Phencyclidine disrupts long- but not short-term memory within a spatial learning task

In the first experiment rats with 1, 2, 3 or 4 mg/kg phencyclidine (PCP), or saline injections were tested for acquisition or retention of a cheese board spatial task (dry land version of a water maze). Results indicate that relative to controls or rats with injections of 1 and 2 mg/kg PCP, rats with 3 or 4 mg/kg PCP injections were impaired in acquisition and retention of the task as measured by increased distances traveled to find the correct food location. This impairment was primarily observed in between days but not within days performance. In the second experiment rats with 4 mg/kg PCP or saline injections were tested for memory performance of a delayed spatial matching-to-sample task. Results indicate that relative to controls rats with 4 mg/kg PCP injections were not impaired at either 1–5 or 30 s delays. It is suggested that PCP through its blocking action of the NMDA receptor mediates long- but not short-term memory for spatial location information as well as the ability to retrieve previously learned spatial location information.     

Memantine improves memory for taste-avoidance learning in day-old chicks exposed to isolation stress

Activation of NMDA receptors by glutamate is particularly important in the initial stages of memory consolidation. Memantine, a noncompetitive NMDA receptor antagonist, ameliorates memory impairment under certain circumstances, despite blocking the activation of NMDA receptors. The present experiments tested the hypothesis that memantine can improve memory deficits induced by isolation stress in day-old chicks (Gallus gallus domesticus) trained in a one-trial taste-avoidance task. Three experiments assessed the effects of memantine at different concentrations and in combination with isolation stress. The results of Experiment 1 indicate that, under normal, non-stressed conditions, memory in control animals is strong and 15.0 mM memantine impairs memory, similar to that seen in many studies of the effects of NMDA receptor antagonists on learning. However, the results of Experiments 2 and 3 showed that, when chicks were exposed to isolation stress during the pre-training period, memory formation for saline-injected control animals was impaired and 5.0 mM memantine significantly improved memory in an inverted U-shaped dose response function. The current results extend the findings that memantine can ameliorate memory impairment and supports the hypothesis that memantine, despite its action to reduce NMDA receptor activity, can facilitate normalized memory acquisition.     

Investigation of the reported protective effect of cycloheximide on memory

Many findings support the hypothesis that formation of long-term memory requires synthesis of proteins in the nervous system close to the time of learning. This hypothesis has been challenged recently by reports that the protein synthesis inhibitor cycloheximide (CYC) injected 2 hr prior to passive avoidance training in mice or rats attenuated the memory impairment induced by a usually amnestic dose of CYC administered 30 min pretraining. To investigate the reports of a "protective" effect of the prior injection, we attempted to replicate them and test their generality. For replication we administered either paired injections of CYC--120 mg/kg 2 hr prior to training and 30 mg/kg 30 min prior to training--or single injections of CYC (either 120 mg/kg or 30 mg/kg) 30 min pretraining and tested for retention of the passive avoidance habit either 1 or 7 days later. No attenuation of amnesia was observed at 1 day tests. Attenuation of amnesia following the double injection of CYC was observed at 7 day tests. When another protein synthesis inhibitor, anisomycin, was used in the same experimental design, there was no "protective" effect; two injections of anisomycin produced greater memory impairment for the passive avoidance habit than did the single low dose. Also, for active avoidance training, two successive injections of CYC caused significantly greater amnesia than did a single dose; this is the opposite of a "protective" effect. We suggest that the reported "protective" effect of CYC on memory is an as yet unexplained phenomenon that does not generalize to other antibiotic drugs and is specific to the passive avoidance task.     

The conditioned place preference is affected by two independent reinforcement processes

The conditioned place preference method for measuring the affective properties of reinforcing events was studied using treatments of known affective value. The size of the place aversion observed increased with dose when the reinforcer was injections of lithium chloride. The size of the place preference observed increased with concentration when the reinforcer was drinking sucrose solutions. However, when the reinforcer was solutions of saccharin (that were consumed in the same amounts as the sucrose solutions) no place preferences were observed. This finding was explained in terms of the dual reinforcement hypothesis [20] which postulates that although sucrose and saccharin both have positive affective properties (based on their tastes) only sucrose has memory improving properties (based on its post-ingestive action). It was therefore proposed that conditioned place preferences depend on the activation of both affective and memory improving processes. This hypothesis was confirmed by the observation of place preferences with a saccharin solution as the reinforcer when the pairing trials were followed by non-contingent, post-pairing injections of glucose or amphetamine (both of which are known to improve memory). Therefore, behavior in the place preference method depends upon both the affective and the memory improving properties of the reinforcers under test.     

