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.     

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.     

Scopolamine-induced deficits in spontaneous alternation performance: attenuation with lateral ventricle injections of glucose.

This experiment determined whether centrally administered glucose can attenuate scopolamine-induced deficits in spontaneous alternation performance. All rats were surgically prepared with indwelling cannulae directed at the lateral ventricle. Thirty min prior to alternation tests, rats received systemic (ip) injections of saline or scopolamine (3 mg/kg). Ten or thirty min prior to training, the rats also received a direct injection into the lateral ventricle of either artificial cerebrospinal fluid (CSF) or glucose (3 micrograms in 1 microliter). Scopolamine significantly impaired spontaneous alternation performance relative to controls. Additional treatment with ICV glucose 30 min, but not 10 min prior to testing, significantly attenuated the scopolamine-induced deficit. These results add support to the view that glucose acts directly on brain systems to attenuate behavioral effects of cholinergic antagonists.     

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.     

d-Serine facilitates the effects of extinction to reduce cocaine-primed reinstatement of drug-seeking behavior

Male Sprague Dawley rats were allowed to self-administer cocaine (0.5 mg/kg) during 90 min sessions for a period of 15 days. On day 16, rats were either held abstinent in their home cage environment or experienced an extinction session in which the active lever had no programmed consequences. Facilitating N-methyl-d-aspartate (NMDA) receptor activity with the coagonist d-serine (100 mg/kg i.p.) before or following the extinction session significantly reduced the subsequent cocaine-primed reinstatement of drug-seeking behavior tested on day 17. d-Serine significantly reduced drug-primed reinstatement only when combined with extinction, and its effectiveness when administered following the training session suggested that an enhancement of consolidation of extinction learning had occurred. In contrast, d-serine treatment did not reduce sucrose-primed reinstatement, indicating that the beneficial effects of this adjunct pharmacotherapy with extinction training were specific to an addictive substance (cocaine) and did not generalize to a natural reward (sucrose).     

The impairment of retention induced by pentylenetetrazol in mice may be mediated by a release of opioid peptides in the brain

Pentylenetetrazol (PTZ, 45 mg/kg, ip) impaired retention of a one-trial step-through inhibitory avoidance task when injected into male Swiss mice 10 min after training, as indicated by retention performance 48 h later. The amnestic effect of PTZ was prevented by naltrexone (0.01 or 0.10 mg/kg, ip) administered after training, but prior to PTZ-treatment. On the contrary, neither naltrexone methyl bromide (0.01, 0.10, or 10.0 mg/kg, ip), a quaternarium analog of naltrexone, nor MR2266 (0.01 or 0.10 mg/kg, ip), a putative kappa opiate receptor antagonist, modified the behavioral effects of PTZ. On the other hand, the body seizures produced by PTZ were unaffected by any of the three opiate receptor antagonists that were given before the convulsant. Taken together, these results suggest that the effects of PTZ on retention are mediated, at least in part, by opioid peptides of central origin, and rules out a possible participation of opioid peptides derived from prodynorphin-precursor molecule. Administration of beta-endorphin (0.01 or 0.10 microgram/kg, ip) 10 min prior to testing attenuate the retrograde amnesia caused by PTZ. The effect of beta-endorphin was prevented by the simultaneous administration of naltrexone (0.10 mg/kg, ip) prior to testing. Naltrexone has no effect of its own upon retrieval. These results suggest that the impairment of retention induced by PTZ is probably due, at least in part, to a release of opioid peptides in the brain during the post-training period. PTZ given after training do not affect consolidation or memory storage, as mice thus treated may retrieve the learned information when they are submitted to an appropriate neurohumoral and/or hormonal state in the test session, that is, beta-endorphin injection. Therefore, the action of PTZ would be primarily at the level of the mechanism that make stored information available for late retrieval.     

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.     

Cocaine tolerance: acute versus chronic effects as dependent upon fixed-ratio size.

