Effects of benzodiazepine receptor ligands on the performance of an operant delayed matching to position task in rats: opposite effects of FG 7142 and lorazepam

The effects of a series of benzodiazepine (BZ) receptor ligands, ranging from a full agonist through to partial inverse agonists, were examined on short term working memory in the rat. The behavioural paradigm used was a discrete trial, operant delayed matching to position task, as originally described by Dunnett (1985), with delays of 0, 5, 15 and 30 s. The benzodiazepine receptor (BZR) full agonist lorazepam (0.25, 0.375 and 0.5 mg/kg) dose and delay dependently impaired matching accuracy. Lorazepam also increased the latency to respond and decreased the number of nose pokes made into the food tray during the delays. In contrast, the BZR partial agonist ZK 95 962 (1, 3, 10 mg/kg) did not affect matching accuracy, but did increase the speed of responding. The BZR antagonist ZK 93 426 (1.25, 5, 25 mg/kg) had no effects in this paradigm. The BZR weak partial inverse agonists Ro 15-4513 (0.1, 1 and 10 mg/kg) and ZK 90 886 (1, 3 and 10 mg/kg) did not affect accuracy of performance. However, both of these drugs increased the latency to respond and decreased nose poke responses. These motoric effects were particularly strong following 10 mg/kg Ro 15-4513. This shows that the effects of drugs on the accuracy of responding and on the speed of responding can be dissociated. The BZR partial inverse agonist FG 7142 had effects on matching accuracy that were dependent upon dose. The lowest dose of FG 7142 (1 mg/kg) significantly improved accuracy, whereas the highest dose (10 mg/kg) impaired accuracy. This impairment induced by FG 7142 (10 mg/kg) was accompanied by an increase in the latency to respond and a decrease in the number of nose pokes. Taken together, these results show that the accuracy of delayed matching performance can be modulated in opposite ways by the BZR full agonist lorazepam and a low dose of the BZR partial inverse agonist, FG 7142.     

Serotonergic drug effects on a delayed conditional discrimination task in the rat; involvement of the 5-HT1A receptor in working memory

We investigated the effects of serotonergic drugs on working memory (WM) in a delayed conditional discrimination task. The 5-HT(1A) receptor full agonist flesinoxan (0.3-3.0 mg/kg) dose- and delay-dependently impaired performance, indicating a specific effect on WM. The 5-HT(1A) receptor partial agonist ipsapirone, the 5-HT( 1B/1D/2C) agonist TFMPP, the 5-HT(1A) antagonist NAN190 and the serotonin re-uptake inhibitor fluvoxamine dose-dependently impaired performance, in a delay-independent manner, indicating no specific effect on WM. The 5-HT( 2) receptor antagonist ketanserin and the 5-HT(3) receptor antagonist ondansetron did not affect performance. It is suggested that the role of central serotonin receptors in WM may be restricted to 5-HT(1A) receptors.     

5-HT1A receptor agonists improve the performance of normal and scopolamine-impaired rats in an operant delayed matching to position task