Relief learning is dependent on NMDA receptor activation in the nucleus accumbens

Background and Purpose

Recently, we demonstrated that the nucleus accumbens (NAC) is required for the acquisition and expression of relief memory. The purpose of this study was to investigate the role of NMDA receptors within the NAC in relief learning.

Experimental Approach

The NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5) was injected into the NAC. The effects of these injections on the acquisition and expression of relief memory, as well as on the reactivity to aversive electric stimuli, were tested.

Key Results

Intra-accumbal AP-5 injections blocked the acquisition but not the expression of relief memory. Furthermore, reactivity to aversive electric stimuli was not affected by the AP-5 injections.

Conclusion and Implication

The present data indicate that NMDA-dependent plasticity within the NAC is crucial for the acquisition of relief memory.     

The reinforcement enhancing effects of nicotine depend on the incentive value of non-drug reinforcers and increase with repeated drug injections

We have hypothesized that nicotine has two effects on reinforcement; it increases the probability of responses resulting in nicotine delivery (primary reinforcement) and enhances the apparent reward value of non-nicotine reinforcers (reinforcement enhancing effect). The present studies investigated two predictions generated by this hypothesis: (1) that the reinforcement enhancing effect will depend on apparent stimulus reward value and (2) that the temporal profile of this effect would depend on the pharmacological profile of nicotine. In Experiment 1, rats were trained to lever press for one of two audio-visual stimuli that differed in their intrinsic reinforcing value and then the effect of pre-session nicotine (0.4 mg/kg base) or saline injections was tested. The stimulus that supported very low rates of operant responding displayed smaller increases in responding after pre-session injections of nicotine. In Experiment 2 the effect of nicotine injected 5 min before the session was compared to the effect of nicotine injected 1h after the session using the more reinforcing stimulus condition from the first experiment. A control group received only vehicle injections. In contrast to nicotine injected just prior to the session, post-session injections of nicotine had no detectable effect on responding for the more reinforcing stimulus. These results indicate that the reinforcement enhancing action of nicotine depends on the intensity of the primary reinforcer and that enhanced reinforcement by nicotine depends on coincident access to a stimulus with reinforcing properties.     

Aurothiomalate inhibits COX-2 expression in chondrocytes and in human cartilage possibly through its effects on COX-2 mRNA stability

Cyclooxygenase-2 (COX-2) is expressed in rheumatoid and osteoarthritic cartilage and produces pro-inflammatory prostanoids in the joint. In the present study, we investigated the effects of disease modifying anti-rheumatic drugs on COX-2 expression in chondrocytes. Unlike the other tested drugs, aurothiomalate was found to inhibit COX-2 expression in chondrocytes. In the further studies, effects and mechanisms of action of aurothiomalate were investigated in more detail. Aurothiomalate inhibited IL-1beta-induced COX-2 protein expression and PGE(2) production in chondrocytes in a dose-dependent manner. Because aurothiomalate did not alter IL-1beta-induced mRNA levels when measured 0-3 h after addition of IL-1beta, its effects on COX-2 mRNA degradation were tested by Actinomycin D assay. The half-life of COX-2 mRNA was reduced from 3 h to less than 1.5 h in aurothiomalate-treated cells. The 3'-untranslated region (3'-UTR) of COX-2 mRNA contains an ARE element which has been shown to bind mRNA stabilizing factor HuR. Interestingly, aurothiomalate inhibited HuR expression which may explain its destabilizing effect on COX-2 mRNA. Aurothiomalate reduced COX-2 expression and PGE(2) production also in human cartilage at drug concentrations which have been measured in serum and synovial fluid during treatment with aurothiomalate. The results show that aurothiomalate reduces COX-2 expression and PGE(2) production in chondrocyte cultures and in human cartilage. The action is likely mediated by enhanced COX-2 mRNA degradation possibly through a mechanism related to reduced expression of HuR. The results provide a novel mechanism of action for aurothiomalate which may be important in the treatment of arthritis.     

