Caffeine and an adenosine A2A receptor antagonist prevent memory impairment and synaptotoxicity in adult rats triggered by a convulsive episode in early life

Seizures early in life cause long‐term behavioral modifications, namely long‐term memory deficits in experimental animals. Since caffeine and adenosine A_2A receptor (A_2AR) antagonists prevent memory deficits in adult animals, we now investigated if they also prevented the long‐term memory deficits caused by a convulsive period early in life. Administration of kainate (KA, 2 mg/kg) to 7‐days‐old (P7) rats caused a single period of self‐extinguishable convulsions which lead to a poorer memory performance in the Y‐maze only when rats were older than 90 days, without modification of locomotion or anxiety‐like behavior in the elevated‐plus maze. In accordance with the relationship between synaptotoxicity and memory dysfunction, the hippocampus of these adult rats treated with kainate at P7 displayed a lower density of synaptic proteins such as SNAP‐25 and syntaxin (but not synaptophysin), as well as vesicular glutamate transporters type 1 (but not vesicular GABA transporters), with no changes in PSD‐95, NMDA receptor subunits (NR1, NR2A, NR2B) or α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor subunits (GluR1, GluR2) compared with controls. Caffeine (1 g/L) or the A_2AR antagonist, KW6002 (3 mg/kg) applied in the drinking water from P21 onwards, prevented these memory deficits in P90 rats treated with KA at P7, as well as the accompanying synaptotoxicity. These results show that a single convulsive episode in early life causes a delayed memory deficit in adulthood accompanied by a glutamatergic synaptotoxicity that was prevented by caffeine or adenosine A_2AR antagonists.     

Inactivation of neuronal forebrain A2A receptors protects dopaminergic neurons in a mouse model of Parkinson’s disease

Adenosine A_2A receptors antagonists produce neuroprotective effects in animal models of Parkinson’s disease (PD). As neuroinflammation is involved in PD pathogenesis, both neuronal and glial A_2A receptors might participate to neuroprotection. We employed complementary pharmacologic and genetic approaches to A_2A receptor inactivation, in a multiple MPTP mouse model of PD, to investigate the cellular basis of neuroprotection by A_2A antagonism. MPTP·HCl (20 mg/kg daily for 4 days) was administered in mice treated with the A_2A antagonist SCH58261, or in conditional knockout mice lacking A_2A receptors on forebrain neurons (fbnA_2AKO mice). MPTP‐induced partial loss of dopamine neurons in substantia nigra pars compacta (SNc) and striatum (Str), associated with increased astroglial and microglial immunoreactivity in these areas. Astroglia was similarly activated 1, 3, and 7 days after MPTP administration, whereas maximal microglial reactivity was detected on day 1, returning to baseline 7 days after MPTP administration. SCH58261 attenuated dopamine cell loss and gliosis in SNc and Str. Selective depletion of A_2A receptors in fbnA_2AKO mice completely prevented MPTP‐induced dopamine neuron degeneration and gliosis in SNc, and partially counteracted gliosis in Str. Results provide evidence of a primary role played by neuronal A_2A receptors in neuroprotective effects of A_2A antagonists in a multiple MPTP injections model of PD. With the symptomatic antiparkinsonian potential of several A_2A receptor antagonists being pursued in clinical trials, this study adds to the rationale for broader clinical benefit and use of these drugs early in the treatment of PD.     

Time-course of nigrostriatal degeneration in a progressive MPTP-lesioned macaque model of parkinson’s disease

Parkinson’s disease (PD) is characterized by a progressive loss of substantia nigra pars compacta (SNc) neurons. The onset of clinical symptoms only occurs after the degeneration has exceeded a certain threshold. In most of the current 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) nonhuman primate models, nigrostriatal lesions and the onset of PD symptoms are the result of an immediate neuronal degeneration in the SNc caused by acute injection of the toxin. In order to develop a model that more closely mimics the degeneration pattern of human PD, we eventually established a protocol that produces a progressive parkinsonian state by treating monkeys repeatedly with MPTP for 15 ± 2 d. Mean onset of parkinsonian symptoms occurred after 13.2 d of treatment. At this time, 56.8 ± 6.3% of tyrosine hydroxylase immunoreactive neurons and 75.2 ± 6.2% of Nissl-stained cells remained in the SNc. Striatal dopamine transporter (DAT) binding and dopamine (DA) content decreased to 19.7 ± 4.9% and 18.2 ± 5.6% of untreated monkeys. Parallel ¹²³I-PEI single-photon emission computed tomography (SPECT) imaging in living animals showed a similar decrease in striatal DAT binding. In this article, we examine how this and other chronic MPTP models fit with human pathology.     