A series of experiments examined the effects of 5-HT_1A ligands alone and in combination with the muscarinic antagonist scopolamine on short term working memory in the rat. The behavioural paradigm was a discrete trial, operant delayed matching to position task, with delays of 0, 5, 15 and 30 s. The 5-HT_1A ligands tested were the full agonist, 8-OH DPAT (0, 0.1, 0.3 and 1 mg/kg), the partial agonist, ipsapirone (0, 1, 3 and 10 mg/kg), and the purported antagonist, NAN 190 (0, 1, 2, and 4 mg/kg). 1-PP (0, 0.1, 0.3, 1 mg/kg), the major metabolite of ipsapirone, was also tested. The lowest dose of 8-OH DPAT significantly improved matching accuracy at the longest delay, whereas the highest dose impaired matching accuracy and increased the latency to respond. Ipsapirone also significantly improved the accuracy of performance at a dose of 3 mg/kg, but the doses of 1 and 10 mg/kg did not significantly affect performance. NAN-190, at the highest dose tested (4 mg/kg), impaired matching accuracy, whereas the two lower doses did not significantly affect performance. The highest dose also increased the latency to respond. 1-PP had no effect on performance. Scopolamine HBr (0.14 mg/kg) caused a delay dependent impairment in matching accuracy, and had no effect on missed trials or the latency to respond. Low doses of 8-OH DPAT (0.1 and 0.3 mg/kg) significantly attenuated the scopolamine induced accuracy impairment, whereas 1 mg/kg 8-OH DPAT potentiated the impairment. Ipsapirone (3 mg/kg) also significantly improved the performance of scopolamine impaired rats. NAN-190 increased the latency to respond and reduced the number of nose pokes made during the delays in scopolamine-treated rats, and tended to potentiate the scopolamine-induced accuracy impairment. 1-PP did not affect the performance of scopolamine treated rats. Taken together, these results suggest that modulation of 5-HT_1A receptors influences short term spatial working memory in the rat.     

Effects of chlordiazepoxide, flumazenil and DMCM on plasma catecholamine and corticosterone concentrations in rats.

The effects of drugs representing three classes of benzodiazepine (BDZ) receptor-acting agents on circulating corticosterone (CS), noradrenaline (NA) and adrenaline (A) were examined in unstressed rats. Intragastric administration of a single-dose of the inverse agonist 3-carbomethoxy-4-ethyl-6,7-dimethoxy-beta-carboline (DMCM; 10 mg/kg) evoked 15-, 4- and 1.5-fold increases in plasma CS, A and NA, respectively, as compared to control values. The DMCM-induced CS, A and NA rises were completely blocked by combined treatment with the BDZ antagonist flumazenil (Ro 15-1788; 20 mg/kg). Flumazenil given alone did not affect plasma hormone levels. Administration (either intragastrically or intraperitoneally) of a single-dose of the BDZ agonist chlordiazepoxide (CDP; 20 mg/kg) produced a 10- to 15-fold increase in plasma CS but caused no change in plasma NA and A contents. Pretreatment with flumazenil blocked the CDP-elicited release of CS. The findings indicate that the CNS mechanisms controlling pituitary-adrenocortical and sympatho-adrenal outflow under basal conditions are functionally linked to central-type BDZ receptor system(s). Drugs with agonist or inverse-agonist actions at these receptor sites can be differentiated from each other by their distinct effects on plasma NA and A, but not CS, release.     

Reversal of chlordiazepoxide-induced impairment in successive discrimination performance by RO 15-1788

The effects of chiordiazepoxide (CDP) alone and in combination with Ro 15-1788 on the performance of a previously learned go-no go successive discrimination were studied in male Sprague-Dawley rats. CDP 10 mg/kg impaired discrimination performance in six sucessive sessions, with animals showing recovery in two post-drug sessions. The impairment in disrcimination performance was due to an increase in responding during no go (waiting) periods of the task. The benzodizepine (BDZ) receptor antagonist Ro 15-778 (5 and 10 mg/kg) reversed the impairment in discrimination performance in sessions 2-6 (but not 1) when co-administered with CDP. While the effectiveness of Ro 15-1788 was not dose-dependent, the reversal in discrimination impairment was due to a reduction in responding during no go periods of the task. These findings suggest that the impairment in discrimination performance produced by CDP is mediated by central BDZ receptor sites. When administered alone, Ro 15-1788 10 mg/kg (but not 5mg/kg) produced a mild BDZ-like impairment in discrimination performance and increase in a no go period responding. These findings suggest that Ro 15-1788 is not a neutral antagonist but has some intrinsic action of its own.     

