Lack of general learning ability factor in a rat test battery measuring a wide spectrum of cognitive domains.

Objective: In the framework of a larger project aiming to test putative cognitive enhancer drugs in a system with improved translational validity, we established a rodent test battery, where different, clinically relevant cognitive domains were investigated in the same animal population. The aim of the current study was to check whether performances in the different tasks representing different cognitive functions are assay-specific or may originate in an underlying general learning ability factor. Methods: In the experiments 36 Long-Evans and 36 Lister Hooded rats were used. The test battery covered the following cognitive domains: attention and impulsivity (measured in the 5-choice serial reaction time task), spatial memory (Morris water-maze), social cognition (cooperation task), cognitive flexibility (attentional set shifting test), recognition memory (novel object recognition) and episodic memory (water-maze based assay). The outcome variables were analyzed by correlation analysis and principal component analysis (PCA). The datasets consisted of variables measuring learning speed and performance in the paradigms. From the raw variables composite variables were created for each assay, then from these variables a composite score was calculated describing the overall performance of each individual in the test battery. Results: Correlations were only found among the raw variables characterizing the same assay but not among variables belonging to different tests or among the composite variables. The PCAs did not reduce the dimensionality of the raw or composite datasets. Graphical analysis showed variable performance of the animals in the applied tests. Conclusions: The results suggests the assay outcomes (learning performance) in the system are based on independent cognitive domains.

Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model.

Background: Cariprazine, a D3-preferring dopamine D2/D3 receptor partial agonist, is a new antipsychotic drug recently approved in the United States for the treatment of schizophrenia and bipolar mania. We recently demonstrated that cariprazine also has significant antianhedonic-like effects in rats subjected to chronic stress; however, the exact mechanism of action for cariprazine's antidepressant-like properties is not known. Thus, in this study we examined whether the effects of cariprazine are mediated by dopamine D3 receptors. Methods: Wild-type and D3-knockout mice were exposed to chronic unpredictable stress for up to 26 days, treated daily with vehicle, imipramine (20 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.03, 0.1, 0.2, and 0.4 mg/kg), and tested in behavioral assays measuring anhedonia and anxiety-like behaviors. Results: Results showed that cariprazine significantly attenuated chronic unpredictable stress-induced anhedonic-like behavior in wild-type mice, demonstrating potent antidepressant-like effects comparable with aripiprazole and the tricyclic antidepressant imipramine. This antianhedonic-like effect of cariprazine was not observed in D3-knockout mice, suggesting that the cariprazine antidepressant-like activity is mediated by dopamine D3 receptors. Moreover, cariprazine significantly reduced drinking latency in the novelty-induced hypophagia test in wild-type mice, further confirming its antianhedonic-like effect and showing that it also has anxiolytic-like activity. Conclusions: In combination with previous studies, these results suggest that cariprazine has a unique pharmacological profile and distinct dopamine D3 receptor-dependent mechanism of action that may be beneficial in the treatment of schizophrenia, bipolar disorder, and major depressive disorder.

Long-term effects of aripiprazole exposure on monoaminergic and glutamatergic receptor subtypes: comparison with cariprazine.