Formation of stacking complexes between caffeine (1,2,3-trimethylxanthine) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine may attenuate biological effects of this neurotoxin

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin causing symptoms that may resemble those observed in patients suffering from Parkinson's disease. Therefore, MPTP-treated laboratory animals are currently the most favored models to study therapeutic intervention strategies in this disease. It was demonstrated recently that caffeine (1,2,3-trimethylxanthine) intake decreases the risk of Parkinson's disease in various human populations and attenuates MPTP-induced neurological effects in animal models. Since the effects of caffeine on MPTP-treated animals were mimicked by several antagonists of the adenosine A(2A) receptor, it was suggested that caffeine attenuates MPTP toxicity by blocking this receptor. Here, using microcalorimetry and molecular modeling, we demonstrate that caffeine can form stacking (pi-pi) complexes with MPTP. We found that a biological activity of MPTP (induction of mutations in a microbiological mutagenicity assay), which is completely independent on the A(2A) receptor blockade, is significantly reduced by caffeine. Therefore, we suggest that caffeine may attenuate neurotoxicity of MPTP (and possibly other polycyclic aromatic toxins) and reveal its protective effects on the risk of Parkinson's disease not only by blocking the A(2A) receptor but also by sequestering neurotoxin molecules in mixed complexes, especially in stomach.     

Hippocampal-dependent spatial memory in the water maze is preserved in an experimental model of temporal lobe epilepsy in rats

Cognitive impairment is a major concern in temporal lobe epilepsy (TLE). While different experimental models have been used to characterize TLE-related cognitive deficits, little is known on whether a particular deficit is more associated with the underlying brain injuries than with the epileptic condition per se. Here, we look at the relationship between the pattern of brain damage and spatial memory deficits in two chronic models of TLE (lithium-pilocarpine, LIP and kainic acid, KA) from two different rat strains (Wistar and Sprague-Dawley) using the Morris water maze and the elevated plus maze in combination with MRI imaging and post-morten neuronal immunostaining. We found fundamental differences between LIP- and KA-treated epileptic rats regarding spatial memory deficits and anxiety. LIP-treated animals from both strains showed significant impairment in the acquisition and retention of spatial memory, and were unable to learn a cued version of the task. In contrast, KA-treated rats were differently affected. Sprague-Dawley KA-treated rats learned less efficiently than Wistar KA-treated animals, which performed similar to control rats in the acquisition and in a probe trial testing for spatial memory. Different anxiety levels and the extension of brain lesions affecting the hippocampus and the amydgala concur with spatial memory deficits observed in epileptic rats. Hence, our results suggest that hippocampal-dependent spatial memory is not necessarily affected in TLE and that comorbidity between spatial deficits and anxiety is more related with the underlying brain lesions than with the epileptic condition per se.     

Leptin attenuates the detrimental effects of β-amyloid on spatial memory and hippocampal later-phase long term potentiation in rats

β-Amyloid (Aβ) is the main component of amyloid plaques developed in the brain of patients with Alzheimer's disease (AD). The increasing burden of Aβ in the cortex and hippocampus is closely correlated with memory loss and cognition deficits in AD. Recently, leptin, a 16 kD peptide derived mainly from white adipocyte tissue, has been appreciated for its neuroprotective function, although less is known about the effects of leptin on spatial memory and synaptic plasticity. The present study investigated the neuroprotective effects of leptin against Aβ-induced deficits in spatial memory and in vivo hippocampal late-phase long-term potentiation (L-LTP) in rats. Y maze spontaneous alternation was used to assess short term working memory, and the Morris water maze task was used to assess long term reference memory. Hippocampal field potential recordings were performed to observe changes in L-LTP. We found that chronically intracerebroventricular injection of leptin (1 μg) effectively alleviated Aβ1–42 (20 μg)-induced spatial memory impairments of Y maze spontaneous alternation and Morris water maze. In addition, chronic administration of leptin also reversed Aβ1–42-induced suppression of in vivo hippocampal L-LTP in rats. Together, these results suggest that chronic leptin treatments reversed Aβ-induced deficits in learning and memory and the maintenance of L-LTP.     