The effects of cocaine on operant behavior were studied by examining fixed-ratio value as a factor in the development of tolerance. Pigeons pecked a response key under a three-component multiple schedule, with each bird being exposed to fixed-ratio values that were categorized as small, medium, or large. Administered acutely, cocaine (1.0 to 10.0 mg/kg) produced dose-related decreases in overall rate of responding. Responding maintained by the largest ratio was decreased by lower doses than those required to reduce rates of responding maintained by the other two ratio schedules. Following repeated daily administration of 5.6 mg/kg of cocaine, dose-effect functions (obtained from sessions during the chronic regimen by making substitutions for the daily dose) indicated tolerance under the smaller ratios, but no tolerance or less tolerance under the largest ratio. Thus, whether tolerance developed, and the degree to which it developed, depended on the ratio value. The results are partially consistent with the notion that tolerance to drug effects on schedule-controlled behavior will develop if drug administration initially reduces reinforcement frequency, but they indicate that reinforcement loss alone is not a sufficient condition for the generation of tolerance under such conditions. The findings suggest that amount of responding required for reinforcement, or "effort," may contribute to the development of tolerance to effects of cocaine.     

Intra-amygdala anxiogenic drug infusion prior to retrieval biases rats towards the use of habit memory

In a dual-solution plus-maze task that can be acquired using either hippocampus-dependent "cognitive/place" learning or dorsal striatal-dependent "habit/response" learning, pre-acquisition peripheral or intra-basolateral amygdala (BLA) injections of anxiogenic drugs result in the predominant use of response learning. The present experiments examined the effect of anxiogenic drug treatment on the relative use of multiple memory systems when administered prior to memory retrieval. Adult male Long-Evans rats were trained for two days (6 trials/day, 30s ITI) in a dual-solution plus-maze task to swim from the same start point (south) to an escape platform that was located in a consistent goal arm (west). On day three, prior to a memory retrieval probe trial from a novel start point (north), rats received a peripheral (0.03, 0.1 or 0.3 mg/kg), or intra-BLA (0.1 microg/0.5 microl) injection of the anxiogenic alpha(2)-adrenoreceptor antagonist RS 79948-197, or saline. Relative to saline controls, rats receiving either peripheral or intra-BLA infusions of RS 79948-197 predominantly displayed response learning on the probe trial. In an additional experiment peripheral (0.1 mg/kg) or intra-BLA (0.1 microg) drug injections administered prior to both acquisition and retrieval also resulted in the predominant use of response learning. The findings indicate that (1) similar to acquisition, peripheral injection of an anxiogenic drug prior to memory retrieval biases rats towards the use of habit/response memory, (2) intra-BLA infusions of an anxiogenic drug is sufficient to produce this modulatory effect of emotional state on memory retrieval, and (3) state-dependency does not appear to play a role in the effects of anxiogenic drug treatment on multiple memory system use. The findings may have implications for understanding the interaction between brain function, emotion, and the relative use of multiple memory systems in human psychopathology.     

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.     

Diazepam prevents post-training drug effects related to state dependency, but not post-training memory facilitation by epinephrine

Rats were trained and tested in a step-down inhibitory avoidance task (0.3-mA footshock). Training-test interval was 6 h. In Experiment 1, animals received, 1 h before training, an ip injection of vehicle or diazepam (2.0 mg/kg) and, 30 s after training and/or 30 min prior to testing, ip saline, epinephrine (6.25 micrograms/kg or 125.0 micrograms/kg), naloxone (0.5 mg/kg), or beta-endorphin (1 micrograms/kg). In the vehicle-pretreated animals, post-training epinephrine (6.25 micrograms/kg) and naloxone enhanced, and post-training beta-endorphin and epinephrine (125.0 micrograms/kg) reduced, retention test performance; and pretest beta-endorphin and epinephrine (125.0 micrograms/kg) reversed the latter effect and enhanced retention on their own. Diazepam lowered memory scores on its own and prevented all other drug effects with the exception of post-training facilitation by epinephrine (6.25 micrograms/kg). In previous papers it was shown that post-training facilitation by epinephrine is due to an influence on storage processes, whereas all the other drug effects described above result from the post-training establishment of state dependency to either beta-endorphin or epinephrine, and therefore to a process involving further acquisition and storage. The present findings suggest that diazepam selectively hindered the acquisition and/or storage processes involved in state dependency. This conclusion is strengthened by the findings from Experiment 2, which showed, using a classic 2 x 2 design, that diazepam itself did not induce state dependency but, rather, depressed acquisition and/or storage of the avoidance task.     

