reward on Trial 1, a second was shifted on Trial 11, and a third was given 1 more pellet each trial and then 12 pellets for the last 10 trials. The speeds of all three groups increased to a level above that of a control group given a 12-pellet food reward throughout training (positive contrast). In experiment 2, rats were shifted from 1 to 12 pellets either gradually or abruptly following either abbreviated training (9 trials) or extended training (20 trials). One group of control subjects received 12 pellets throughout training. The results revealed a positive contrast effect for gradually shifted subjects following extended training but not following abbreviated training. The abrupt shift procedure produced positive contrast following abbreviated training but only a marginal effect following extended training. These results indicate that, contingent upon the amount of preshift training, either gradual or abrupt reward increases may produce positive contrast.     

Glucose effects on memory: behavioral and pharmacological characteristics

Recent findings indicate that post-training glucose injections can modulate memory storage for inhibitory (passive) avoidance training. Experiment I extended these findings to determine whether glucose, like other memory modulating treatments, enhances memory storage when administered after training with low footshock and impairs memory storage after high footshock training. In Experiment I, male Sprague-Dawley rats were trained in a one-trial inhibitory avoidance task using either a brief footshock (0.5 mA, 0.7 s) or slightly more intense footshock kept on until escape (0.7 mA, mean escape latency = 3.4 s). Immediately after training, each rat received a subcutaneous injection of glucose (100 mg/kg). When tested for retention performance 24 h later, the glucose-injected animals exhibited enhanced retention performance for low footshock training and impaired retention for high footshock training. Experiment II determined whether pretreatment with adrenergic antagonists blocked the effects of glucose on memory. Pretreatment with the alpha- or beta-adrenergic receptor antagonists, phenoxybenzamine, or propranolol, respectively, had no effect on acquisition or retention in animals trained with the brief footshock and did not affect glucose facilitation of that memory. In animals trained to escape footshock, phenoxybenzamine did not attenuate the amnesia produced by glucose. Propranolol-pretreated animals had impaired retention whether or not they received post-training amnestic injections of glucose; glucose had no effect on retention in these amnestic animals. These findings add further support to the view that glucose release after training and treatment may represent a physiological response subsequent to epinephrine release in modulating memory storage processing.     

Amnesia produced by anisomycin in an appetitive task is not due to conditioned aversion

Two experiments investigated the effects of lithium chloride (LiCl) and anisomycin (ANI) in a water reward Y-maze task. In Experiment 1, male CD-1 mice given weak or strong training were injected post-training with either saline or LiCl (150 mg/kg), which has been reported to produce conditioned aversion in mice. One day after training, both LiCl groups avoided the rewarded arm of the maze and drank less water than saline-injected controls. Two days after training, the strongly trained LiCl mice showed avoidance, while both LiCl groups drank less water. In Experiment 2, weakly trained mice given pre- and post-training ANI (30 mg/kg) were amnesic on the second test day compared to mice that received post-trial saline. However, water consumption was increased on the test day for both groups. LiCl produced a different pattern of results than ANI in this task. On the basis of these results, it is suggested that amnesia produced by ANI is due to impaired memory formation and not to conditioned aversion.     

Discrimination of methadone and cocaine by pigeons without explicit discrimination training.

Pigeons were trained to peck a key on a variable-interval 2-min schedule of food reinforcement. Prior to each session, either 2.0 mg/kg methadone (n = 3), 3.0 mg/kg cocaine (n = 4), or 5.6 mg/kg cocaine (n = 2) was administered. When each pigeon's rate of pecking was stable, a range of doses of the training drug and saline were administered prior to 20-min extinction sessions separated by at least four training sessions. Rate of pecking during these extinction tests was generally an increasing function of dose, with the lowest rates obtained following saline and low doses and the highest rates obtained following doses near the training doses. Dose functions from pigeons trained with 5.6 mg/kg cocaine were steeper than those from pigeons trained with 3.0 mg/kg cocaine. Pigeons trained with methadone or 3.0 mg/kg cocaine were then given discrimination training, in which food reinforcement followed drug administration and 20-min extinction sessions followed saline administration. Rates of pecking under these conditions quickly diverged until near-zero rates were obtained following saline and high rates were obtained following drug. Discrimination training steepened dose functions for the training drugs, and the effects of several other substituted drugs depended on the pharmacology of the training drug. The pigeons trained with 5.6 mg/kg cocaine were tested with d-amphetamine, methadone, and morphine prior to discrimination training. d-Amphetamine increased rates dose dependently, and methadone and morphine did not. The results suggest that discriminative control by methadone and cocaine was established without explicit discrimination training.     