Estrogen and NMDA receptor antagonism: effects upon reference and working memory.

Since both estrogen and NMDA receptor antagonists act on the hippocampus CA1 region and behaviorally affect hippocampal memory tasks, we examined how estrogen depletion (ovariectomy) and NMDA receptor antagonism interact upon spatial memory of the mouse. After ovariectomy or sham operation, mice were given a 2-week recovery before behavioral tests began under the influence of vehicle or (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP 2, 5 and 10 mg/kg) intraperitoneal injections. CPP is a competitive, full NMDA receptor antagonist. Spatial reference memory was tested by the water maze, spatial working memory was tested by the radial arm maze, while overall locomotive activity was monitored by the Y-maze. Results from the water maze and the Y-maze did not show any spatial reference memory or activity differences between sham-operated and ovariectomized mice. The radial arm maze, however, highlighted some working memory differences between intact and ovariectomized mice. CPP treatment impaired dose dependently--the performance of ovariectomy and sham-operated mice equally on both water maze and radial arm maze, while the drug had no effect on Y-maze performance. These results suggest that short term estrogen deprivation has no effect upon spatial-reference memory, while it impairs spatial working memory. This effect is probably not mediated by NMDA receptors.     

Modulation of memory processes and cellular excitability in the dentate gyrus of freely moving rats by a 5-HT4 receptors partial agonist, and an antagonist

Firstly, olfactory association learning was used to determine the modulating effect of 5-HT4 receptor involvement in learning and long-term memory. Secondly, the effects of systemic injections of a 5-HT4 partial agonist and an antagonist on long-term potentiation (LTP) and depotentiation in the dentate gyrus (DG) were tested in freely moving rats. The modulating role of the 5-HT4 receptors was studied by using a potent, 5-HT4 partial agonist RS 67333 [1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-n-butyl-4-piperidinyl)-1-propanone] and a selective 5-HT4 receptor antagonist RS 67532 [1-(4-amino-5-chloro-2-(3,5-dimethoxybenzyloxyphenyl)-5-(1-piperidinyl)-1-propanone]. Agonist or antagonist systemic chronic injections prior to five training sessions yielded a facilitatory effect on procedural memory during the first session only with the antagonist. Systemic injection of the antagonist only before the first training session improved procedural memory during the first session and associative memory during the second session. Similar injection with the 5-HT4 partial agonist had an opposite effect. The systemic injection of the 5-HT4 partial agonist prior to the induction of LTP in the dentate gyrus by high-frequency stimulation was followed by a population spike increase, while the systemic injection of the antagonist accelerated the depotentiation 48 h later. The behavioural and physiological results pointed out the involvement of 5-HT4 receptors in processing related to the long-term hippocampal-dependent memory system, and suggest that specific 5-HT4 agonists could be used to treat amnesic patients with a dysfunction in this particular system.     

Amino acids and memory consolidation in the cricket. II: Effect of injected amino acids and opioids on memory

The effect of injections of selected amino acids on memory, given before a maze-learning, was investigated. Thirsty crickets (Pteronemobius sp.) were trained to turn only to one side of a symmetrical Y-shaped maze using reinforcements with water. The insects retained the learned task 24 hr later. N2 anoxia applied immediately after training produced retrograde amnesia. Injections of Ala, Arg, Gln or morphine prior to training blocked the amnesic action of anoxia, whereas those of Cys, Met, Pro, Orn, octopamine or naloxone did not. Naloxone blocked long-term memory formation, but not learning, whereas Pro and Orn blocked both. The antiamnesic effect of morphine and Arg, but not that of Ala, was blocked by naloxone. A hypothesis assigning a neuromodulatory role to some amino acids is put forward.     