MPTP modulates hippocampal synaptic transmission and activity-dependent synaptic plasticity via dopamine receptors

Parkinson's disease (PD)-like symptoms and cognitive deficits are inducible by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). Since cognitive abilities, including memory formations rely also on hippocampus, we set out to clarify the effects of MPTP on hippocampal physiology. We show that bath-application of MPTP (25?μM) to acute hippocampal slices enhanced AMPA receptor-mediated field excitatory postsynaptic potentials (AMPAr-fEPSPs) transiently, whereas N-methyl-D-aspartate (NMDA) receptor-mediated fEPSPs (NMDAr-fEPSPs) were facilitated persistently. The MPTP-mediated transient AMPAr-fEPSP facilitation was antagonized by the dopamine D2-like receptor antagonists, eticlopride (1?μM) and sulpiride (1 and 40?μM). In contrast, the persistent enhancement of NMDAr-fEPSPs was prevented by the dopamine D1-like receptor antagonist SCH23390 (10?μM). In addition, we show that MPTP decreased paired-pulse facilitation of fEPSPs and mEPSCs frequency. Regarding activity-dependent synaptic plasticity, 25?μM MPTP transformed short-term potentiation (STP) into a long-term potentiation (LTP) and caused a slow onset potentiation of a non-tetanized synaptic input after induction of LTP in a second synaptic input. This heterosynaptic slow onset potentiation required activation of dopamine D1-like and NMDA-receptors. We conclude that acute MPTP application affects basal synaptic transmission by modulation of presynaptic vesicle release and facilitates NMDAr-fEPSPs as well as activity-dependent homo- and heterosynaptic plasticity under participation of dopamine receptors.     

Altered expression of NCAM in hippocampus and cortex may underlie memory and learning deficits in rats with streptozotocin-induced diabetes mellitus

Neurological and structural changes are paralleled by cognitive deficits in diabetes mellitus. The present study was designed to evaluate the expression of neural cell adhesion molecules (NCAM) in the hippocampus, cortex and cerebellum and to examine cognitive functions in diabetic rats. Diabetes was induced in male albino rats via intraperitoneal streptozotocin injection. Learning and memory behaviors were investigated using a passive avoidance test and a spatial version of the Morris water maze test. NCAM expression was detected in the hippocampus, cortex and cerebellum by an immunoblotting method. The diabetic rats developed significant impairment in learning and memory behaviours as indicated by deficits in passive avoidance and water maze tests as compared to control rats. Expression of NCAM 180 and 120 kDa were found to be higher in hippocampus and cortex of diabetic rat brains compared to those of control, whereas expression of NCAM 140 kDa decreased in these brain regions. Our findings suggest that streptozotocin-induced diabetes impairs cognitive functions and causes an imbalance in expression of NCAM in those brain regions involved in learning and memory. Altered expression of NCAM in hippocampus may be an important cause of learning and memory deficits that occur in diabetes mellitus.     

Modified water maze for studying spatial memory of rats

A method for evaluation of impairments of spatial memory in rats is put forward. Sensitivity of the advanced method based on the principles of Morris' water maze was compared with that of the classic prototype. Efficiency of the advanced method was assessed by dose- and time-dependent effects of agroclavine on the spatial memory of rats. Agroclavine (10 micrograms/kg) was shown to produce spatial memory impairment in rats. The obtained results also indicate that the modernized maze is more sensitive in revealing impairments of the spatial memory in rats than the classic water maze.     

Changes in HPA reactivity and noradrenergic functions regulate spatial memory impairments at delayed time intervals following cerebral ischemia