Effects of the NMDA antagonists CPP and MK-801 on radial arm maze performance in rats

The dose- and time-dependent effects of N-methyl-D-aspartate receptor/channel antagonists on radial 8-arm maze performance were examined in rats. Both CPP (1.0-30 mg/kg), a competitive NMDA antagonist, and MK-801 (0.1-1.0 mg/kg), a noncompetitive NMDA antagonist, produced dose-dependent increases in the number of errors made to sample all 8 baited arms. The effective doses of both drugs produced maximal performance impairments 2 hr after IP injection, and no effects after 24 hr. In a second radial arm maze task where only 4 arms were baited, CPP (10 mg/kg) had a somewhat greater effect on the number of working memory errors than on reference memory errors. MK-801 (0.1, 0.33 mg/kg) had no effects on either this task or on a task involving a 1-hr delay between correct choices 4 and 5 on the 8 choice task. CPP (10 mg/kg), however, impaired performance on this latter task. These results indicate that doses of NMDA antagonists, sufficient to block hippocampal long-term potentiation, also disrupt radial arm maze performance.     

Characteristics of learning and memory impairment induced by delta9-tetrahydrocannabinol in rats

We investigated the characteristics of delta9-tetrahydrocannabinol (THC)-induced impairment of learning and memory using an 8-arm radial maze task, a water maze, a visual discrimination task with 2 figures and a passive avoidance test in rats. THC (6 mg/kg, i.p.) impaired spatial memory in the standard task of the 8-arm radial maze. THC (4-6 mg/kg, i.p.) selectively impaired working memory in a reference and working memory task of the 8-arm radial maze. Even at a dose of 10 mg/kg, THC did not impair spatial memory in the water maze. In addition, THC at a dose of 6 mg/kg, which had inhibitory effects in the 8-arm radial maze, did not affect performance in the visual discrimination task. These results indicate that at low doses (2-6 mg/kg), THC may not produce visual function abnormalities. THC impaired retrieval (6 mg/kg, i.p.) as well as acquisition (10 mg/kg, i.p.) in the passive avoidance test. The consolidation process was also impaired by i.c.v. injection (100 microg), but not i.p. injection (6-10 mg/kg) of THC. These results suggest that THC-induced impairment of spatial memory is based on the selective impairment of working memory through its effects on acquisition and retrieval processes.     

Intrahippocampal injections of benzodiazepine and muscimol impair working memory but not reference memory of rats in the three-panel runway task.

In a three-panel runway task, the benzodiazepine chlordiazepoxide at 3.2 and 10 mg/kg i.p. significantly increased the number of errors (attempts to pass through two incorrect panels of the three panel-gates at four choice points) in a test of working memory, but it had no effect on errors in a test of reference memory. This effect of 10 mg/kg chlordiazepoxide on working memory was blocked by the benzodiazepine receptor antagonist flumazenil at 10 mg/kg. Intrahippocampal injection of chlordiazepoxide at 10 and 32 micrograms/side significantly increased the number of working memory errors. This effect of intrahippocampal chlordiazepoxide (32 micrograms/side) was attenuated not only by flumazenil at 10 mg/kg but also by the gamma-aminobutyric acid (GABA)A receptor antagonist bicuculline at 3.2 mg/kg. Intrahippocampal injection of the GABAA receptor agonist muscimol at 100 and 320 ng/side also significantly increased working memory errors. Neither chlordiazepoxide nor muscimol affected the number of reference memory errors when injected into the hippocampus at doses up to 32 micrograms/side or 320 ng/side, respectively. These results suggest that activation of the GABAA/benzodiazepine receptor complex in the hippocampus impairs working memory, but does not affect reference memory.     

Inverse agonist properties of the FG 7142 discriminative stimulus.