Memory retention test performance in mice: Improvement by chronic oral cholinergic drug treatment

Mice consumed solutions containing 0, 0.025, 0.050 or 0.075 mg/ml of arecoline hydrobromide (ARE) one week prior to training (T-maze, footshock, active avoidance) and a total of two weeks prior to testing memory retention. The mean daily doses of ARE were estimated to be 0, 157, 302, or 500 μg per mouse, respectively. An inverted-U dose-response curve was obtained; the best retention test performance was by the group receiving 0.050 mg/ml of ARE. Measures of activity and weight taken over the experiment indicated no significant differences between ARE groups and the control group; thus no apparent toxicity. Separate groups of mice consumed 0 or 0.050 mg/ml of ARE for one week, then were trained to a criterion of 5 avoidances in 6 training trials. There were no significant differences in trials to first avoidance response or to criterion. Thus the enhanced retention test performance of the 0.050 mg/ml ARE group reflected improved memory processing rather than better learning.     

Deletion of Melanin-Concentrating Hormone Receptor-1 gene accentuates D-amphetamine-induced psychomotor activation but neither the subsequent development of sensitization nor the expression of conditioned activity in mice

The present study aimed to test the hypothesis that mice lacking the MCHR1 receptor (Melanin-Concentrating Hormone Receptor-1) present an elevated vulnerability towards the neurobehavioural effects of D-amphetamine, presumably due to previously established up-regulations of dopamine D1 receptors in these mice. We examined the psychomotor effects of five once-daily injections of 1.5 and 3 mg/kg D-amphetamine (i.p.) or ten once-daily injections of 2.25 mg/kg D-amphetamine in knockout (KO) mice lacking the MCHR1 receptor. The first injection of D-amphetamine induced a greater psychomotor response amongst the KO mice at 2.25 and 3.0 mg/kg. On all subsequent d-amphetamine injections, KO mice still showed greater levels of psychomotor activity than the WT mice, but with no between-genotype difference in the rate of development of sensitization (similar slopes of the curves). Furthermore, 24 h after the last injection of 2.25 mg/kg D-amphetamine both genotypes exhibited a significant post-sensitization conditioned activity. Thus, MCHR1 receptors are likely not deeply involved in the mechanisms of induction of sensitization and related conditioned activity induced by D-amphetamine, albeit our results confirm a contribution of these receptors to the mechanisms of the acute effects of that drug, possibly via an inhibitory action on the dopaminergic mesolimbic system. Our results do not support the hypothesis of a functional contribution of MCHR1 receptors to the addictive effects of D-amphetamine.     

Effects of scopolamine and unilateral lesions of the basal forebrain on T-maze spatial discrimination and alternation in rats

Cholinergic systems are thought to play a role in memory. It has been suggested that cholinergic neurons, possibly the cortically projecting cells of the nucleus basalis magnocellularis, are differentially involved in working and reference memory. To evaluate this hypothesis the effects on memory of scopolamine (0, 0.3, 0.6 mg/kg) or unilateral kainic acid (4.7 nmoles in 1 microliter) lesions of the basal forebrain of rats were tested. Working memory, the recall of recent events of transient importance that is vulnerable to interference, was tested using a T-maze alternation task; reference memory, information stored over the long term that is relatively resistant to interference, was evaluated using a spatial discrimination task in the T-maze. The differential sensitivity of the two tasks to interference effects was confirmed by the finding that the insertion of a 30-sec delay between trials significantly reduced performance in the alternation but not the spatial discrimination task. Furthermore, scopolamine or the lesions significantly impaired alternation but not spatial discrimination performance. Biochemical assays of the kainate-injected brains confirmed that the cortical cholinergic marker, choline acetyltransferase, was significantly reduced. These results support the hypothesis that working and reference memory may be differentially controlled by cholinergic systems.     