Nicotine vs. Ethanol Discrimination: Extinction and Spontaneous Recovery of Responding

Studies regarding extinction and spontaneous recovery of the discriminative stimulus effects of drugs are limited. Eight rats were initially trained to discriminate nicotine (0.4 mg/kg) vs. ethanol (800 mg/kg). For four rats, itraperitaneal (IP) administrations of nicotine fifteen minutes prior to fifteen-minute training sessions served as a discriminative stimulus (SD) for predicting food-reinforced lever pressing (VI-1 min). On other sessions ethanol functioned in predicting nonreinforcement (SA). The stimulus roles of the drugs were counterbalanced for the remaining four rats. SA and SD sessions alternated quasi-randomly with two daily sessions at 1000 and 1400 hours. Discriminative control was not disrupted following ten extinction sessions under a non-drug/saline condition, but was disrupted following extinction sessions under the original training drugs. Instances of spontaneous recovery (SR) occurred throughout extinction under the drug condtions. There was no evidence for SR two weeks following extinction, but partial recovery four weeks following the final extinction phase. Contextual status (context renewal) had neither a restorative or disruptive impact on extinguished or discriminated responding, respectively. These results support and extend the limited number of other studies by demonstrating extinction and spontaneous recovery of responding discriminated by two distinct drugs. Some theoretical interpretations regarding history effects and training in the context of drug discrimination are entertained.     

NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse

Previous research from our laboratory has implicated the basolateral amygdala (BLA) complex in the acquisition and consolidation of cue-cocaine associations, as well as extinction learning, which may regulate the long-lasting control of conditioned stimuli (CS) over drug-seeking behavior. Given the well established role of NMDA glutamate receptor activation in other forms of amygdalar-based learning, we predicted that BLA-mediated drug-cue associative learning would be NMDA receptor dependent. To test this hypothesis, male Sprague-Dawley rats self-administered i.v. cocaine (0.6 mg/kg/infusion) in the absence of explicit CS pairings (2-h sessions, 5 days), followed by a single 1-h classical conditioning (CC) session, during which they received passive infusions of cocaine discretely paired with a light+tone stimulus complex. Following additional cocaine self-administration sessions in the absence of the CS (2-h sessions, 5 days) and extinction training sessions (no cocaine or CS presentation, 2-h sessions, 7 days), the ability of the CS to reinstate cocaine-seeking on three test days was assessed. Rats received bilateral intra-BLA infusions (0.5 microl/hemisphere) of vehicle or the selective NMDA receptor antagonist, 2-amino-5-phosphonovalerate (AP-5), immediately prior to the CC session (acquisition), immediately following the CC session (consolidation), or immediately following reinstatement testing (consolidation of conditioned-cued extinction learning). AP-5 administered before or after CC attenuated subsequent CS-induced reinstatement, whereas AP-5 administered immediately following the first two reinstatement tests impaired the extinction of cocaine-seeking behavior. These results suggest that NMDA receptor-mediated mechanisms within the BLA play a crucial role in the consolidation of drug-CS associations into long-term memories that, in turn, drive cocaine-seeking during relapse.     

Repeated post- or presession cocaine administration: roles of dose and fixed-ratio schedule

Effects of repeated administration of cocaine to animals behaving under operant contingencies have depended on when the drug is given. Moderate doses given presession have generally led to a decrease in the drug's effect, an outcome usually referred to as tolerance. When these same doses have been given after sessions, the usual result has been no change or an increase in the drug's effects, with the latter usually referred to as sensitization. In the present study, repeated postsession administration of a relatively small dose of cocaine (3.0 or 5.6 mg/kg) to pigeons responding under a multiple fixed-ratio 5, fixed-ratio 100 schedule of food presentation generally resulted in tolerance to the rate-decreasing effects of the drug. When the same dose was given before sessions, little additional tolerance was observed, although some subjects showed further tolerance in the small-ratio component. A regimen of repeated postsession injection of larger (10.0-23.0 mg/kg) doses suppressed key pecking during the session; responding resumed following discontinuation of postsession administrations. Effects of postsession administration of cocaine, therefore, depended on the dose, with smaller doses leading to tolerance and larger ones to suppression of behavior during the session. Effects of postsession drug administration of either small or large doses were not related to whether effects of postsession drug were experienced mainly in the operant test chamber or in the pigeon's home cage. The results with large postsession doses are compatible with a view that the drug acted as a Pavlovian unconditional stimulus, with the session-related stimuli acting as a long-duration Pavlovian conditional stimulus. Tolerance following postsession administration of the smaller doses challenges the view that it depended on experiencing the drug's effects while the arranged reinforcement contingencies were in effect.     