A two-lever, food-motivated discrimination was established between the benzodiazepine receptor partial inverse agonist FG 7142 (5.0 mg/kg) and its vehicle. The FG 7142 discriminative stimulus was pharmacologically characterized by testing trained rats with a variety of benzodiazepine receptor ligands. Administration of the inverse agonist DMCM (0.15-0.30 mg/kg) dose-dependently mimicked the FG 7142 stimulus. In contrast, the benzodiazepine receptor agonist chlordiazepoxide, partial agonist ZK 91 296, mixed agonist/antagonist CGS 9896 and antagonist RO 15-1788 blocked the FG 7142 cue. These results indicate that the FG 7142 discriminative stimulus is based on its inverse agonist activity. The generalization of FG 7142 to the anxiogenic/convulsant compound pentylenetetrazole (PTZ), but not to the anorectic agent norfenfluramine, indicates that the anxiogenic properties of FG 7142, rather than its anorectic actions, may underlie the FG 7142 discriminative stimulus.     

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.     

Analysis of the role of the 5-HT1B receptor in spatial and aversive learning in the rat.

The present study examined the role of the 5-HT1B receptor in learning and memory. The ability of the 5-HT1B receptor agonist anpirtoline and the selective 5-HT1B receptor antagonist NAS-181 to affect spatial learning in the water maze (WM) and aversive learning in the passive avoidance (PA) task were examined in the rat. Anpirtoline (0.1-1.0 mg/kg, s.c.) caused a dose-dependent impairment of learning and memory in both the WM and PA tasks. NAS-181 (1.0-10 mg/kg, s.c.) failed to alter performance of the WM task, but produced a dose-dependent (0.1-20 mg/kg) facilitation of PA retention. Furthermore, treatment with NAS-181 (10 mg/kg) fully blocked the impairment of the WM and PA performance caused by anpirtoline (1.0 mg/kg). In contrast, NAS-181 (3.0-10 mg/kg) did not attenuate the spatial learning deficit and the impairment of PA retention caused by scopolamine (0.1 mg/kg in WM task, 0.3 mg/kg in PA task, s.c.), a nonselective muscarinic antagonist. Moreover, a subthreshold dose of scopolamine (0.1 mg/kg) blocked the facilitation of PA retention induced by NAS-181 (1.0-10 mg/kg). In addition, the behavioral disturbances (eg thigmotaxic swimming and platform deflections) induced by anpirtoline and scopolamine were analyzed in the WM task and correlated with WM performance. These results indicate that: (1) 5-HT1B receptor stimulation and blockade result in opposite effects in two types of cognitive tasks in the rat, and that (2) the 5-HT1B antagonist NAS-181 can facilitate some aspects of cognitive function, most likely via an increase of cholinergic transmission. These results suggest that 5-HT1B receptor antagonists may have a potential in the treatment of cognitive deficits resulting from loss of cholinergic transmission.     

Alpha-2 adrenoceptor activation inhibits phencyclidine-induced deficits of spatial working memory in rats.

N-methyl-D-aspartate (NMDA)/glutamate receptor antagonists, such as phencyclidine (PCP), induce behavioral abnormalities (locomotor hyperactivity, sensorimotor gating deficits, impairments of cognition) in animals that are thought to model aspects of schizophrenia. The administration of PCP increases noradrenaline transmission in the rat prefrontal cortex, a brain structure required for normal cognitive processes. Noradrenaline, in turn, works through a set of receptors that have themselves been implicated directly in NMDA antagonist-induced deficits; we recently reported that the alpha-2 agonist, clonidine, is effective at preventing PCP-induced deficits of working memory and visual attention in rats. Here, we further investigated the role for alpha-2 adrenoreceptors in the effects of PCP on spatial working memory performance. The alpha-2 agonist clonidine (0.001-0.01 mg/kg, subcutaneously (s.c.)) produced a significant amelioration of PCP-induced working memory deficits; the effects of PCP (1.0 mg/kg, s.c.), but not clonidine, were reduced in noradrenaline-depleted rats. In addition, the alpha-2A-preferring agonist guanfacine (0.05-1.0 mg/kg, s.c.) dose-dependently prevented the deficits of spatial working memory performance produced by PCP. Although the highly selective alpha-2 receptor antagonist, atipamezole (ATI), failed to affect spatial working memory on its own, at the doses studied (0.1-0.5 mg/kg, s.c.), it dramatically enhanced the working memory deficit produced by PCP. These data indicate that alpha-2 adrenoreceptors tonically inhibit PCP-induced deficits of spatial working memory, suggesting an important role for these receptors in cognitive deficits associated with NMDA receptor hypofunction.     

