Time-dependent effects of post-trial amphetamine treatment in rats: evidence for enhanced storage of representational memory

Two studies were conducted to test the ability of post-trial amphetamine treatment to improve later recall in a nonaversively motivated task. These studies utilized 8- and 12-arm radial mazes, respectively, with an 11-h retention interval imposed after the rat traversed half the arms of the maze (termed, the to-be-remembered-event, or TBRE). In Experiment 1, the rats were injected with amphetamine (0, .25, and .50 mg/kg) immediately after the TBRE. Because the drug treatment improved retention, a time dependency study was conducted in which the drug (0 and .33 mg/kg) was administered 0, 3, and 6 h after the TBRE. The finding that amphetamine injection at 0, but not 3, h post-trial improved later recall indicates that the benefit derived from the former treatment is not due to proactive influences at the time of the retention test. Drug treatment 6 h post-trial produced a borderline improvement of recall; possible mechanisms are discussed. Two conclusions can be drawn from these results: (1) amphetamine administration can improve recall under conditions in which this effect cannot be attributed to alterations in information processing during either the learning or the retention sessions, indicating that the drug modulates memory storage processes; and (2) amphetamine treatment can improve working memory, thus excluding an alternative interpretation for the previous reports of impaired short-term memory in animals, all of which entailed assessments of working memory. The possibility remains, however, that the impairment seen in these tasks reflects the requirement for erasure of information from previous trials within each daily session, rather than the duration of the retention interval.     

The effect of scopolamine and physostigmine on working and reference memory in pigeons

A comparison of the effects of scopolamine and physostigmine on working memory and reference memory in White Carneaux pigeons was undertaken. In Experiment 1, the pigeons received injections of scopolamine hydrobromide (0.03 mg/kg), or saline. Scopolamine hydrobromide had greater disruptive effects on working memory trials than on reference memory trials, and the centrally active form of scopolamine disrupted working memory trial accuracy more than the peripherally active form. The differential sensitivity of accuracy on working memory trials to disruption by central cholinergic blockade was obtained even though the discrimination required on reference memory trials was more difficult. In Experiment 2, the pigeons received injections of scopolamine hydrobromide (0.015 mg/kg), physostigmine (0.075 mg/kg) both scopolamine and physostigmine, or saline. Physostigmine given with scopolamine was able to reverse the scopolamine-induced reduction of accuracy on working memory trials. In neither study did scopolamine promote accelerated forgetting as the delay interval was increased. These results indicate that manipulation of central cholinergic neurotransmitter systems influences working memory processes in the pigeon, but these effects occur without alterations in the ability of the birds to actively maintain information during the retention interval.     

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

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

Intraseptal administration of muscimol produces dose-dependent memory impairments in the rat

The present study examined the effects of intraseptal administration of the GABAergic agonist muscimol on performance of a radial-arm maze (RAM) task. Male Long-Evans rats were trained to perform a RAM task in which a 1-h delay was imposed between the sample and the test session. In this task rats have access to four out of eight maze arms during a predelay session. Following a 1-h delay, rats are returned to the maze and allowed to freely choose among all eight arms. Arms not blocked during the predelay session are baited, and entry into an arm chosen during the predelay session or a repeated entry into a postdelay chosen arm constitutes an error. Following acquisition, animals were implanted with a single cannula aimed at the medial septum. A within-subjects design was utilized to examine the effects of intraseptal administration of muscimol (0.0, 0.75, 1.5 or 3.0 nmol) on performance in this task. All drugs or artificial cerebrospinal fluid were administered immediately following the predelay session. Muscimol, a GABA-A agonist, produced a dose-dependent impairment in maze performance as evidenced by fewer correct choices in the first four postdelay choices and an increase in the number of errors. Intraseptal administration of muscimol did not significantly alter latency per choice on the RAM task nor did it affect locomotor activity levels. Muscimol-induced impairments were also observed when a 4-h delay was imposed between the fourth and the fifth maze selection, suggesting that the behavioral deficit represents an inability to store or retain spatial working memories rather than a general performance deficit. These data indicated that pharmacological manipulation of GABA-A receptors within the medial septum modifies working memory processes. The potential interaction of GABAergic and cholinergic mechanisms in the modulation of working memory processes is discussed.     