This study investigates the association of ischemia-induced spatial memory impairment to alterations of the HPA axis and noradrenergic activation post insult. Experiment 1 characterized the effects of 10 min forebrain ischemia on corticosterone (CORT) secretion following ischemia and in response to spatial memory assessment in the Barnes maze, as well as the impact of pre-ischemia treatment with the glucocorticoid inhibitor metyrapone (175 mg/kg; s.c.). The results showed that cerebral ischemia represents a significant physiological stressor that upregulated CORT secretion 1, 24 and 72 h post-ischemia but not at 7 days. In response to testing in the Barnes maze ischemic animals showed elevated CORT secretion simultaneously with spatial memory deficits. The single dose of metyrapone attenuated the ischemia-induced adrenocortical hyper-responsiveness and subsequent memory deficits despite not providing neuroprotection in the hippocampal CA1 pyramidal cells. To complement these findings, we examined whether norepinephrine which provides positive feedback to the HPA axis and is upregulated following brain ischemia could influence memory performance at delayed intervals after ischemia. Experiment 2 demonstrated that pre-testing administration of the alpha2-adrenoceptor agonist clonidine (.04 mg/kg, s.c.) attenuated ischemia-induced working memory impairments in a radial maze while opposite effects were obtained with the antagonist yohimbine (.3 mg/kg, s.c.). Post-testing administration of clonidine produced spatial reference memory impairments in ischemic rats. The findings from the current study demonstrate increased sensitization and responsiveness of systems regulating stress hormones at long intervals post ischemia. Importantly, we demonstrate that these effects contribute to post ischemic cognitive impairments which can be attenuated pharmacologically even in the presence of hippocampal degeneration at time of testing.     

Static magnetic field exposure affects behavior and learning in rats

The present work investigated the behavioral effects of a moderate exposure (1 h per day for 5 consecutive days) to a static magnetic field (SMF, 128 mT) in male rats. SMF effects were evaluated in two sets of control and SMF-exposed rats. One set of animals was used for evaluation of SMF potential effects on emotional behaviors in the elevated plus maze and in the open field. The other set of animals was tested for learning and memory abilities in different procedures of the Morris water maze task. We found no significant difference between control and SMF-exposed rats in anxiety tests. However, the ratio of open arms time in the plus maze was reduced by half in SMF-exposed rats. In the Morris water maze, SMF-exposed rats were partially impaired during the initial learning task as well as in the retention task at one week. We conclude that static magnetic field exposure altered emotional behaviors in the plus maze and led to cognitive impairments, or at least to substantial attention disorders, in the Morris water maze.     

Preventive action of Ginkgo biloba in stress- and corticosterone-induced impairment of spatial memory in rats

In this study, we tested preventive effects of a natural medicine the extract of Ginkgo biloba (EGB 761) on post-stress cognitive dysfunction. Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and have been linked to the pathophysiology of mood and anxiety disorders.Our findings indicate that chronic restraint stress impaired egocentric spatial memory as observed in the eight-arm radial maze but it did not alter the allocentric spatial memory in the Morris water maze. In control rats EGB 761 (100 mg/kg, orally) improved spatial memory in these two tests. Also, EGB 761 normalized cognitive deficits seen in rats chronically stressed or treated with an ‘equivalent’ dose of exogenous corticosterone (5 mg/kg, subcutaneously).We conclude that, in rats, repeated administration of EGB 761 prevents stress- and corticosterone-induced impairments of spatial memory.     

Impairment of long-term depression induced by chronic brain inflammation in rats

Although deficits in synaptic plasticity have been identified in aged or neuroinflamed animals with memory impairments, few studies have examined the cellular basis of plasticity in such animals. Here, we examined whether chronic neuroinflammation altered long-term depression (LTD) and studied the underlying mechanism of LTD impairment by neuroinflammation. Chronic neuroinflammation was induced by administration of lipopolysaccharide (LPS) to the fourth ventricle. Excitatory postsynaptic potentials were recorded extracellularly in the rat hippocampal CA1 area to examine alterations in synaptic plasticity. Chronic administration of LPS induced remarkable memory impairment in the Morris water maze test. N-methyl-d-aspartate receptor (NMDAR)-dependent LTD was almost absent in LPS-infused animals. The AMPA receptor (AMPAR)-mediated synaptic response was reduced in the LPS-infused group. These results suggest that reduction in NMDAR-dependent LTD might arise because of alterations in postsynaptic AMPARs as well as NMDARs and that such changes may be present in mild and early forms of Alzheimer-type dementia.     

