The effects of d-cycloserine and MK-801 on the performance of rats in two spatial learning and memory tasks

The present study was undertaken to investigate the effects of modulation of the (NMDA) receptor on learning and memory. Thus, the performance of rats treated with d-cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor complex, and MK-801, a noncompetitive NMDA receptor antagonist, either alone or concurrently were assessed in radial arm maze and water maze tasks. Administration of MK-801 (0.1 mg/kg, i.p.) impaired acquisition in the water maze (increased escape latency and distance) and working memory in the radial arm maze (increased re-entries) in rats. Moreover, in the radial arm maze, MK-801 disrupted locomotion (increased latencies and decreased arm entries per minute) and impaired the acquisition of reference memory (increased number of errors) performance of rats. d-Cycloserine (0.03, 0.3, 1.0, 3.0, 10 mg/kg, i.p.) had no effects on acquisition or memory performance of control or MK-801-treated rats in either of these tasks. However, d-cycloserine (0.03, 0.3, 3.0 mg/kg) reversed the MK-801-induced disruption in locomotion. Furthermore, 3.0 mg/kg d-cycloserine increased behavioral activity and also decreased the time needed to complete the task in control animals. To conclude, our results suggest that the consequences of NMDA receptor modulation on learning and memory processes and sensorimotor functions may be functionally different or have distinct anatomical locations.     

MK-801 impedes the acquisition of a spatial memory task in rats

Several studies have reported that MK-801 impairs the acquisition of various learning and memory tasks, while others suggest that MK-801 may interfere with performance rather than having a specific effect on memory. To characterize further the effects of MK-801 on learning and memory, MK-801 (0.05 mg/kg, SC) was administered prior to or immediately after learning trials in a trial-independent water maze task. Since MK-801 may affect nonassociative variables that may influence learning and memory, motor activity and general reactivity measures were also determined for 0.0125, 0.025, or 0.05 mg/kg of MK-801 administered SC. Since MK-801 may also be used to treat children with epilepsy, we investigated the possible persistent cognitive effects on neonates. MK-801 (0.02 mg/kg, SC) was administered at postnatal days 9-15 and tested in the same task as above starting at day 36 of age. There were no persistent effects of neonatal treatment. However, in adult rats, MK-801 impaired the acquisition of the water maze task but did not affect performance during a recall task in the same apparatus. At doses affecting learning, there were no effects on motor activity or general reactivity in adult rats. These results are consistent with the conclusion that MK-801 interferes with acquisition of spatial learning in the rat.     

Effects of the NMDA antagonists CPP and MK-801 on delayed conditional discrimination

N-methyl-D-aspartate (NMDA) receptor/channel antagonists have previously been shown to impair spatial working memory and hippocampal long-term potentiation. The present experiment investigated the effects of a variety of doses of NMDA antagonists on a working memory task in rats involving an auditory delayed conditional discrimination. Signal detection analysis and an exponential memory decay model were used to extract independent measures of stimulus discriminability and rate of forgetting. A competitive NMDA antagonist, (CPP, 0.33, 1.0, 10.0 mg/kg, IP) produced a reduction in discriminability which was linearly related to log dose, but which was only clear at the 10 mg/kg dose. Rate of forgetting was not increased by any dose. Similar results were obtained with a non-competitive antagonist (MK-801, 0.1, 0.33 mg/kg, IP). These data suggest that doses of NMDA receptor channel antagonists sufficient to disrupt hippocampal long-term potentiation and radial arm maze performance will also disrupt delayed conditional discrimination. The effect on delayed conditional discrimination is due to a disruption of stimulus discriminability and not to an increased rate of forgetting. The extent to which these effects relate to the reported changes in hippocampal long-term potentiation and radial arm maze performance remains to be determined.     