氟哌啶醇与丙咪嗪交互作用对成本效益决策的影响

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

Chlordiazepoxide-induced working memory impairments: site specificity and reversal by flumazenil (RO15-1788).

The following studies examined the dose and time dependence, site specificity, and reversibility of chlordiazepoxide (CDP)-induced working memory impairments in adult male Sprague-Dawley rats. The rats were tested in a delayed non-match-to-sample radial-arm maze task in which a 1-h delay was imposed between the first four (predelay) and all subsequent (postdelay) arm choices. Intraperitoneal (ip) injection of 2.5 or 5.0 but not 1.25 mg/kg CDP immediately following the predelay session impaired performance in the task. CDP increased the number of errors and decreased the number of correct choices during the postdelay session. The observed working memory impairments also appeared to be site specific since injection of CDP into the medial septum, but not into the anterior amygdala nuclei, immediately following the predelay session also impaired working memory in a dose-related manner. Furthermore, there was a time window for CDP-induced working memory impairments since intraseptal injection of the drug immediately but not 15 min following the predelay session disrupted memory. This observation suggests that the performance deficits reflect disrupted working memory and not proactive effects on performance or the induction of state-dependent learning. In the final experiment, rats were injected ip with either saline or an amnestic dose of CDP (5.0 mg/kg) following the predelay session and then were immediately infused with 10 nmol flumazenil (RO15-1788), a benzodiazepine receptor antagonist or vehicle, into either the medial septum or anterior nuclei of the amygdala. Intraseptal injection of flumazenil prevented the working memory impairments produced by ip injection of CDP. In contrast, intra-amygdala injection of flumazenil did not attenuate, enhance, or modify the CDP-induced working memory impairment. These observations suggest that CDP disrupts working memory by interacting with benzodiazepine receptors in the medial septum.     

Retention deficit after d-amphetamine treatment: memory defect or performance change?

Retention deficits in discrete trial delayed alternation and delayed matching to sample tasks following administration of d-amphetamine have been interpreted to support the view that arousal facilitates the decay of information from shortterm memory (STM) (Kesner, 1973). But since amphetamine causes numerous changes in performance, alternative explanations of the deficit are also plausible. In an attempt to separate drug effects on memory from those on performance, the effects of d-amphetamine on spatial memory in the radial maze were studied in rats. The unusually long span of accurate working memory in this setting permits drug administration within the retention interval as well as prior to the to-be-remembered event (TBRE). In rats tested at a 5-hr retention interval d-amphetamine (2 mg/kg) disrupted retention when given 0.5 hr before or 4.5 hr after the TBRE, but the same treatment 0 or 2 hr after the TBRE or 3 hr before the TBRE was without effect. At a 5-hr retention interval 3 mg/kg d-amphetamine impaired performance if given 2 hr after the TBRE, but not when given 0 hr after the TBRE or 3 hr before the TBRE. However, when the retention interval was lengthened to 7 hr, administering 3 mg/kg d-amphetamine 2 hr after the TBRE did not disrupt performance. The effects of d-amphetamine on spatial memory are best explained in terms of the well established effects of the drug on motor activity and appetite. Similar changes in performance may account for the "memory" impairments observed after amphetamine treatment in other tasks.     

Hippocampal stimulation disrupts spatial working memory even 8 h after acquisition

The present experiment used hippocampal stimulation to determine the temporal gradient of consolidation of spatial working memory. Rats were trained to perform a spatial working memory task on a radial maze with 12 arms. Each rat went to the ends of 6 arms to obtain a food reward. After 8 h, the rat chose among all the arms to find the ones not previously chosen (and consequently still having food). During some test sessions, the hippocampus was stimulated electrically either at a current level just high enough to produce an electrophysiological seizure, or at a current level below this seizure threshold. Stimulation occurred at one of five intervals (0 to 8 h) following the completion of the first six choices. During other test sessions, the hippocampus was not stimulated. After seizure stimulation, the number of retroactive errors (returning to arms chosen prior to stimulation) increased at all delay intervals; the number of proactive errors (returning to arms chosen after stimulation) increased only with the delay of 8 h. Subthreshold stimulation had no influence on either type of error. These results indicate that normal hippocampal function is required for the maintenance of spatial information in working memory, and that the time course of consolidation of this information is significantly greater than that seen in other types of memory, or consolidation may not take place at all.     