Chronic 17beta-estradiol pretreatment and ischemia-induced hippocampal degeneration and memory impairments: a 6-month survival study

Exogenous administration of estrogen has been shown to significantly reduce ischemia-induced neuronal degeneration. However, the long-term impact of such treatment on neuronal protection and functional recovery remain largely unknown. The present study assessed the effects of a 15-day pretreatment with 17beta-estradiol on memory deficits and neuronal damage up to 6 months following a 10-min global ischemia in rats. Four groups of ovariectomized female rats [sham-operated and ischemic rats receiving a 15-day pretreatment of either the vehicle or 17beta-estradiol (100 microg/kg)] were tested. The 8-arm radial maze and object recognition tests served to evaluate the impact of 17beta-estradiol treatment on ischemia-induced spatial and recognition memory impairments, respectively. Testing in the radial maze was initiated at two distinct time intervals following reperfusion (7 and 120 days) to evaluate changes in memory functions over time. Our findings revealed long-lasting neuroprotective effects of 17beta-estradiol treatment on hippocampal CA1 pyramidal cells in ovariectomized ischemic rats (43.5% greater neuronal survival than observed in vehicle-treated ischemic animals). Importantly, this neuronal protection translated into significant improvements of recognition and spatial memory functions in estradiol-treated ischemic rats.     

Aging of the dopaminergic system and motor behavior in mice intoxicated with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

J. Neurochem. (2012) 122, 1032-1046. ABSTRACT: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication of mice is a standard model of Parkinson's disease (PD). However, it does not reproduce functionally PD. Given the occurrence of PD during aging, symptoms might only be detected in MPTP-intoxicated mice after aging. To address this, mice injected with MPTP at 2.5?months were followed up to a maximum age of 21?months. There was no loss of dopamine cells with aging in control mice; moreover, the initial post-MPTP intoxication decrease in dopamine cell was no longer significant at 21?months. With aging, striatal dopamine level remained constant, but concentrations of the dopamine metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were markedly reduced in both groups. There was also a late impairment of fine motor skills. After MPTP intoxication, hyperactivity was immediately detected and it became greater than in control mice from 14?months of age; fine motor skills were also more impaired; both these symptoms were correlated with striatal dopamine, DOPAC and HVA concentrations. In bothgroups, neither motor symptoms nor dopamine changes worsened with age. These findings do not support the notion that PD develops with age in mice after MPTP intoxication and that the motor deficits seen are because of an aging process.     

Long-Term Moderate Dose Exogenous Erythropoietin Treatment Protects from Intermittent Hypoxia-Induced Spatial Learning Deficits and Hippocampal Oxidative Stress in Young Rats

Exposure to intermittent hypoxia (IH) is associated with cognitive impairments and oxidative stress in brain regions involved in learning and memory. In earlier studies, erythropoietin (EPO) showed a neuroprotective effect in large doses. The aim of the present study was to explore the effect of smaller doses of EPO, such as those used in the treatment of anemia, on IH-induced cognitive deficits and hippocampal oxidative stress in young rats. The effect of concurrent EPO treatment (500 and 1,000 IU/kg/day ip) on spatial learning and memory deficits induced by long-term exposure to IH for 6 weeks was tested using the Morris water maze (MWM) test and the elevated plus maze (EPM) test. Moreover, the effect on hippocampal glutamate and oxidative stress were assessed. Exposure to IH induced a significant impairment of spatial learning and cognition of animals in both MWM and EPM performance parameters. Moreover, hippocampal glutamate and thiobarbituric acid reactive substances (TBARS) increased while antioxidant defenses (GSH and GSH-Px) decreased. EPO in the tested doses significantly reduced the IH-induced spatial learning deficits in both MWM and EPM tests and dose-dependently antagonized the effects of IH on hippocampal glutamate, TBARS, GSH levels, and GSH-Px activity. Treatment with EPO in moderate doses that used for anemia, concurrently with IH exposure can antagonize IH-induced spatial learning deficits and protect hippocampal neurons from IH-induced lipid peroxidation and oxidative stress-induced damage in young rats, possibly through multiple mechanisms involving a potential antioxidative effect.     

Influences of Chronic Mild Stress Exposure on Motor,Non-Motor Impairments and Neurochemical Variables in Specific Brain Areas of MPTP/Probenecid Induced Neurotoxicity in Mice