Effect of the GABAergic system on memory formation and state-dependent learning induced by morphine in rats

In the present study, the effects of intraperitoneal injections of GABA(A) receptor agonist and antagonist on memory formation and morphine state-dependent learning were investigated in rats. Pre-training administration of morphine (1-15 mg/kg) in a step-down passive avoidance task induced state-dependent learning with impaired memory retrieval on the test day. The impairment of memory was restored after the pre-test administration of the same dose of morphine. The pre-test administration of the GABA(A) receptor agonist, muscimol (0.01, 0.05 and 0.1 mg/kg), significantly decreased state-dependent retrieval induced by pre-test morphine (5 mg/kg). The state-dependency effect of morphine (1 mg/kg) was significantly potentiated by the pre-test administration of the GABA(A) receptor antagonist, bicuculline (0.125, 0.25 and 0.5 mg/kg). Furthermore, the pre-training injection of muscimol (0.01 mg/kg) impaired memory retrieval which was restored by pre-test morphine (1, 3 and 5 mg/kg) administration. However, the pre-training administration of bicuculline did not affect retention by itself. In addition, amnesia induced by pre-training morphine (5 mg/kg) was significantly reversed in rats which had received pre-test injections of muscimol (0.01, 0.05 and 0.1 mg/kg). Pre-test injections of bicuculline (0.125, 0.25 and 0.5 mg/kg) significantly decreased morphine-induced amnesia. It is concluded that the GABA(A) receptor mechanisms may be involved in the memory formation and it is postulated that these receptors may play an important role in morphine state-dependent learning.     

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.     

Effects of strychnine-insensitive glycine receptor antagonists and sigma agents on working memory performance: comparison with dizocilpine and scopolamine

The strychnine insensitive glycine receptor antagonists (+/-) HA 966 (2.5, 3.5, 4.25 and 5.0mg/kg) and 7 chlorokynurenic acid (5.0, 10.0, and 15.0mg/kg), the putative sigma agents NPC 16377 (5.0 and 8.0mg/kg), BMY 14802 (5.0, 7.5 and 10.0mg/kg), and ifenprodil (5.0 and 7.0mg/kg) and the reference agents scopolamine and dizocilpine [(+) MK 801] were evaluated in a nonspatial delayed matching to sample working memory task in rats. (+/-) HA 966 impaired accuracy at the longest retention interval and decreased response probability measures. 7-Chlorokynurenic acid was essentially without effect. The noncompetitive NMDA antagonist dizocilpine reduced accuracy at all retention intervals, decreased the probability of a choice response and increased the probability of an intertrial interval response. The anticholinergic agent scopolamine selectively reduced accuracy at the longest retention interval but did not affect other performance measures. Sigma agents decreased response probability measures but did not affect accuracy at any retention interval. The results support the notion that sigma agents, glycine antagonists and NMDA antagonists produce different effects in cognitive tasks including working memory performance.     

Effects of chlordiazepoxide and FG 7142 on a rat model of diencephalic amnesia as measured by delayed-matching-to-sample performance