Effects of coincident 5-HT1A receptor stimulation and NMDA receptor antagonism on l-DOPA-induced dyskinesia and rotational behaviors in the hemi-parkinsonian rat

Rationale

Serotonin 1A receptor (5-HT1AR) agonists reduce l-DOPA-induced dyskinesia and enhance motor function in experimental and clinical investigations of Parkinson’s disease (PD). While the mechanism(s) by which these effects occur are unclear, recent research suggests that modulation of glutamate neurotransmission contributes.

Objective

To further delineate the relationship between 5-HT_1A receptors and glutamate, the current study examined the effects of the 5-HT_1AR agonist, ±8-OH-DPAT and the N-methyl-d-aspartic acid receptor (NMDAR) antagonist, MK-801, on l-DOPA-induced motor behavior.

Materials and methods

Unilateral 6-hydroxydopamine lesioned male Sprague–Dawley rats were rendered dyskinetic with 1 week of daily l-DOPA (12 mg/kg, i.p.) + benserazide (15 mg/kg, i.p.). On test days, one group of rats received pretreatments of: ±8-OH-DPAT (0, 0.03, 0.1, 0.3 mg/kg, i.p.) or MK-801 (0, 0.03, 0.1, 0.3 mg/kg, i.p.). A second group was administered combined ±8-OH-DPAT (0, 0.03 or 0.1 mg/kg, i.p.) + MK-801 (0, 0.1 mg/kg, i.p.). Pretreatments were followed by l-DOPA administration, after which, abnormal involuntary movements (AIMs) and rotations were monitored. To investigate effects on motor performance, subthreshold doses of ±8-OH-DPAT (0.03 mg/kg, i.p.) + MK-801 (0.1 mg/kg, i.p.) were administered to l-DOPA-naïve hemiparkinsonian rats before the forepaw adjusting steps test.

Results

Individually, both ±8-OH-DPAT and MK-801 dose-dependently decreased l-DOPA-induced AIMs without affecting rotations. Combined subthreshold doses of ±8-OH-DPAT+MK-801 reduced l-DOPA-induced AIMs and potently enhanced contralateral rotations without altering l-DOPA-induced motor improvements.

Conclusions

The current results indicate a functional interaction between 5-HT_1AR and NMDAR that may improve pharmacological treatment of PD patients.     

Effects of MK-801 on learning and memory as assessed using a novel water maze

The effects of the NMDA receptor antagonist MK-801 [(+)-10,11-dihydro-5-methyl-5H-dibenzo [a,d]-cyclohepten-5,10 imine hydrogen maleate] on learning and memory were assessed using a water maze. The maze was a traditional type of maze with alleys and choices between various paths, but set inside a pool of water to a height of 25 cm. Different mazes could be configured by altering the arrangement of open vs. closed doors. Both the time required to reach an out-of-the-water exit platform and the errors made during the swim from start to finish were recorded. Learning was assessed during the first 10 to 20 trials in a new maze configuration, while memory was tested after the maze was well learned. Three experiments, some with several phases, were performed. These experiments compared the effects of 0.1 mg/kg of either (+)-MK-801, or (-)-MK-801 vs. saline on learning new maze configurations as well as swimming well-learned mazes. Neither of the MK-801 isomers impaired performance of a previously learned maze. (+)-MK-801 clearly slowed learning of new mazes as measured by both maze completion time and errors committed, while (-)-MK-801 had a significant but smaller effect on learning. Rats given (+)- or (-)-MK-801 (0.1 mg/kg) for 16 days while learning one maze and then challenged to learn a new maze without drug administration performed no differently on the new maze than controls, suggesting that the acute effect of MK-801 on learning is not long lasting.     