Parkinson''s disease (PD) is regarded as a movement disorder mainly affecting the elderly population and occurs due to progressive loss of dopaminergic (DAergic) neurons in nigrostriatal pathway. Patients suffer from non-motor symptoms (NMS) such as depression, anxiety, fatigue and sleep disorders, which are not well focussed in PD research. Depression in PD is a predominant /complex symptom and its pathology lies exterior to the nigrostriatal system. The main aim of this study is to explore the causative or progressive effect of chronic mild stress (CMS), a paradigm developed as an animal model of depression in1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg. body wt.) with probenecid (250 mg/kg, s.c.) (MPTP/p) induced mice model of PD. After ten i.p. injections (once in 3.5 days for 5 weeks) of MPTP/p or exposure to CMS for 4 weeks, the behavioural (motor and non-motor) impairments, levels and expressions of dopamine (DA), serotonin (5-HT), DAergic markers such as tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporters—2 (VMAT 2) and α-synuclein in nigrostriatal (striatum (ST) and substantia nigra (SN)) and extra-nigrostriatal (hippocampus, cortex and cerebellum) tissues were analysed. Significantly decreased DA and 5-HT levels, TH, DAT and VMAT 2 expressions and increased motor deficits, anhedonia-like behaviour and α-synuclein expression were found in MPTP/p treated mice. Pre and/or post exposure of CMS to MPTP/p mice further enhanced the MPTP/p induced DA and 5-HT depletion, behaviour abnormalities and protein expressions. Our results could strongly confirm that the exposure of stress after MPTP/p injections worsens the symptoms and neurochemicals status of PD.     

Effect of Cardiac Arrest on Cognitive Impairment and Hippocampal Plasticity in Middle-Aged Rats

Cardiopulmonary arrest is a leading cause of death and disability in the United States that usually occurs in the aged population. Cardiac arrest (CA) induces global ischemia, disrupting global cerebral circulation that results in ischemic brain injury and leads to cognitive impairments in survivors. Ischemia-induced neuronal damage in the hippocampus following CA can result in the impairment of cognitive function including spatial memory. In the present study, we used a model of asphyxial CA (ACA) in nine month old male Fischer 344 rats to investigate cognitive and synaptic deficits following mild global cerebral ischemia. These experiments were performed with the goals of 1) establishing a model of CA in nine month old middle-aged rats; and 2) to test the hypothesis that learning and memory deficits develop following mild global cerebral ischemia in middle-aged rats. To test this hypothesis, spatial memory assays (Barnes circular platform maze and contextual fear conditioning) and field recordings (long-term potentiation and paired-pulse facilitation) were performed. We show that following ACA in nine month old middle-aged rats, there is significant impairment in spatial memory formation, paired-pulse facilitation n dysfunction, and a reduction in the number of non-compromised hippocampal Cornu Ammonis 1 and subiculum neurons. In conclusion, nine month old animals undergoing cardiac arrest have impaired survival, deficits in spatial memory formation, and synaptic dysfunction.     

Anti-amnesic properties of (±)-PPCC, a novel sigma receptor ligand, on cognitive dysfunction induced by selective cholinergic lesion in rats

Previous studies have reported that selective sigma-1 agonists may improve cognitive abilities in experimental animals possibly via a cholinergic mechanism. However, the issue of a direct action on to sigma-1 receptors in memory-related brain areas has been much less investigated. The newly synthetised compound methyl(1 R ,2 S /1 S ,2 R )-2-[4-hydroxy-4-phenylpiperidin-1-yl)methyl]-1-(4-methylphenyl) cyclopropanecarboxylate [(±)-PPCC] has recently been shown to possess high affinity for the sigma-1 receptor where it specifically acts as an agonist. Here, the functional effects of (±)-PPCC were investigated in rat models of mild or severe cognitive dysfunction based on a sub-total (≤ 70–80%) or complete (≥ 90–95%) central cholinergic depletion induced by different doses of the selective immunotoxin 192 IgG-saporin injected intraventricularly. At 5–6 weeks post-surgery, the lesioned animals exhibited dose-dependent deficits in reference memory, as assessed using the Morris water maze task, whereas working memory abilities, evaluated using the radial arm water maze task, appeared equally impaired in the two dose groups. Daily treatment with (±)-PPCC significantly improved both reference and working memory performance in all lesioned animals but it did not affect intact or sham-lesioned subjects. In a separate test, treatment with (±)-PPCC reversed the learning deficits induced by the muscarinic receptor antagonist atropine sulphate in both control and mild-lesioned rats. The effect was blocked in lesioned, but not normal animals by pre-treatment with the sigma-1 antagonist N -[2-(3,4-dichlorophenyl)ethyl]- N -methyl-2-(dimethylamino)ethylamine. The results suggest that (±)-PPCC may efficiently ameliorate perturbed cognitive abilities, and that these anti-amnesic effects most probably occur via a direct interaction of the compound with sigma-1 receptors.