Sexual experience effects are blocked both by the protein-synthesis inhibitor, cycloheximide, and by the noncompetitive NMDA antagonist, MK-801.

Three studies were done to determine the effects of a brief 2-h sexual experience on the maintenance of sexual behavior in male rats; the effects on the experience-based maintenance of sexual behavior of gonadal hormones (study 1), a protein-synthesis inhibitor (study 2), and an N-methyl-D-aspartate receptor blocker (study 3) were determined. Naive male rats were provided with a 2-h sexual experience with sexually receptive hormonally "primed" females or they received no experience. In the first study animals under each of these conditions then underwent castration or sham surgery. In the second study animals under each of the experience conditions received either cycloheximide (CYX) or saline (SAL; 1.5 or 3.0 mg/kg CYX or SAL sc, 10 min after the experience). In study 3 experienced and inexperienced animals received either 0.07 or 0.10 mg/kg MK-801 ip (15 min before the experience). In all studies animals were tested for sexual behavior 3, 6, and 9 days after surgery or injection. These studies showed that the most consistent effect of a 2-h sexual experience was to facilitate the initiation of mounting, especially on the first test; they show, further, that most experience effects were reduced or eliminated if animals were castrated between experience and test, if they received a drug (CYX) at the time of the experience that blocks the synthesis of proteins, or if they received an NMDA receptor antagonist prior to the experience.     

Post-training, but not post-reactivation, administration of amphetamine and anisomycin modulates Pavlovian conditioned approach

The psychostimulant, amphetamine (AMPH), and the protein synthesis inhibitor, anisomycin (ANI), have been shown to modulate the consolidation and reconsolidation of several types of learning. To determine whether Pavlovian conditioned approach (PCA) is modulated in a similar manner, we examined the effects of post-training and post-reactivation administration of both AMPH and ANI on memory for PCA. Male Long-Evans rats received PCA training sessions during which presentations of a CS+ were followed by sucrose delivery. AMPH (1 mg/kg, s.c.) injected immediately but not 6h after the first training session enhanced PCA behavior. ANI (150 mg/kg, s.c.) injected immediately but not 3h after the first training session impaired PCA behavior. This impairment was not due to the development of a conditioned taste aversion. To examine whether PCA can also be modulated by post-reactivation administration of AMPH and ANI, rats were given an injection of AMPH, ANI, or vehicle immediately after a memory reactivation session. Upon testing, the behavior of both the AMPH- and the ANI-treated rats was unaffected. This result remained consistent when the experiment was repeated with changes to various behavioral parameters (i.e., amount of training, length of memory reactivation). These findings indicate that AMPH and ANI act during the post-training but not the post-reactivation period to enhance and impair, respectively, the learning of PCA. This suggests that the consolidation of PCA can be modulated in a manner comparable to other types of learned associations, but once learned, the memory appears to be relatively robust and stable.     

Enhancement of the Post-training Cholinergic Tone Antagonizes the Impairment of Retention Induced by a Nitric Oxide Synthase Inhibitor in Mice