 The intralaminar thalamic nuclei (ILn) have been implicated as a critical site of pathology in amnesia. Lesions of the ILn have been found to produce behavioral effects comparable to benzodiazepine (BDZ) receptor agonists. We compared the effects of chlordiazepoxide (CDP), a BDZ agonist, and FG 7142, a partial inverse agonist at the BDZ receptor, in rats with thalamic lesions and in unlesioned controls. Delayed matching-to sample (DMS) performances were studied during treatment with ascending doses of CDP, counterbalanced trials with 2.5 mg/kg CDP and saline, ascending doses of FG 7142, and (for unlesioned controls only) counterbalanced trials with saline and higher doses of CDP. CDP had effects similar to the ILn lesion, decreasing response speed and percent correct responding in a delay-independent fashion. These effects were additive with the impairments associated with the ILn lesion. The effects of FG 7142 were more complex. At lower doses, it increased response speed without affecting response accuracy. At higher doses, it diminished both the speed and the accuracy of DMS responding. These results support the hypothesis that ILn lesions and BDZ agonists have similar effects on DMS performance. The biphasic effects observed for FG 7142 are consistent with other evidence that low doses of this drug enhance while higher doses impair memory performance. Although DMS accuracy was not improved, the enhancement observed for response speed provides evidence that partial inverse BDZ agonists have potential utility as treatments for cognitive impairments associated with amnesia. Received: 24 June 1998 / Final version: 1 October 1998     

Interactions of Ro15-4513, Ro15-1788 (flumazenil) and ethanol on measures of exploration and locomotion in rats

The present study investigated the role of the GABA_A-benzodiazepine (BDZ) receptor complex in mediating ethanol (ETOH)-induced increases in exploration (head-dipping) and locomotion of rats in a holeboard test. Male Sprague-Dawley rats were selected based on low basal exploratory rates to increase the likelihood that ETOH would increase these behaviors. The effects of the BDZ partial inverse agonist, Ro15-4513 (2.5 mg/kg), and the BDZ receptor antagonist, Ro15-1788 (flumazenil) (8.0 mg/kg), alone, and in combination with ETOH (0.25, 0.50 and 0.75 g/kg, IP) were investigated. The 0.25 and 0.50 g/kg doses of ETOH markedly increased both exploration and locomotion in low exploratory rats. The ETOH-induced increases were prevented by Ro15-4513 on both measures at a dose that produced no observable intrinsic action; however, this apparent lack of intrinsic activity on exploration may have been related to the low basal rates of responding in the subjects. The BDZ antagonist, flumazenil, completely reversed the antagonistic action produced by Ro15-4513 of the ETOH-induced stimulant effects on locomotion, however, flumazenil exerted only a marginal statistically significant effect on Ro15-4513's actions on head-dipping. When flumazenil was given alone, it increased head-dipping, but was without effect on locomotion. Flumazenil did not affect ETOH-induced increases in locomotion; however, ETOH and flumazenil appeared to show agonistic effects on exlporation. The different effects exerted by flumazenil alone, and in combination with ETOH on head-dipping and locomotion suggest that the actions of flumazenil on these behaviors are mediated through separate mechanisms. The research further suggests that both the anxiolytic and locomotor activational effects of ETOH are mediated through the GABA_A-BDZ receptor complex.I would like to dedicate this paper to the late Dr. Richard G. Lister, a friend, teacher, colleague and exceptional scientist who contributed substantially to the area of alcohol abuse and alcoholism. Over the past years, Dr. Lister investigated the interaction of alcohol with benzodiazepine inverse agonists and benzodiazepine receptor antagonists. His seminal and more recent papers played an important role delineating the neuromechanisms of alcohol in relation to the GABA-benzodiazepine receptor complex. Richard, we will miss you.     

Working memory in the odor span task: effects of chlordiazepoxide, dizocilpine (MK801), morphine, and scopolamine

Rationale

A number of tasks are used to assess working memory in rodents, but the odor span task (OST) is unique in studying performance as a function of the number of stimuli to remember.

Objectives

The purpose of the present study was to better characterize the behavioral pharmacology of the OST by exploring the effects of several amnestic agents including an NMDA antagonist (dizocilpine), a positive GABA-A modulator (chlordiazepoxide), an anticholinergic compound (scopolamine), and as a negative control, an opiate receptor agonist (morphine).

Methods

Rats were trained to perform on the OST which is a non-match-to-sample procedure with an incrementing number of sample odors to remember as the session progresses. Trials with a simple odor discrimination task (SD) were interspersed to provide a control for effects unrelated to memory load.