Rolipram reverses scopolamine-induced and time-dependent memory deficits in object recognition by different mechanisms of action

In this study, the effect of the selective phosphodiesterase type 4 (PDE4) inhibitor rolipram on memory performance was investigated using the object recognition task. First, three doses of rolipram (0.01, 0.03 or 0.1 mg/kg) were tested with a 24h delay between the learning (T1) and the test (T2) trial. Doses of rolipram were injected at different time points (30 min before T1, immediately after T1 or 3 h after T1). In a second experiment, the effects of rolipram (0.03, 0.1 or 0.3 mg/kg) were tested in combination with scopolamine (0.1 mg/kg) applying a 1 h delay between trials. Both substances were administered 30 min before T1. Using a 24h interval, rolipram showed an improvement in long-term memory performance when injected 3 h after T1 at a dose of 0.03 mg/kg. Further, rolipram reversed the scopolamine-induced short-term memory deficit at a dose of 0.1 mg/kg. Although the improved memory performance in both conditions is likely to be explained by elevated cAMP levels, two separate working mechanisms might explain these effects.     

Radial arm maze performance of mice: acquisition and atropine effects

CD-1 mice were successfully trained in a six-arm radial maze in which half of the arms were baited, a procedure which had been used to differentiate between reference and working memory. Stable performance was achieved following eight daily training sessions, as measured by decreasing running time and number of errors. This finding strengthens the foraging hypothesis as a basis for the performance of rodents in the radial maze. Acute subcutaneous administration of the cholinergic antagonist atropine sulfate (1-6 mg/kg) to trained mice produced dose-related increases in running time and working memory errors, with a slight decrease in reference memory errors. This is in agreement with other studies on the role of the cholinergic system in memory processes. The peripheral cholinergic blocker, atropine methyl nitrate (4 mg/kg), somewhat increased running time without decreasing performance accuracy. In contrast to the prolonged pharmacological and physiological effects of atropine, behavioral decrements disappeared within 3 hr. It is concluded that mice trained in the radial arm maze may be used for screening of the effects of drugs on cognitive function.     

Damage to the retrosplenial cortex produces specific impairments in spatial working memory

Mounting evidence indicates that the retrosplenial cortex (RSP) has a critical role in spatial navigation. The goal of the present study was to characterize the specific nature of spatial memory deficits that are observed following damage to RSP. Rats with RSP lesions or sham lesions were first trained in a working memory task using an 8-arm radial arm maze. Rats were allowed 5 min to visit each arm and retrieve food pellets and a 5-s delay was imposed between arm choices. Consistent with previous research, rats with RSP damage committed more errors than controls. In particular, RSP-lesioned rats committed more errors of omission (failing to visit an arm of the maze), but there were no lesion effects on errors of commission (revisiting an arm). Neither group of rats exhibited a turn bias (i.e., always turning a certain direction when choosing an arm). At the end of the training phase of the experiment, both groups had reached asymptote and committed very few errors. In the subsequent test phase, a longer delay (30-s) was imposed during some sessions. Both control and RSP-lesioned rats continued to make few errors during sessions with the standard 5-s delay, but RSP-lesioned rats were impaired at the 30-s delay and committed more errors of commission, consistent with an increase in taxing spatial working memory.     