The present experiments examined the role of the central cholinergic system in the memory impairment induced by post-training administration of a nitric oxide synthase (NOS) inhibitor in mice. Male Swiss mice received a one-trial inhibitory avoidance training (0.8 mA, 50 Hz, 1-s footshock) followed immediately by an ip injection of the NOS inhibitor -N^G-nitroarginine methyl ester ( -NAME; 100 mg/kg). Retention (cut-off time, 300 s) was tested 48 h after training. The administration of -NAME results in memory impairment for the inhibitory avoidance task. The effects of -NAME (100 mg/kg, ip) on retention were reversed in a dose-related manner by the centrally acting anticholinesterase physostigmine (35, 70, or 150 μg/kg, sc) administered 30 min after the NOS inhibitor. Further, -NAME (100 mg/kg, ip)-induced memory impairment was completely antagonized by the centrally acting muscarinic cholinergic agonist oxotremorine (OTM; 25, 50, or 100 μg/kg, sc) when given 30 min after -NAME. The peripherally acting anticholinesterase neostigmine (150 μg/kg, sc) did not modify the memory-impairing effects of -NAME. These findings suggest that the memory impairment following post-training administration of a NOS inhibitor is mediated, at least in part, by a reduction of the activity of central muscarinic cholinergic mechanisms and are consistent with our previous view that nitric oxide may be involved in post-training neural processes underlying the storage of newly acquired information.     

Noradrenergic receptor blockade of the NTS attenuates the mnemonic effects of epinephrine in an appetitive light-dark discrimination learning task

These experiments examined the contribution of noradrenergic neurons in the nucleus of the solitary tract (NTS) in mediating the memory-facilitating effects of epinephrine. In Experiment 1, saline or 0.05 or 0.1 mg/kg of epinephrine was given intraperitoneally (ip) to rats after the second day of training in a light-dark Y-maze discrimination task. On a 20-trial retention test given 2 and 7 days later, the 0.1 mg/kg epinephrine group made significantly more correct responses than controls and required fewer trials to reach criterion. In Experiment 2, phosphate-buffered saline or the noradrenergic antagonist dl-propranolol (0.3 or 1.0 microg/0.5 microl) was infused into the NTS prior to an ip injection of saline or 0.1 mg/kg of epinephrine. The memory-enhancing effects of epinephrine were attenuated by the infusion of 0.3 microg/0.5 microl of dl-propranolol into the NTS. These findings indicate an involvement of NTS noradrenergic neurons in mediating the effects of peripheral epinephrine on memory storage processes.     

Modulatory influence of dopamine receptors on consolidation of object recognition memory

The role of dopamine receptors in regulating the formation of recognition memory remains poorly understood. Here we show the effects of systemic administration of dopamine receptor agonists and antagonists on the formation of memory for novel object recognition in rats. In Experiment I, rats received an intraperitoneal (i.p.) injection of vehicle, the selective D1 receptor agonist SKF38393 (1.0 and 5.0mg/kg), or the D2 receptor agonist quinpirole (1.0 and 5.0mg/kg) immediately after training. In Experiment II, rats received an injection of vehicle, the dopamine receptor antagonist SCH23390 (0.1 and 0.05 mg/kg), or the D2 receptor antagonist raclopride (0.5 and 0.1mg/kg) before training, followed by an injection of vehicle or the nonselective dopamine receptor agonist apomorphine (0.05 mg/kg) immediately after training. SKF38393 at 5mg/kg produced an enhancement of novel object recognition memory measured at both 24 and 72 h after training, whereas the dose of 10mg/kg impaired 24-h retention. Posttraining administration of quinpirole did not affect 24-h retention. Apomorphine enhanced memory in rats given pretraining raclopride, suggesting that the effect was mediated by selective activation of D1 receptors. The results indicate that activation of D1 receptors can enhance recognition memory consolidation. Importantly, pharmacological activation of D1 receptors enhanced novel object recognition memory even under conditions in which control rats showed significant retention.     

A Nitric Oxide Synthase Inhibitor Impairs Memory Storage in Mice

Posttraining administration of the -enantiomer of the competitive inhibitor of nitric oxide synthase,N^G-nitro- -arginine methyl ester ( -NAME, 3–100 mg/kg, ip), impaired 48-h retention of a one-trial step-through inhibitory shock-avoidance task in male Swiss mice. The effects were dose-dependent and were not observed when the -enantiomer ( -NAME, 3–100 mg/kg, ip) was injected instead of -NAME. Retention latencies of mice that had not received a footshock during training were not affected by -NAME. The memory impairment produced by -NAME was time-dependent, suggesting an action on memory storage. The effects of -NAME on memory were overcome by the injection of -(but not -)arginine (300 mg/kg, ip) along with the inhibitor. Considered together, these findings suggest that the -arginine/nitric oxide pathway may be involved in memory storage of an inhibitory avoidance response in mice.