Results

All four drugs disrupted performances on the OST task in a dose-dependent fashion, but only the NMDA antagonist dizocilpine produced impairments that were clearly dependent on the number of stimuli to remember. Dizocilpine impaired OST performance at a dose (0.1 mg/kg) that did not affect SD, and that impairment depended on memory load. Chlordiazepoxide (3.0 mg/kg) also produced amnestic effects that were manifest by shorter memory spans and runs of correct responding. In contrast, morphine and scopolamine impaired OST accuracy only at doses that also disrupted SD (18.0 and 0.3 mg/kg, respectively).

Conclusions

These results provide evidence of NMDA and benzodiazepine modulation of working memory as assessed by the OST.     

Co-administration of fluoxetine and WAY100635 improves short-term memory function

The aim of this study was to determine whether the action of the antidepressant fluoxetine or the anxiolytic buspirone could be modified by specific 5-hydroxytriptamine (5-HT(1A)) receptor blockade in a short-term memory paradigm. Male Wistar rats were trained to perform the putative short-term memory task, delayed non-matching to position. WAY100635, a selective 5-HT(1A) receptor antagonist (0.15 mg/kg), was administered 15 min before either the selective serotonin reuptake inhibitor fluoxetine (3 mg/kg), or the partial 5-HT(1A) receptor agonist and dopamine D2 receptor antagonist, buspirone (0.3 mg/kg). 8-Hydroxy-di-n-propylamino tetralin (8-OH-DPAT), a full 5-HT(1A) receptor agonist (0.3 mg/kg), was also included in the study as a positive control. WAY100635 alone had no effect on any behavioural parameter measured (response accuracy, delay lever press activity and trial completion). 8-OH-DPAT impaired response accuracy in a delay-dependent manner, an effect reversed by WAY100635. Fluoxetine also impaired response accuracy delay-dependently. WAY100635 pretreatment not only reversed this deficit but improved response accuracy, in the presence of a significant deficit in trial completion. At the dose used, buspirone showed no significant differences compared to the control group. The data suggest that fluoxetine impairs short-term memory function by the indirect activation of 5-HT(1A) receptors, but that its co-administration with WAY100635 improves short-term memory function.     

Effects of selective inhibition of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase) on mice in learning and memory tasks

The purpose of the present study was to examine the effects of 2-(phosphonomethyl)-pentanedioic acid (2-PMPA), a selective inhibitor of N-acetylated-alpha-linked-acidic dipeptidase (NAALADase, glutamate carboxypeptidase II), an enzyme catalyzing the cleavage of glutamate from the neuropeptide N-acetyl-aspartyl-glutamate (NAAG), on memory processes in mice. Long-term memory was evaluated in step-through passive avoidance task while alternation behavior, as a measure involving spatial working memory, was assessed in Y-maze task. Additionally, horizontal activity was evaluated by means of electronically monitored locomotor activity system. The mice were treated with either 2-PMPA (50, 100 and 150 mg/kg i.p.) or N-methyl-d-aspartate (NMDA) receptor antagonist, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate (MK-801) at doses of: 0.05, 0.1, 0.15 and 0.2 mg/kg i.p., as a comparator. In the passive avoidance task, the drugs were administered once before or immediately after training, and before retention test. 2-PMPA at the doses used did not affect retention of passive avoidance; however, it increased the latency to enter the dark box during the training day. In the Y-maze task, 2-PMPA (150 mg/kg i.p.) impaired spontaneous alternation and reduced locomotion while the lower dose of 100 mg/kg was ineffective. In the locomotor activity test, 2-PMPA (100 and 150 mg/kg i.p.) did not significantly affect horizontal activity. MK-801 (0.2 mg/kg i.p.) injected before training reduced retention in the passive avoidance task. In the Y-maze task, MK-801 (0.1 mg/kg i.p.) impaired alternation behavior and considerably increased locomotion in the Y-maze and locomotor activity test. These results indicate that NAALADase inhibition may impair alternation behavior.