OBJECTIVE: This study examined the chronic effects of aripiprazole and cariprazine on serotonin (5-HT1A and 5-HT2A) and glutamate (NMDA and AMPA) receptor subtypes. In addition, the effects of aripiprazole on D2 and D3 receptors were tested and compared with previously reported cariprazine data. METHODS: Rats received vehicle, aripiprazole (2, 5, or 15 mg/kg), or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Receptor levels were quantified using autoradiographic assays on brain sections from the medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), nucleus accumbens (NAc), caudate-putamen medial (CPu-M), caudate-putamen lateral (CPu-L), hippocampal CA1 (HIPP-CA1) and CA3 (HIPP-CA3) regions, and the entorhinal cortex (EC). RESULTS: Similar to previous findings with cariprazine, aripiprazole upregulated D2 receptor levels in various regions; D3 receptor changes were less than those reported with cariprazine. All aripiprazole doses and higher cariprazine doses increased 5-HT1A receptors in the MPC and DFC. Higher aripiprazole and all cariprazine doses increased 5-HT1A receptors in HIPP-CA1 and HIPP-CA3. Aripiprazole decreased 5-HT2A receptors in the MPC, DFC, HIPP-CA1, and HIPP-CA3 regions. Both compounds decreased NMDA receptors and increased AMPA receptors in select brain regions. CONCLUSIONS: Long-term administration of aripiprazole and cariprazine had similar effects on 5-HT1A, NMDA, and AMPA receptors. However, cariprazine more profoundly increased D3 receptors while aripiprazole selectively reduced 5-HT2A receptors. These results suggest that the unique actions of cariprazine on dopamine D3 receptors, combined with its effects on serotonin and glutamate receptor subtypes, may confer the clinical benefits, safety, and tolerability of this novel compound in schizophrenia and bipolar mania.

The influence of 5-HT(2A) activity on a 5-HT(2C) specific in vivo assay used for early identification of multiple acting SERT and 5-HT(2C) receptor ligands.

As a result of our exploratory programme aimed at elaborating dually acting compounds towards the serotonin (5-HT) transporter (SERT) and the 5-HT2C receptor a novel series of 3-amino-1-phenylpropoxy substituted diphenylureas was identified. From that collection two promising compounds (2 and 3) exhibiting highest 5-HT2C receptor affinity strongly inhibited the 5-HT2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) induced hypomotility in mice. In further pursuance of that objective (2-aminoethyl)(benzyl)sulfamoyl diphenylureas and diphenylpiperazines have also been elaborated. Herein we report the synthesis of potent multiple-acting compounds from this new class. However, when two optimized representatives (6 and 14) possessing the desired in vitro profile were tested neither reduced the motor activity of mCPP treated animals. Comparative albeit limited in vitro structure-activity relationship (SAR) analysis and detailed in vivo studies are discussed and explanation for their intricate behaviour is proposed.

Thieno[2,3-b]pyridines as negative allosteric modulators of metabotropic GluR5 receptors: Lead optimization.

An HTS campaign of our corporate compound library, and hit-to lead development resulted in thieno[2,3-b]pyridine derivative leads with mGluR5 negative allosteric modulator effects. During the lead optimization process, our objective was to improve affinity and metabolic stability. Modification of the first two targeted regions resulted in compounds with nanomolar affinity, then optimal substitution of the third region improved metabolic stability. One of the most promising compounds showed excellent in vivo efficacy and is a potential development candidate.

Chronic escitalopram treatment attenuated the accelerated rapid eye movement sleep transitions after selective rapid eye movement sleep deprivation: a model-based analysis using Markov chains.

BACKGROUND: Shortened rapid eye movement (REM) sleep latency and increased REM sleep amount are presumed biological markers of depression. These sleep alterations are also observable in several animal models of depression as well as during the rebound sleep after selective REM sleep deprivation (RD). Furthermore, REM sleep fragmentation is typically associated with stress procedures and anxiety. The selective serotonin reuptake inhibitor (SSRI) antidepressants reduce REM sleep time and increase REM latency after acute dosing in normal condition and even during REM rebound following RD. However, their therapeutic outcome evolves only after weeks of treatment, and the effects of chronic treatment in REM-deprived animals have not been studied yet. RESULTS: Chronic escitalopram- (10 mg/kg/day, osmotic minipump for 24 days) or vehicle-treated rats were subjected to a 3-day-long RD on day 21 using the flower pot procedure or kept in home cage. On day 24, fronto-parietal electroencephalogram, electromyogram and motility were recorded in the first 2 h of the passive phase. The observed sleep patterns were characterized applying standard sleep metrics, by modelling the transitions between sleep phases using Markov chains and by spectral analysis. Based on Markov chain analysis, chronic escitalopram treatment attenuated the REM sleep fragmentation [accelerated transition rates between REM and non-REM (NREM) stages, decreased REM sleep residence time between two transitions] during the rebound sleep. Additionally, the antidepressant avoided the frequent awakenings during the first 30 min of recovery period. The spectral analysis showed that the SSRI prevented the RD-caused elevation in theta (5-9 Hz) power during slow-wave sleep. Conversely, based on the aggregate sleep metrics, escitalopram had only moderate effects and it did not significantly attenuate the REM rebound after RD. CONCLUSION: In conclusion, chronic SSRI treatment is capable of reducing several effects on sleep which might be the consequence of the sub-chronic stress caused by the flower pot method. These data might support the antidepressant activity of SSRIs, and may allude that investigating the rebound period following the flower pot protocol could be useful to detect antidepressant drug response. Markov analysis is a suitable method to study the sleep pattern.