The effects of beta-noradrenergic receptor blockade on acquisition of eyeblink conditioning in 3-month-old F344 rats

There is evidence that blocking beta-noradrenergic receptors will cause deficits in some forms of learning. We investigated the effects of systemic injections of 1, 5, and 10 mg/kg doses of propranolol on acquisition of delay eyeblink conditioning in 3-month-old Fischer 344 rats. We presented a 3-kHz, 90-dB tone as a conditioning stimulus and a 6 psi airpuff as our unconditioned stimulus to freely moving rats. We monitored eyelid activity using EMG signals. The treatment subjects were injected with either propranolol or saline 0.5 h prior to daily training sessions. Two groups of control subjects, one receiving injections of saline and one receiving injections of 5 mg/kg propranolol, received daily training sessions with unpaired and randomized presentation of the tone and airpuff. Each daily training session for the treatment groups consisted of 27 paired training trials and 3 conditioned stimulus-alone training trials. Rats injected with saline vehicle or with 1 mg/kg propranolol achieved a 60% or better learned response rate within two training sessions. Rats injected with 5 or 10 mg/kg propranolol never achieved a response rate significantly different from animals that received unpaired, random presentations of the tone and airpuff stimuli. These results agree with prior studies from our lab that have shown a dose-dependent effect of beta-noradrenergic receptor blockade on learning in rabbit eyeblink conditioning as well as in a runway, motor learning paradigm. We believe that the beta-noradrenergic system plays an important role in learning and memory in more than one cerebellar-dependent learning paradigm.     

Response suppression by visual stimuli paired with postsession d-amphetamine injections in the pigeon

Responding of pigeons, maintained under a fixed-interval 3-minute schedule of food presentation, was decreased on days that the color of the lights illuminating the food magazine was changed and d-amphetamine (1.0 mg/kg, i.m.) was injected after the session. Responding was not decreased by keylight color changes paired with postsession d-amphetamine or by postsession injections of saline. Administration of pentobarbital (3.0 to 5.6 mg/kg), but not d-amphetamine (.3 to 3.0 mg/kg), before the session increased rates of responding suppressed by drug-paired magazine lights. Responding maintained under a fixed-ratio 30-response schedule was not decreased when differently colored magazine lights were paired with a low (.3 mg/kg) postsession dose of d-amphetamine; with high (3.0 mg/kg) postsession doses, however, responding was completely suppressed after two pairings. The effects of pairing magazine stimuli with an intermediate (1.0 mg/kg) postsession dose of d-amphetamine depended upon the magnitude of prior postsession doses. After being paired with a low dose, stimuli paired with 1.0 mg/kg did not suppress responding. After being paired with a high dose, stimuli paired with 1.0 mg/kg completely suppressed responding. The suppression of food-maintained responding by stimuli paired with postsession drug administration depends upon both behavioral and pharmacological variables.     

Opioid mechanisms are involved in the disruption of arcaine-induced amnesia by context pre-exposure

Previous exposure to the training context disrupts glutamatergic N-methyl-d-aspartate receptor (NMDAr) antagonist-induced amnesia, indicating that novelty is necessary for such an amnestic effect. While there are reports that novelty-related release of opioids cause amnesia, no study has addressed whether the amnestic effect of NMDAr antagonists involve opioid mechanisms. In this study we investigated whether pharmacological manipulation of the opioid system immediately after context pre-exposure alters the amnestic effect of arcaine, a NMDAr antagonist. Adult male Wistar rats were habituated (pre-exposed) to a fear conditioning training apparatus or to a different context (open field). Immediately after pre-exposure, animals were injected with saline or naloxone (0.5 mg/kg, i.p.) or anti-beta-endorphin antibody (1:500, i.c.v.). Forty eight hours after pre-exposure session, all animals were subjected to fear conditioning acquisition protocol and saline or arcaine (30 mg/kg, i.p.) was administered immediately after training. Testing was carried out 24 h later, and freezing responses due to re-exposure to the training apparatus were recorded. Pre-exposure to the training apparatus prevented the impairment of memory induced by post-training arcaine. Administration of naloxone or anti-beta-endorphin antibody, immediately after pre-exposure to the training apparatus, reinstated the amnesic effect of post-training arcaine. The results suggest that endogenous opioid mechanisms are involved in the pre-exposure-induced loss of the amnestic effect of arcaine.     