Functional interaction of NMDA and group I metabotropic glutamate receptors in negatively reinforced learning in rats

Rationale The role of glutamatergic system in learning and memory has been extensively studied, and especially N-methyl-d-aspartate (NMDA) receptors have been implicated in different learning and memory processes. Less is known, however, about group I metabotropic glutamate (mGlu) receptors in this field. Recent studies indicated that the coactivation of both NMDA and group I mGlu receptors is required for the induction of long-term potentiation (LTP) and learning. Objective The purpose of the study is to evaluate if there is a functional interaction between NMDA and group I mGlu receptors in two different models of aversive learning. Methods Effects of NMDA, mGlu1, and mGlu5 receptor antagonists on acquisition were tested after systemic coadministration of selected ineffective doses in passive avoidance (PA) and fear-potentiated startle (FPS). Results Interaction in aversive learning was investigated using selective antagonists: (3-ethyl-2-methyl-quinolin-6-yl)-(4-methoxy-cyclohexyl)-methanone methanesulfonate (EMQMCM) for mGlu1, [(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) for mGlu5, and (+)-5-methyl-10,11-dihydro-5H-dibenzocyclohepten-5,10-imine maleate [(+)MK-801] for NMDA receptors. In PA, the coapplication of MTEP at a dose of 5 mg/kg and (+)MK-801 at a dose of 0.1 mg/kg 30 min before training impaired the acquisition tested 24 h later. Similarly, EMQMCM (2.5 mg/kg) plus (+)MK-801 (0.1 mg/kg), given during the acquisition phase, blocked the acquisition of the PA response. In contrast, neither the combination of MTEP (1.25 mg/kg) nor EMQMCM (5 mg/kg) plus (+)MK-801 (0.05 mg/kg) was effective on the acquisition assessed in the FPS paradigm. Conclusion The findings suggest differences in the interaction of the NMDA and mGlu group I receptor types in aversive instrumental conditioning vs conditioning to a discrete light cue.     

Immediate and long-lasting effects of MK-801 on motor activity,spatial navigation in a swimming pool and EEG in the rat

In a series of experiments, rats received the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 and measures were made of motor behavior, spatial navigation in a swimming pool, and electroencephalographic (EEG) activity. High doses (0.25–10 mg/kg IV) produced somnolence and akinesia, impaired food consumption, locomotion and swimming, and also impaired navigation to a hidden platform but complete recovery on all measures was obtained between 3 and 5 days postinjection. Lower doses (0.05–0.10 mg/kg, IV) impaired acquisition of a new place response in a swimming pool and produced hyperactivity but did not impair performance on a new cue response or on a well-learned place response. Two forms of hippocampal EEG activity, atropine-sensitive and atropine-resistant EEG were present with the low doses. The results demonstrate that a single dose of MK-801 causes changes in motor behavior and learning lasting a few days, but complete recovery occurs within 5 days of administration of even very high doses of MK-801. They further demonstrate that low doses of the drug selectively impair acquisition of new place responses. Although the general changes in behavior produced by MK-801 suggest that NMDA receptors are involved in many aspects of the control of behavior, the results additionally suggest that NMDA receptors are improtant for place learning.     

Dizocilpine (MK-801), ketamine and phencyclidine: low doses affect brain field potentials in the freely moving rat in the same way as activation of dopaminergic transmission

The effects of dizocilpine (MK-801), (±)-5-methyl-10,11-dihydro-5Hdibenzo-[a,d]-cyclohepten-5,10-imine maleate, after IP injection into freely behaving rats, have been compared with the action of ketamine-chloride and phencyclidine (PCP). MK-801 produced strongly dose-dependent effects which could be followed quantitatively over a time of 4 h. During this time spectral analysis of the field potentials continuously recorded from frontal cortex, hippocampus, striatum, and reticular formation revealed a particular pattern of changes which was very stable over time, and, after low doses of 0.05 and 0.1 mg/kg, matched that produced by phencyclidine (2 and 4 mg/kg) or ketamine chloride (10 and 20 mg/kg). With higher doses of MK-801 a continuous change from power decreases to power increases was observed. These increases were accompanied by strong behavioral effects in terms of impaired locomotor control. All three non-competitive NMDA antagonists showed a high degree of similarity with respect to the changes of the frequency content of the field potentials over time. The same pattern of electrical changes could be observed after the application ofl-dopa (50 mg/kg) or amphetamine (0.2 mg/kg). This can be interpreted in the sense that the same population of cells within the recording area which is under dopaminergic control is at the same time under glutamate control. This leads to the hypothesis that it might be possible to bypass the missing dopaminergic control during parkinsonism by noncompetitive NMDA-receptor blocking drugs.     