Possible involvement of mu-opioid receptors in effect of lithium on inhibitory avoidance response in mice

In the present study, effects of intracerebroventricular (i.c.v.) injections of mu-opioid receptor agonist and antagonist on lithium state-dependency were investigated. For memory assessment, a one-trial step-down inhibitory avoidance task was used in adult male NMRI mice. Intraperitoneal (i.p.) administration of lithium (10 mg/kg) after training impaired memory when retrieval was tested 24 h later. The memory impairment was reversed by pretest administration of the same dose of lithium, suggesting state-dependency induced by lithium. In addition, i.c.v. administration of both lithium (2 and 4 microg/mouse, i.c.v.) and morphine (3 and 6 microg/mouse, i.c.v.) before the test reversed memory impairment induced by post-training lithium (10 mg/kg, i.p.). On the other hand, pretest administration of naloxone (1 and 2 mg/kg) which had no effects alone on inhibitory avoidance response, prevented the improving effects of both morphine (3 microg/mouse, i.c.v.) and lithium (2 microg/mouse, i.c.v.) on memory retrieval. The results suggest that the mu-opioid receptors in the central nervous system may be involved in the retrieval of lithium state-dependent learning.     

An alpha 2-adrenergic mode of action of chlordimeform on rat visual function

The hypothesis that chlordimeform increased the amplitude of components N1P1 and P1N3 in rat pattern-reversal visual evoked potentials through actions on alpha 2-adrenergic receptors was tested with two sets of experiments. First, rats received single injections of either vehicle, an alpha 2-adrenergic antagonist yohimbine (0.1, 0.5, or 2.0 mg/kg), or an alpha 2-adrenergic agonist clonidine (0.05, 0.1, or 0.5 mg/kg). Yohimbine alone had no effect on pattern-reversal evoked potential amplitude. Clonidine treatment produced a dosage related increase in amplitude of both components similar to that produced by chlordimeform (W.K. Boyes and R.S. Dyer, 1984, Brain Res. Bull., 10, 817-823). Second, rats were given double injections of either vehicle or yohimbine (0.05, 0.5, 2.0, or 5.0 mg/kg) followed by either vehicle, clonidine (0.1 or 0.2 mg/kg) or chlordimeform (10, 20, or 40 mg/kg). Yohimbine pretreatment attenuated the effects of subsequent treatment with either clonidine or chlordimeform. These results support the hypothesis that chlordimeform alters rat pattern-reversal evoked potentials through actions as a central nervous system alpha 2-adrenergic agonist.     

Phencyclidine injections into the dorsal hippocampus disrupt long- but not short-term memory within a spatial learning task

Since the hippocampus is likely to be a major site of phencyclidine (PCP) action, the effects of various doses of PCP (1.8, 18 or 36 nM) as well as 3.6 nM MK-801 or saline injected directly into the dentate gyrus of the hippocampus was tested for acquisition of a spatial navigation task (dry land version of a water maze) using a paradigm that assesses short term memory based on learning within a day and long term memory based on learning between days. Results indicated that relative to saline or 1.8 nM PCP injected rats, rats with 18 or 36 nM PCP or 3.6 nM MK-801 injections were impaired in acquisition of the task as measured by increased distances traveled to find the food location between days but not within days. In additional experiments 36 nM PCP or 3.6 nM MK-801 did not produce any deficits in the acquisition of an object discrimination task. It is suggested that PCP through its blocking action of the NMDA receptor in the dentate gyrus or CA1 region of the dorsal hippocampus mediates the consolidation of new spatial location information.     

The effects of scopolamine and cues to forget on pigeons' memory for time.

Pigeons were trained with a 0-s delayed symbolic matching-to-sample procedure to indicate whether a houselight sample stimulus was short (2 s) or long (8 s) by pecking a red or a green comparison stimulus. In Experiment 1, the pigeons received injections of scopolamine hydrobromide (0.015 mg/kg), or saline, and the delay interval was manipulated (0, 1, 3, and 9 s). Memory for time was significantly poorer following scopolamine injections than following saline injections. A significant choose-short bias was observed under scopolamine at delays as brief as 3 s, but not under saline. In Experiment 2, a brief postsample cue (a vertical or horizontal line) signaled whether the comparison stimuli would be presented or omitted on each trial. During training, comparison stimuli were always presented following the remember (R) cue, but never following the forget (F) cue. During testing, memory for time was significantly poorer on F-cue trials than on R-cue trials. A significant choose-short bias was observed on F-cue trials at the 5- and 10-s delays, but not on R-cue trials. The results suggest that anticholinergic blockade accelerates the rate at which memory for temporal events is foreshortened in working memory. This effect is similar to that produced by an explicit cue to forget the temporal sample.