Context extinction following conditioning with delayed reward enhances subsequent instrumental responding

In Experiment 1, delayed reward generated low response rates relative to immediate reward delivered with the same frequency. Lister rats exposed to delayed reward subsequently responded at a higher rate in extinction if they received nonreinforced exposure to the conditioning context after instrumental training and prior to test, compared with animals that received home cage exposure. In Experiment 2, a signaled delay of reinforcement resulted in higher rates than an unsignaled delay. Nonreinforced exposure to the conditioning context elevated response rate for subjects in the unsignaled condition relative to a home cage group, but had no effect on response rates for subjects that had received the signaled delay. In Experiment 3, following an unsignaled reinforcement delay, groups receiving either no event or signaled food in the context responded faster in extinction than groups receiving no context exposure or unsignaled food.     

Post-training amphetamine administration enhances memory consolidation in appetitive Pavlovian conditioning: Implications for drug addiction

It has been suggested that some of the addictive potential of psychostimulant drugs of abuse such as amphetamine may result from their ability to enhance memory for drug-related experiences through actions on memory consolidation. This experiment examined whether amphetamine can specifically enhance consolidation of memory for a Pavlovian association between a neutral conditioned stimulus (CS-a light) and a rewarding unconditioned stimulus (US-food), as Pavlovian conditioning of this sort plays a major role in drug addiction. Male Long-Evans rats were given six training sessions consisting of 8 CS presentations followed by delivery of the food into a recessed food cup. After the 1st, 3rd, and 5th session, rats received subcutaneous injections of amphetamine (1.0 or 2.0 mg/kg) or saline vehicle immediately following training. Conditioned responding was assessed using the percentage of time rats spent in the food cup during the CS relative to a pre-CS baseline period. Both amphetamine-treated groups showed significantly more selective conditioned responding than saline controls. In a control experiment, there were no differences among groups given saline, 1.0 or 2.0 mg/kg amphetamine 2 h post-training, suggesting that immediate post-training amphetamine enhanced performance specifically through actions on memory consolidation rather than through non-mnemonic processes. This procedure modeled Pavlovian learning involved in drug addiction, in which the emotional valence of a drug reward is transferred to neutral drug-predictive stimuli such as drug paraphernalia. These data suggest that amphetamine may contribute to its addictive potential through actions specifically on memory consolidation.     

Effects of opiate antagonists on spatial memory in young and aged rats

The effects of post-training opiate antagonist administration on spatial memory were assessed in young and aged male Long Evans rats. In Experiment I rats were trained to visit each arm of an eight-arm radial maze once in a session to obtain a food reward placed at the end of each arm. During training aged rats required significantly more trials to achieve criterion performance when compared to young mature rats. However, administration of the opiate antagonist naloxone (2.0 mg/kg) immediately after each training trial did not significantly alter the rate of achieving accurate performance in either age group. In Experiment II young and aged rats that were previously trained to a comparable criterion on the radial maze were tested on the same maze apparatus in novel spatial environments. When animals were exposed to novel spatial information, the effects of post-trial opiate antagonists were examined using a within-subjects counter-balanced design. In Experiment IIa naloxone (2 mg/kg) enhanced the performance of both young and aged rats. In Experiment IIB naltrexone (1.0 mg/kg) was found to have a comparable effect of enhancing the performance of both age groups. In addition, in Experiment IIb a significant age-related deficit was found in rats tested in novel spatial environments. These results indicate that opiate antagonists are capable of improving memory for new spatial information in both young and aged rats on a task that is sensitive to behavioral deficits during normal aging.     