Effects of dopamine D1 and D2 receptor blockade on MK-801-induced hyperlocomotion in rats

Blocking glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptor complex with MK-801 (0.15–0.5 mg/kg, IP) was found to induce a robust, dose-dependent increase in locomotor activity. This behavioural activation was similar in intensity to that observed afterd-amphetamine (1 mg/kg, SC). The locomotor stimulation induced by MK-801 at 0.3 mg/kg was significantly inhibited by the D₂ dopamine receptor antagonist raclopride (0.1–0.3 mg/kg, SC) and by the D₁ receptor antagonist SCH 23390 (0.04 mg/kg, SC). The locomotor activity induced by a higher dose of MK-801 (0.5 mg/kg) was reduced by higher doses of raclopride or SCH 23390 administered alone (0.3 and 0.08 mg/kg, respectively), and was inhibited by simultaneous administration of ineffective doses. Raclopride significantly reducedd-amphetamine-induced locomotor activity at a dose (0.2 mg/kg) that also blocked the effects of a low dose of MK-801. In contrast, SCH 23390 blocked the effects ofd-amphetamine at a dose (i.e. 0.01 mg/kg) lower than that needed to block MK-801. These results suggest that the dopaminergic system may in part mediate the locomotor effects induced by the NMDA antagonist, MK-801, in rats. However, the locomotor activity induced by MK-801 appears to be less sensitive to dopaminergic receptor blockade than that induced byd-amphetamine, suggesting that the underlying mechanisms, although similar, are not identical.     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

Effects of dizocilpine (MK-801) on motor activity and memory

 The effects of MK-801 upon motor activity and memory were assessed in a novel use of open-field behavior testing. In this study, rats were treated with different doses of MK-801 (0.025, 0.05, 0.1 and 0.2 mg/kg) and given a brief 10-min exposure to an open-field in which locomotor activity and within-session habituation were measured. Doses of MK-801 ≤0.1 mg/kg had no effect upon locomotor activity or within-session habituation. MK-801 0.2 mg/kg produced a marked hyperlocomotion and completely prevented within-session habituation. One day later, the animals were tested for their retention of habituation to evaluate the effects of MK-801 on memory processes. In that animals treated with 0.2 mg/kg MK-801 failed to habituate to the novel environment under the influence of 0.2 mg/kg MK-801, it was not surprising that these animals were impaired on the retention test for the novel environment. Importantly, however, the 0.1 mg/kg MK-801 treatment, which did not affect locomotor activity or within-session habitation to the novel environment, severely interfered with retention of the novel environment. Additional experiments indicated that this result could not be accounted for by drug conditioning or drug state-dependent effects. Thus, the results indicated that MK-801 can produce profound effects upon motor activity and memory and that these two effects can be disassociated. Received: 11 June 1997 / Final version: 5 January 1998     

Spatial learning deficit after NMDA receptor blockade and state-dependency

The non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) (0.08 and 0.12 mg/kg, i.p.) was used to examine whether spatial memory is learned state-dependently. Rats pre-treated with drug or saline were trained for 9 days in an eight-arm radial maze, in which four arms were baited. On the tenth day MK-801-treated rats were injected with saline and one group of saline-treated rats were injected with MK-801 (0.12 mg/kg) while another received saline. Performance of spatial memory was analysed for state-dependency. Neither rats treated with 0.08 mg/kg nor 0.12 mg/kg of MK-801 for 9 days were impaired in recall of spatial memory under saline. However, MK-801 impaired acquisition of spatial memory, with deficits in working memory and less marked deficits in reference memory. Motor activity (speed) was enhanced at both doses. Thus, learning under NMDA receptor blockade does not necessarily produce a condition that impedes the expression of the learning task under a different condition.     