Attenuation of anhedonia by cariprazine in the chronic mild stress model of depression.

The aim of this study was to evaluate whether chronic treatment with cariprazine, a dopamine D2 and D3 receptor partial agonist with preferential binding to D3 receptors, shows antidepressant-like effects in the chronic mild stress (CMS)-induced anhedonia model. Male Wistar rats were subjected to the CMS procedure for 7 weeks; nonstressed animals served as controls. For the last 5 weeks of the CMS procedure, rats were injected once daily with vehicle, imipramine (10 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.01, 0.03, 0.065, 0.25, and 1.0 mg/kg). Activity in reversing CMS-induced decreases in consumption of 1% solution of sucrose was measured. CMS significantly reduced sucrose intake. Imipramine, and both doses of aripiprazole and cariprazine 0.03, 0.065, and 0.25 mg/kg significantly attenuated CMS-induced reductions in sucrose intake; the lowest and highest cariprazine doses (0.01 and 1 mg/kg) did not have this effect. Cariprazine showed greater potency (ED50=0.052) relative to aripiprazole (ED50=4.4) in this model. Thus, in the rat CMS model, cariprazine showed antidepressant-like action with greater potency than aripiprazole. These results suggest that cariprazine may have clinical utility in the treatment of depression and the negative symptoms of schizophrenia.

Design of novel multiple-acting ligands towards SERT and 5-HT2C receptors.

This Letter describes our attempts to elaborate dually acting compounds possessing serotonin re-uptake transporter inhibitor and serotonin 5-HT2C receptor antagonist properties. A novel series of 1,3-diphenylureas and N-phenylbenzamides have thus been prepared and evaluated. Based on its in vitro and in vivo activities, as well as pharmacokinetic profile, compound 16a was identified as a lead compound. The synthesis and structure-activity relationship of this series of compounds is presented herein.

Thieno[2,3-b]pyridines as negative allosteric modulators of metabotropic GluR5 receptors: hit-to-lead optimization.

An HTS campaign of our corporate compound library resulted in thieno[2,3-b]pyridines derivative hits with mGluR5 negative allosteric modulator effects. During the hit-to-lead development our objective was to improve affinity, and to keep the ligand efficiency values at an acceptable level. After different modifications of the linker resulted in a 2-sulfonyl-thieno[2,3-b]pyridines derivative, which fulfilled the lead criteria.

Chronic escitalopram treatment caused dissociative adaptation in serotonin (5-HT) 2C receptor antagonist-induced effects in REM sleep, wake and theta wave activity.