Memory systems in the rat: effects of reward probability,context, and congruency between working and reference memory

The interaction of working and reference memory was studied in rats on an eight-arm radial maze. In two experiments, rats were trained to perform working memory and reference memory tasks. On working memory trials, they were allowed to enter four randomly chosen arms for reward in a study phase and then had to choose the unentered arms for reward in a test phase. On reference memory trials, they had to learn to visit the same four arms on the maze on every trial for reward. Retention was tested on working memory trials in which the interval between the study and test phase was 15 s, 15 min, or 30 min. At each retention interval, tests were performed in which the correct WM arms were either congruent or incongruent with the correct RM arms. Both experiments showed that congruency interacted with retention interval, yielding more forgetting at 30 min on incongruent trials than on congruent trials. The effect of reference memory strength on the congruency effect was examined in Experiment 1, and the effect of associating different contexts with working and reference memory on the congruency effect was studied in Experiment 2.     

Distinct Profile of Working Memory Errors Following Acute or Chronic Disruption of the Cholinergic Septohippocampal Pathway

The behavioral effects of two amnestic treatments (intraseptal chlordiazepoxide (CDP) and intraventricular AF64A) were examined in a delayed-nonmatch-to-sample radial-arm maze (DNMTS) paradigm. The types of errors induced by these treatments in this working memory task were assessed to determine how acute and chronic disruptions of the medial septum affect different phases of working memory (encoding, maintenance, retrieval). Rats were initially trained to perform the DNMTS task with a 1-h delay imposed between the training and the testing sessions. The first experiment demonstrated that intraseptal injection of 30 nmoles of CDP did not produce state-dependent learning. Rats were injected immediately following training with CDP or artificial cerobrospinal fluid (CSF; drug vehicle) and then prior to testing with CDP or CSF. Injection of CDP immediately following training (CDP–CSF) impaired performance of the task regardless of whether CDP was also administered before the postdelay test (CDP–CDP). Rats infused with CDP only before the postdelay test (CSF–CDP) exhibited a proactive deficit characterized by intact retention of the predelay information (i.e., arms entered prior to the delay) but impaired performance on the postdelay component (arms entered only after the delay). These data indicate: (i) that state dependency does not explain the working memory deficits induced by intraseptal CDP; (ii) that pretest CDP disrupts the storage and utilization of working memory for current arm selections. The second experiment examined the behavioral effects induced by a permanent disruption of the cholinergic septohippocampal pathway produced by icv injection of the cholinotoxin AF64A. Rats were initially trained on the DNMTS task and then bilaterally injected icv with either AF64A (2.5 nmoles/side) or CSF. AF64A-treated rats exhibited a significant impairment of performance compared to CSF-treated controls. In contrast to the impairment exhibited by CDP-treated rats in Experiment 1, the performance of AF64A-treated rats displayed a deficit in the maintenance/retrieval of information acquired during RAM trainingandan impairment in ability to store current spatial information in working memory to guide postdelay testing performance. These studies demonstrate that acute and chronic disruptions of the septohippocampal pathway produce distinct profiles of cognitive impairment that should help to reveal the behavioral and neurobiological characteristics of spatial memory.     

东莨菪碱对大鼠空间参考记忆和工作记忆的不同影响

观察东莨菪碱对空间参考记忆和空间工作记忆的编码、保持和提取过程的作用。应用Morris水迷宫实验测定大鼠的空间参考记忆和空间工作记忆,分别在训练的不同阶段腹腔注射东莨菪碱（1mg/kg）和相同容量的生理盐水,比较各东莨菪碱组和生理盐水组之间游泳潜伏期、路径长度、轨迹和游泳速度的差异。结果发现：与注射生理盐水相比,在训练前和探测实验前注射东莨菪碱的大鼠在探测实验中对目标象限不表现出空间偏爱,说明东莨菪碱干扰参考记忆的信息编码和提取过程;而在训练结束后注射东莨菪碱的大鼠探测实验的结果与生理盐水组相比没有显著差异,说明东莨菪碱对参考记忆的保持过程没有影响。在工作记忆实验中,无论第一次测试前、第一次测试后和第2次测试前注射东莨菪碱,均造成大鼠游泳潜伏期延长,说明东莨菪碱干扰工作记忆的编码、保持和提取过程。研究提示M受体在空间工作记忆和参考记忆中发挥不同作用     