Chronic NMDA antagonism impairs working memory, decreases extracellular dopamine, and increases D1 receptor binding in prefrontal cortex of conscious monkeys.

This study demonstrates that dizocilpine (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, impairs working memory of conscious behaving monkeys. In addition, acute and chronic MK-801 produces different effects on D(1) and D(2) receptor binding in prefrontal cortex (PFC). Extrastriatal neocortical receptor D(1) (D(1)R) and D(2) (D(2)R) binding were assayed by [(11)C]NNC112 and [(11)C]FLB457, respectively, using high-specific radioactivity and a specially designed monkey positron emission tomograph (PET). Acute single dose (0.03, 0.1, and 0.3 mg/kg) i.v. administration of MK-801 resulted in dose-related impairment of working memory performance of an oculomotor delayed response (ODR) task. There was no impairment of performance of a visually guided saccade (VGS) task with low doses of 0.03 and 0.1, but it was depressed with 0.3 mg/kg. Chronic daily MK-801 (0.03 mg/kg, i.m., b.i.d. for 13 days) induced impaired ODR task performance with no effect on the VGS task. Although acute single doses of MK-801 caused no significant changes in [(11)C]NNC112 binding to PFC D(1)R, chronic daily treatment increased binding about 14% (P<.05). Acute MK-801 dose-dependently decreased [(11)C]FLB457 binding about 35% (P<.01) to PFC D(2)R; chronic treatment had no significant effect. Microdialysis analyses demonstrated that acute single doses of MK-801 (0.03 and 0.1 mg/kg) increased extracellular glutamate and dopamine (DA) levels in PFC. Chronic MK-801 gradually lowered glutamate and DA levels in PFC. The results demonstrate in conscious, unanesthetized primates that MK-801 induces impairment of PFC function, as measured by working memory performance. Furthermore, in response to lowered levels of DA in PFC, D(1)R binding is increased, whereas D(2)R binding is not.     

Modulators of the glycine site on NMDA receptors, <Emphasis Type="SmallCaps">d</Emphasis>-serine and ALX 5407, display similar beneficial effects to clozapine in mouse models of schizophrenia

Rationale Schizophrenia is characterized by disturbances in sensorimotor gating and attentional processes, which can be measured by prepulse inhibition (PPI) and latent inhibition (LI), respectively. Research has implicated dysfunction of neurotransmission at the NMDA-type glutamate receptor in this disorder.Objectives This study was conducted to examine whether compounds that enhance NMDA receptor (NMDAR) activity via glycine B site, d-serine and ALX 5407 (glycine transporter type 1 inhibitor), alter PPI and LI in the presence or absence of an NMDAR antagonist, MK-801.Methods C57BL/6J mice were tested in a standard PPI paradigm with three prepulse intensities. LI was measured in a conditioned emotional response procedure by comparing suppression of drinking in response to a noise in mice that previously received 0 (non-preexposed) or 40 noise exposures (preexposed) followed by two or four noise–foot shock pairings.Results Clozapine (3 mg/kg) and d-serine (600 mg/kg), but not ALX 5407, facilitated PPI. MK-801 dose dependently reduced PPI. The PPI disruptive effect of MK-801 (1 mg/kg) could be reversed by clozapine and ALX 5407, but not by d-serine. All the compounds were able to potentiate LI under conditions that disrupted LI in controls. MK-801 induced abnormal persistence of LI at a dose of 0.15 mg/kg. Clozapine, d-serine, and ALX 5407 were equally able to reverse persistent LI induced by MK-801.Conclusions d-Serine and ALX 5407 display similar effects to clozapine in PPI and LI mouse models, suggesting potential neuroleptic action. Moreover, the finding that agonists of NMDARs and clozapine can restore disrupted LI and disrupt persistent LI may point to a unique ability of the NMDA system to regulate negative and positive symptoms of schizophrenia.     