Several multi-target drugs used in treating psychiatric disorders, such as antidepressants (e.g. agomelatine, trazodone, nefazodone, amitriptyline, mirtazapine, mianserin, fluoxetine) or most atypical antipsychotics, have 5-hydroxytryptamine 2C (5-HT2C) receptor-blocking property. Adaptive changes in 5-HT2C receptor-mediated functions are suggested to contribute to therapeutic effects of selective serotonin reuptake inhibitor (SSRI) antidepressants after weeks of treatment, at least in part. Beyond the mediation of anxiety and other functions, 5-HT2C receptors are involved in sleep regulation. Anxiety-related adaptive changes caused by antidepressants have been studied extensively, although sleep- and electroencephalography (EEG)-related functional studies are still lacking. The aim of this study was to investigate the effects of chronic SSRI treatment on 5-HT2C receptor antagonist-induced functions in different vigilance stages and on quantitative EEG (Q-EEG) spectra. Rats were treated with a single dose of the selective 5-HT2C receptor antagonist SB-242084 (1 mg/kg, i.p.) or vehicle at the beginning of passive phase following a 20-day-long SSRI (escitalopram; 10 mg/kg/day, osmotic minipump) or VEHICLE pretreatment. Fronto-parietal electroencephalogram, electromyogram and motility were recorded during the first 3 h of passive phase. We found that the chronic escitalopram pretreatment attenuated the SB-242084-caused suppression in rapid eye movement sleep (REMS). On the contrary, the 5-HT2C receptor antagonist-induced elevations in passive wake and theta (5-9 Hz) power density during active wake and REMS were not affected by the SSRI. In conclusion, attenuation in certain, but not all vigilance- and Q-EEG-related functions induced by the 5-HT2C receptor antagonist, suggests dissociation in 5-HT2C receptor adaptation.

Long-term effects of cariprazine exposure on dopamine receptor subtypes.

INTRODUCTION: All clinically effective antipsychotics are known to act on the dopaminergic system, and previous studies have demonstrated that repeated treatment with antipsychotics produced region-specific changes in dopamine receptor levels. Cariprazine is a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. We examined the effects of chronic cariprazine administration on dopamine receptor levels. METHODS: Rats were administered either vehicle or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Dopamine receptor levels were quantitated using autoradiographic assays on brain tissue sections from the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIPP), olfactory tubercle (OT), and islands of Calleja (ICj). RESULTS: Chronic treatment with cariprazine did not alter D1 receptor levels in any brain region tested. Cariprazine increased D2 receptor levels in mPFC (27%-43%), NAc (40%-45%), medial (41%-53%) and lateral (52%-63%) CPu, and HIPP (38%). Cariprazine dose-dependently upregulated D3 receptor levels in ICj (32%-57%), OT (27%-67%), and NAc shell (31%-48%). Repeated cariprazine treatment increased D4 receptor in NAc (53%-82%), medial (54%-98%) and lateral (58%-74%) CPu, and HIPP (38%-98%). CONCLUSION: Similar to other antipsychotics, cariprazine upregulated D2 and D4 receptor levels in various brain regions. Cariprazine was unique among antipsychotics in increasing D3 receptor levels, which may support its unique psychopharmacologic properties.

Age-related decline of various cognitive functions in well-experienced male rats treated with the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP).

Aging-associated cognitive disorders lack proper medication. To meet this need translation-wise, modification of the animal models is also required. In the present study, effect of the putative anti-aging compound (2R)-1-(1-benzofuran-2-yl)-N-propylpentane-2-amine ((-)BPAP, a deprenyl derivative) on age-related cognitive decline was investigated in experienced, aged Long-Evans rats. During their lifetime, animals had acquired knowledge in various cognitive assays. Their performance in these tests was then parallel followed from the age of 27 months until their death meanwhile half of them were treated with BPAP. Cognitive performance in various tasks showed different sensitivities/resistances to age-related impairment. Pot jumping performance (motor skill-learning) started to impair first, at 21 months of age, followed by decreasing performance in five-choice serial reaction time task (attention) at 26 months. Navigation performance in Morris water maze (spatial learning) started to decline at 31 months. Performance in a cooperation task (social cognition) started to decline the latest, at 34 months. Our findings suggest that in this process, the primary factor was the level of motivation to be engaged with the task and not losing the acquired knowledge. The average lifespan of the tested rat population was 36 months. BPAP could not improve the cognitive performance; neither could it prolong lifespan. A possible reason might be that dietary restriction and lifelong cognitive engagement had beneficial effects on cognitive capabilities and lifespan creating a "ceiling effect" for further improvement. The results confirmed that experienced animals provide a translationally relevant model to study age-related cognitive decline and measure the effect of putative anti-aging compounds.