Interference due to shared features between action plans is influenced by working memory span

In this study, we examined the interactions between the action plans that we hold in memory and the actions that we carry out, asking whether the interference due to shared features between action plans is due to selection demands imposed on working memory. Individuals with low and high working memory spans learned arbitrary motor actions in response to two different visual events (A and B), presented in a serial order. They planned a response to the first event (A) and while maintaining this action plan in memory they then executed a speeded response to the second event (B). Afterward, they executed the action plan for the first event (A) maintained in memory. Speeded responses to the second event (B) were delayed when it shared an action feature (feature overlap) with the first event (A), relative to when it did not (no feature overlap). The size of the feature-overlap delay was greater for low-span than for high-span participants. This indicates that interference due to overlapping action plans is greater when fewer working memory resources are available, suggesting that this interference is due to selection demands imposed on working memory. Thus, working memory plays an important role in managing current and upcoming action plans, at least for newly learned tasks. Also, managing multiple action plans is compromised in individuals who have low versus high working memory spans.     

The Effects of L-glucose on memory in mice are modulated by peripherally acting cholinergic drugs.

D-Glucose improves memory in animals and humans and in subjects with memory pathologies. To date, the accepted conclusion drawn from animal research is that D-glucose improves memory via alterations in central cholinergic systems. However, recent evidence suggests that a sugar which does not cross the blood-brain barrier also facilitates memory (Talley, Arankowsky-Sandoval, McCarty, & Gold, 1999). The present study examined the effects of peripherally administered L-glucose, a stereoisomer of D-glucose, in male mice. Intraperitoneal administration of L-glucose (300 mg/kg) before testing enhanced place learning in the Morris water maze. Mice injected with L-glucose had significantly shorter escape latencies than mice injected with saline (1 ml/kg). Effects were observed on both reference memory and working memory tasks. L-Glucose did not facilitate performance on either task when it was simultaneously administered with cholinergic antagonists that are excluded from the central nervous system. Thus, simultaneous administration of either methyl-scopolamine (0.3 mg/kg), a peripherally acting muscarinic receptor blocker, or hexamethonium (1 mg/kg), a peripherally acting nicotinic receptor blocker, reversed the effect of L-glucose on memory. These findings suggest that the memory effects of l-glucose may be mediated by facilitated acetylcholine synthesis and/or release in the peripheral nervous system.     

On the nonassociative nature of working memory

Rats were trained in an eight-arm radial maze in two experiments. A “fixed set” of four arms, randomly selected and sequenced, was assigned to each rat. The fixed set was always presented in the same order. Each training trial began with rewarded forced choices of the four arms in the fixed set. The trial concluded with a free-choice test among all eight arms after a delay of about 40 min; choices of the four arms not in the fixed set were rewarded. The degree to which the identities and order of the arms in the fixed set had been learned was assessed in a reversal test. The four arms that were not in the fixed set were presented at the beginning of the reversal test trial; after the usual delay a free-choice test was given, but choices of arms in the fixed set were rewarded. In both experiments, the rats showed no negative transfer in the reversal test. Moreover, sequences of postdelay choices during training varied across days, and the sequence of choices during the reversal test did not match the sequence of arms in the fixed set. The rats therefore learned little if anything about the identities and the order of arms in the fixed set in spite of the consistencies between trials and the maintenance of the fixed set in memory for 40 min within trials. The finding is congruent with the view of working memory as nonassociative.     

Facilitation of memory for extinction of drug-induced conditioned reward: role of amygdala and acetylcholine

These experiments examined the effects of posttrial peripheral and intra-amygdala injections of the cholinergic muscarinic receptor agonist oxotremorine on memory consolidation underlying extinction of amphetamine conditioned place preference (CPP) behavior. Male Long-Evans rats were initially trained and tested for an amphetamine (2 mg/kg) CPP. Rats were subsequently given limited extinction training, followed by immediate posttrial peripheral or intrabasolateral amygdala injections of oxotremorine. A second CPP test was then administered, and the amount of time spent in the previously amphetamine-paired and saline-paired apparatus compartments was recorded. Peripheral (0.07 or 0.01 mg/kg) or intra-amygdala (10 etag/0.5 microL) postextinction trial injections of oxotremorine facilitated CPP extinction. Oxotremorine injections that were delayed 2 h posttrial training did not enhance CPP extinction, indicating a time-dependent effect of the drug on memory consolidation processes. The findings indicate that memory consolidation for extinction of approach behavior to environmental stimuli previously paired with drug reward can be facilitated by posttrial peripheral or intrabasolateral amygdala administration of a cholinergic agonist.     