Naloxone administration impairs autoshaped learning

Effects of naloxone on acquisition of autoshaped behavior were investigated. Rats deprived to 85% of free-feeding weights were trained to touch a retractable lever; delivery of a food pellet occurred on every trial following lever retraction. The lever was retracted immediately if a touch occurred within 15 s, or automatically after 15 s. Analyses were conducted on number and latencies of touches of the extended lever, nose-pokes (touches) directed at the retracted lever during intertrial intervals (a measure less constrained by ceiling effects than extended lever touches), and unconditioned exploratory rearing activity, measured as touches of a metal strip mounted above the grid floor of the apparatus. In an initial experiment, male Sprague-Dawley rats were given saline or naloxone (2.0 mg/kg, ip) 5 min before a training session of 12 trials. Two days later they were tested, in the absence of drug, in a session of 36 (three blocks of 12) trials. Naloxone depressed training levels of lever responding, in addition to slowing acquisition rate. No effect of naloxone was observed on rearing activity. Previous work showed that injection of saline 5 min before behavioral testing increases the rate of autoshaping compared to injections 30 min before (Messing & Sparber, 1984). Thus, effects of naloxone on acquisition of lever-directed behaviors may have been confounded by behavioral depressant effects and/or by an injection effect such a short time before testing. In a second experiment naloxone (0.5 or 2.0 mg/kg) was injected after five of seven training sessions (12 trials each) to male and female rats. A 6-s delay of reinforcement was inserted between lever retraction and food delivery, slowing acquisition rates and providing the opportunity to test the effects of naloxone throughout a multiple-session task. The low dose retarded acquisition of extended lever touching in both sexes; both doses retarded acquisition of interim lever touching in males. Thus, in some circumstances, post-training naloxone administration may impair learning. The results support the notion that low doses of naloxone may have agonist activity.     

Memory as a state dependent phenomenon: role of ACTH and epinephrine

Rats received an ip injection of saline, epinephrine HCl (5.0 micrograms/kg), or ACTH1--24(0.2 microgram/kg) immediately after training in a step-down inhibitory avoidance task, and an ip injection of saline, or epinephrine (0.5, 1.0, 2.0, 3.0, 5.0, or 10.0 mu/kg), or ACTH (0.02, 0.04 0.08, 0.12, 0.2, or 0.4 microgram/kg) 6 min prior to a test session of the same task 24 hr after training. Retention was excellent in the groups treated with saline after training, and poor in those treated with ACTH or epinephrine after training and tested under saline. The amnestic effect of the drugs was counteracted by their administration prior to testing, and there was a dose-response curve for this effect: partial recovery from amnesia was obtained with 20 or 40% of the amnestic dose and full recovery was obtained with 60 to 100% of that dose when the same drug was given after training and prior to testing; if the drugs given after training and prior to testing were not the same, full recovery was obtained only with twice the amnestic dose of the latter. These findings are consistent with the hypothesis that learning depends on the relation between the endogenous levels of these two hormones in the post-training period and during testing. The animals seem capable of discriminating between the two drugs only partially.     

Incentive shift in the rat following training to resist punishment

An incentive shift paradigm was used to test for the similarity of fear and frustration. In Experiment 1, rats trained to resist electric shock punishment showed neither a negative contrast effect nor any performance decrement when reward was shifted from 10 to one pellet. Experiment 2 replicated the basic findings of Experiment 1, but also showed that punishment training did not influence the magnitude of performance shift for animals receiving increases in reward magnitude. Finally, Experiment 3 additionally found that rats sensitized to punishment showed an increase in negative contrast effect. These results support the hypothesized functional similarity between conditioned fear and conditioned frustration with learned persistence or sensitivity to one generalizing to the other as suggested by Amsel's (1972) theory of persistence.     

氟哌啶醇与丙咪嗪交互作用对成本效益决策的影响

本实验采用T迷宫延迟奖赏模型研究多巴胺D2受体拮抗剂氟哌啶醇和5-羟色胺重摄取抑制剂丙咪嗪的交互作用对成本效益决策的影响, 同时探讨了延迟时间对决策的影响。T迷宫两臂分别设置为低成本-低奖赏端和高成本-高奖赏端。实验结果发现：氟哌啶醇能够降低大鼠选择高成本-高奖赏端的次数, 丙咪嗪则能够增加大鼠选择高成本-高奖赏端的次数; 在同时注射这两种药物情况下, 丙咪嗪能够抑制由氟哌啶醇引起的对低成本-低奖赏端的选择倾向。另外, 实验发现, 随延迟时间的增加大鼠选择高成本-高奖赏端的次数相对减少。由此可见, 丙咪嗪能够反转由氟哌啶醇导致的对低成本-低奖赏端的选择倾向, 这可能是由于细胞间5-羟色胺含量的升高部分反转了由多巴胺系统受损导致的行为倾向; 延迟时间的改变可对决策倾向产生逆转, 因此成本的支出即延迟时间也是影响成本效益决策的重要因素。     

Amygdala and "emotional" modulation of the relative use of multiple memory systems