The effects of -cycloserine and MK-801 on the performance of rats in two spatial learning and memory tasks

The present study was undertaken to investigate the effects of modulation of the (NMDA) receptor on learning and memory. Thus, the performance of rats treated with -cycloserine, a partial agonist at the glycine recognition site of the NMDA receptor complex, and MK-801, a noncompetitive NMDA receptor antagonist, either alone or concurrently were assessed in radial arm maze and water maze tasks. Administration of MK-801 (0.1 mg/kg, i.p.) impaired acquisition in the water maze (increased escape latency and distance) and working memory in the radial arm maze (increased re-entries) in rats. Moreover, in the radial arm maze, MK-801 disrupted locomotion (increased latencies and decreased arm entries per minute) and impaired the acquisition of reference memory (increased number of errors) performance of rats. -Cycloserine (0.03, 0.3, 1.0, 3.0, 10 mg/kg, i.p.) had no effects on acquisition or memory performance of control or MK-801-treated rats in either of these tasks. However, -cycloserine (0.03, 0.3, 3.0 mg/kg) reversed the MK-801-induced disruption in locomotion. Furthermore, 3.0 mg/kg -cycloserine increased behavioral activity and also decreased the time needed to complete the task in control animals. To conclude, our results suggest that the consequences of NMDA receptor modulation on learning and memory processes and sensorimotor functions may be functionally different or have distinct anatomical locations.     

Habituation of acoustic startle is disrupted by psychotomimetic drugs: differential dependence on dopaminergic and nitric oxide modulatory mechanisms

Rationale A deficit in attention and information processing has been considered a central feature in schizophrenia, which might lead to stimulus overload and cognitive fragmentation. It has been shown that patients with schizophrenia display a relative inability to gate incoming stimuli. Thus, patients repeatedly subjected to acoustic startle-eliciting stimuli habituate less to these stimuli than controls. Furthermore, schizophrenia-like symptoms can be induced by pharmacological manipulations in humans by psychotomimetic drugs, e.g. phencyclidine (PCP) and d-amphetamine (d-AMP). Recent studies show that the behavioural and biochemical effects of PCP in rodents are blocked by nitric oxide synthase (NOS) inhibitors, suggesting that NO plays an important role in at least the pharmacological effects of PCP.Objectives The first aim of the present study was to investigate if PCP, MK-801 and d-AMP impair habituation of acoustic startle in mice. Secondly, we examine the effect of the NOS inhibitor, l-NAME, and the dopamine receptor antagonist, haloperidol, on drug-induced deficit in habituation.Results PCP (4 mg/kg), MK-801 (0.4 mg/kg) and d-AMP (5.0 mg/kg), impaired habituation of the acoustic startle response in mice. This effect was reversed by the NOS inhibitor, l-NAME. The typical antipsychotic, haloperidol, reversed the effects of PCP and d-AMP, but not that of MK-801.Conclusions The finding that PCP, MK-801 and d-AMP impair habituation in mice is consistent with the idea that these treatments model certain filter deficits seen in schizophrenic patients. Furthermore, the present results suggest that NO is critically involved in these effects on habituation, whereas that of dopamine is less clear.     

Systemic pretreatment with MK-801 (dizocilpine) increases breaking points for self-administration of cocaine on a progressive-ratio schedule in rats

 The effects of the noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, on cocaine self-administration were investigated. Forty-six male Wistar rats were trained to intravenously self-administer four unit doses of cocaine (0.19, 0.38, 0.75 and 1.5 mg/kg per injection) on a progressive-ratio schedule of reinforcement. The effects of increasing doses of MK-801 (0.05, 0.1, 0.15 and 0.2 mg/kg, IP, 30 min before test sessions) on breaking point (BP) for cocaine self-administration were investigated. The results showed that pretreatment with MK-801 produced effects on cocaine BPs that fit on an inverted-U function. That is, the 0.05 and 0.1 mg/kg doses of MK-801 produced no effect or a small enhancement of BPs across all doses of cocaine, respectively. The 0.15 mg/kg dose of MK-801 produced a significant treatment effect characterized by increased BPs, relative to baseline BPs, across all doses of cocaine. The 0.2 mg/kg dose of MK-801 produced a nonsignificant decrease in BPs across most doses of cocaine. The dose-dependent effects on cocaine BPs after pretreatment with MK-801 suggest that MK-801 can potentiate, and at higher doses attenuate, the rewarding effects of self-administered cocaine. Received: 3 January 1996 / Final version: 12 June 1996     