Food and amphetamine self-administration by baboons: effects of alternatives.

The effects of the availability of an alternative reinforcer on responding maintained by food pellets or fluid solutions were examined in 6 adult male baboons (Papio cynocephalus anubis). During daily 23-hr experimental sessions, baboons had concurrent access to both food pellets and fluid, with responding maintained under fixed-ratio schedules of reinforcement that varied between the two commodities. The fixed-ratio requirement, or cost, for pellets was increased when (a) no fluid, (b) a dilute dextrose vehicle, (c) 0.002 mg/kg d-amphetamine, or (d) 0.004 mg/kg d-amphetamine was available. When given nonrestricted concurrent access to food pellets and amphetamine at minimal cost (FR 2), baboons self-administered sufficient amphetamine to decrease pellet intake. Increasing the response requirement for pellets decreased pellet intake at a similar rate regardless of the available fluid and increased fluid intake in a variable manner among baboons such that there were no statistically significant increases in fluid intake. In contrast, when access to pellets was restricted to 70% of maximal intake under nonrestricted conditions, increasing pellet cost decreased pellet intake and increased fluid intake more rapidly when the high amphetamine dose was available. Thus, amphetamine was more effective as an economic substitute for pellets when access to pellets was restricted. The response cost for vehicle and both amphetamine concentrations was increased when baboons had nonrestricted and restricted access to pellets. Increasing the response requirement for fluid delivery decreased intake of all three fluids similarly under both pellet-access conditions. The results indicate that substitution between commodities with minimal commonalities can be studied under controlled laboratory conditions and is dependent upon reinforcement schedule and commodity restrictions.     

SLV330, a cannabinoid CB1 receptor antagonist,ameliorates deficits in the T-maze,object recognition and Social Recognition Tasks in rodents

Cannabinoid CB₁ receptor (CB₁R) signaling has been suggested to play an important role in the regulation of memory and cognition. In the present study, our aim was to investigate whether the CB₁R antagonist SLV330 (doses ranging from 0.3 to 10 mg/kg, given orally, p.o.) could ameliorate impairments in distinct aspects of cognition using different disruption models in both mice and rats. Effects of SLV330 were tested on working memory deficits in the T-maze Continuous Alternation Task (T-CAT) in mice; episodic memory deficits in the Object Recognition Task (ORT) and Social Recognition Task (SRT) in rats. The acetylcholinesterase inhibitor (AChEI) donepezil (Aricept®, approved for symptomatic treatment of Alzheimer’s disease) and nicotine were used as reference compounds.SLV330 markedly improved aging and scopolamine-induced memory deficits in the T-CAT in mice with a lowest effective dose (LED) of 1 mg/kg p.o., while reversing the cognitive dysfunction induced by the N-methyl-d-aspartate (NMDA) antagonist dizocilpine (MK-801) only at the middle dose of 3 mg/kg. In the ORT, we have found that combined administration of subthreshold doses of SLV330 (1 mg/kg, p.o.) and the AChEI donepezil (0.1 mg/kg, p.o.), that had no discernable effects on performance when given alone, enhanced memory performance in Wistar rats with deficits induced by the muscarinic antagonist scopolamine, suggestive of additive synergistic effects of SLV330 and donepezil on cognitive impairment. Finally, SLV330 was found to have cognition enhancing properties in a time delay paradigm in the SRT at a LED dose of 3 mg/kg (p.o.).In conclusion, the CB₁R antagonist SLV330 was found to clearly improve memory in several preclinical models for cognitive impairment.