The basolateral amygdala modulates the cognitive and habit memory processes mediated by the hippocampus and caudate nucleus, respectively. The present experiments used a plus-maze task that can be acquired using either hippocampus-dependent "place" learning or caudate-dependent "response" learning to examine whether peripheral or intra-basolateral amygdala injection of anxiogenic drugs would bias rats towards the use of a particular memory system. In Experiment 1, adult male Long-Evans rats were trained to swim from the same start point to an escape platform located in a consistent goal arm, and received pre-training peripheral injections of the alpha(2)-adrenoceptor antagonists yohimbine (2.5 or 5.0 mg/kg), RS 79948-197 (0.05, 0.1, or 0.2 mg/kg), or vehicle. On a drug-free probe trial from a novel start point administered 24h following acquisition, vehicle treated rats predominantly displayed hippocampus-dependent place learning, whereas rats previously treated with yohimbine (2.5, 5.0 mg/kg) or RS 79948-197 (0.1 mg/kg) predominantly displayed caudate-dependent response learning. In Experiment 2, rats receiving pre-training intra-basolateral amygdala infusions of RS 79948-197 (0.1 microg/0.5 microl) also predominantly displayed response learning on a drug-free probe trial. The findings indicate (1) peripheral injections of anxiogenic drugs can influence the relative use of multiple memory systems in a manner that favors caudate-dependent habit learning over hippocampus-dependent cognitive learning, and (2) intra-basolateral amygdala infusion of anxiogenic drugs is sufficient to produce this modulatory influence of emotional state on the use of multiple memory systems.     

Role of magnitude of reinforcement in spaced-trial instrumental learning in turtles (Geoclemys reevesii)

The runway performance of turtles (Geoclemys reevesii) was studied as a function of magnitude of reinforcement under spaced training conditions (one trial per day). A large reward magnitude (24 pellets) produced faster acquisition than a small magnitude (2 pellets). After a shift from the large to the small magnitude, latencies of the shifted animals continued to be significantly lower than the latencies of the non-shifted, small-magnitude controls, and similar to those of the non-shifted, large-magnitude controls. There was no evidence of the successive negative contrast effect. Extinction latencies were also significantly lower after training with the large magnitude than after training with the small magnitude; that is, there was no evidence of the magnitude of reinforcement extinction effect. The results are discussed in relation to the comparative analysis of the so-called paradoxical effects of reward, a family of learning phenomena that has not yet been found in a variety of experiments with fish, amphibians, and reptiles trained under widely spaced conditions.     

Navigation in the Morris swim task as a baseline for drug discrimination: a demonstration with morphine

A morphine versus saline discrimination was demonstrated using the Morris swim task as the behavioral baseline. The apparatus was a large circular pool filled with water made opaque by floating polypropylene pellets. Rats were placed in the tank in randomly selected locations (12 trials per session) and could escape by swimming to a platform submerged 2 cm below the surface. Morphine (5.6 mg/kg) or saline was injected prior to training sessions. The position of the platform in a given session depended on the drug condition, thus forming the basis for discriminative responding. Three of the 4 rats acquired the discrimination, as evidenced by direct swims to the condition-appropriate platform. Generalization probe sessions were conducted following acquisition. Probe sessions were preceded by injections of morphine (0, 1.0, 3.0, 5.6, or 10.0 mg/kg) and involved placing the rat in the pool for 1 min without a platform. Swim patterns revealed a gradient, with probe swimming more concentrated in the area of the morphine platform position after higher morphine doses. In addition, dose-dependent increases in the likelihood of swimming first to the morphine-associated platform location were obtained. These results illustrate the generality of drug discrimination across different behavioral procedures, and of particular interest with respect to spatial learning, demonstrate interoceptive stimulus control of navigation.     

Reconsolidation after remembering an odor-reward association requires NMDA receptors

A rapidly learned odor discrimination task based on spontaneous foraging behavior of the rat was used to evaluate the role of N-methyl-D-aspartate (NMDA) receptors (NMDARs) in ongoing memory consolidation. Rats were trained in a single session to discriminate among three odors, one of which was associated with palatable food reward. Previous experiments showed that the NMDAR antagonist DL-APV induced amnesia for this task when injected immediately after training. In the present study, memory was reactivated 24 h after training by exposure to the rewarded odor within the experimental context after which rats received an intracerebroventricular injection of APV. Combined reactivation-drug treatment induced profound amnesia when tested 48 h later. Animals receiving drug alone, in absence of reactivation, showed perfect retention. It is concluded that NMDARs support a consolidation process taking place after memory reactivation.