Systemic administration of polyaminergic agents modulate fear conditioning in rats

Rationale The polyamines putrescine, spermine, and spermidine are a group of aliphatic amines that physiologically modulate the N-methyl-d-aspartate (NMDA) receptor, a glutamate receptor implicated in memory formation. Objectives Given the potential application of these drugs in the treatment of memory disorders, we investigated whether agonists and/or antagonists of the NMDA receptor polyamine binding site alters the memory of fear conditioning and determined the time window in which fear conditioning is modulated by polyaminergic agents given by the systemic route. Results Post-training intraperitoneal administration of spermidine (10–100 mg/kg) immediately after training increased, whereas arcaine (10 mg/kg) and MK-801 (0.01–0.1 mg/kg) decreased contextual and auditory fear conditioning. Arcaine and MK-801, at doses that had no effect per se, reversed the facilitatory effect of spermidine. Memory of fear conditioning was impaired by polyaminergic blockade up to 180 min but not at 360 min after training. Conclusion These results provide evidence that systemic administration of polyamine binding site ligands modulate early consolidation of fear conditioning.     

Effects of the novel PDE4 inhibitors MEM1018 and MEM1091 on memory in the radial-arm maze and inhibitory avoidance tests in rats

Rationale Inhibition of cyclic AMP (cAMP)-specific phosphodiesterase (PDE4) enhances memory in rodents. MEM1018 and MEM1091 are newly developed PDE4 inhibitors that had not been evaluated as yet for their effects on working and reference memory.Objective Experiments were carried out to determine whether these two drugs alter memory and if these effects are associated with changes in intracellular cAMP in the brain.Methods The effects of MEM1018 and MEM1091 on memory deficits induced by the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801 were determined in the eight-arm radial maze and step-through inhibitory avoidance tasks in rats. Their effects on cAMP concentrations in primary cultures of rat cerebral cortical neurons and their potency for inhibiting recombinant PDE4 subtypes were examined.Results In the radial-arm maze, MEM1018 and MEM1091 (0.1–2.5 mg/kg, IP) enhanced working and reference memory impaired by MK-801 (0.1 mg/kg). In addition, both drugs antagonized the amnesic effect of MK-801 on passive avoidance behavior. Overall, the behavioral effects of MEM1018 and MEM1091 were similar to the prototypic PDE4 inhibitor rolipram (0.1 mg/kg). Consistent with this, and similar to the effects of rolipram, both MEM1018 (10–30 M) and MEM1091 (10 M) enhanced the ability of NMDA (30 M) to increase cAMP concentrations in rat cerebral cortical neurons, in vitro. MEM1018 and MEM1091 showed greater relative selectivity for PDE4D than rolipram, although the general profiles of the three compounds were similar.Conclusions The novel PDE4 inhibitors MEM1018 and MEM1091 enhance memory in a manner generally similar to rolipram. PDE4D may be the primary target for the PDE4 inhibitors in the mediation of memory.     

Catecholamines and memory: Enhanced verbal learning during l-DOPA administration

Verbal learning was measured during the administration of l-DOPA in large oral doses to depressed patients. Longer-term memory on two different tasks improved during treatment, while short-term memory (immediate recall) was unaffected. In contrast, the catecholamine synthesis inhibitor -methyl-p-tyrosine did not alter either memory process.The effects of l-DOPA on learning may be related to increased arousal produced by this drug.