Brain uptake and distribution of the dopamine D3 /D2 receptor partial agonist [11 C]cariprazine: an in vivo positron emission tomography study in nonhuman primates.

Cariprazine is a dopamine D(3)/D(2) receptor partial agonist antipsychotic candidate, which binds with high affinity to dopamine D(3) and D(2) receptors (with ∼10-fold higher in vitro affinity to D(3) vs. D(2) receptors) and with moderate affinity to 5-HT(1A) receptors. The main objective of the present molecular imaging investigation was to evaluate the uptake and reversible binding of 11-C labeled cariprazine in the nonhuman primate brain, in relation to the known distributions of dopamine D(2) and D(3) receptors. We examined the brains of two cynomolgus monkeys at baseline condition as well as during a pharmacological blocking condition, using unlabeled cariprazine or raclopride as blockers before injection of [(11) C]cariprazine. Of the total injected radioactivity, ∼7% entered the brain and ∼3-4% remained in the brain after 90 min, indicating good blood brain barrier penetration and slow washout. It was possible to block cariprazine binding with unlabeled cariprazine and raclopride indicating that [(11) C]cariprazine binds to dopamine D(3)/D(2) receptors. Nondisplaceable binding potential (BPND) measurements, using a simplified reference tissue model and cerebellum as the reference region, yielded values of ∼1.5 and 0.3 in the striatum and thalamus, respectively. Striatum BPND values were reduced by 80 and 85% following pretreatment with 0.1 mg/kg IV injection of unlabeled cariprazine and 1 mg/kg IV injection of unlabeled raclopride, respectively. The data confirm that cariprazine, a novel antipsychotic drug candidate, enters the nonhuman primate brain readily and binds to dopamine D(3)/D(2) receptors. Furthermore, in PET imaging [(11) C]cariprazine can effectively visualize dopamine D(3)/D(2) receptors in the nonhuman primate brain.

Using Appetitive Motivation to Train Mice for Spatial Learning in the Barnes Maze.

The Barnes maze, a well-known spatial-learning paradigm, is based on the innate fear of rodents of large open spaces and their drive to hide. However, additional aversive stimuli (strong light and threatening sounds) are often necessary to provoke the hiding response while rendering the method cumbersome and more stressful. Our objective was to establish a Barnes maze-learning paradigm in mice using palatable food as a reward. After habituating male C57BL6/J or NMRI mice to the reward, the experimenter and the apparatus, either a slow (2 trials/day) or a massive conditioning schedule (4 trials/day), was run. Acquisition training was carried out until mice could locate the reward box with a maximum of one hole error. Then, the box was replaced to another location (reversal phase). Mice needed to relearn the new position with the same criterion. One week later, retention trials were performed. Both strains could reach the learning criteria; in the massive training within a shorter period. Spatial memory was demonstrated in the reversal and retention trials. Our results show that palatable food can be used as an efficient motivator to acquire allocentric navigation in the Barnes maze with the additional advantage of being less stressful.

Effect of 5-HT5A antagonists in animal models of schizophrenia, anxiety and depression.

The few available data on the pharmacological effect of 5-HT5A receptors suggest that antagonists may have anxiolytic, antidepressant and antipsychotic activity. The aim of our study was to verify these suggestions in relevant animal models. Two 5-HT5A antagonist ligands, SB-699551-A (N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]cyclopentanepropanamide dihydrochloride) (3-60 mg/kg, intraperitoneally) and A-843277 (N-(2,6-dimethoxybenzyl)-N'[4-(4-fluorophenyl)thiazol-2-yl]guanidine) (3-30 mg/kg, intraperitoneally), were examined in the open-field test, in a foot-shock-induced ultrasonic vocalization test, in the forced swim test (FST) and in the amphetamine-induced and phencyclidine-induced hyperlocomotion tests to examine their effect on general behavioural patterns, and their anxiolytic-like, antidepressant-like and antipsychotic-like properties, respectively. In the open-field test, SB-699551-A induced sedation and A-843277 induced writhing. In the ultrasonic vocalization test, SB-699551-A reduced vocalizations, whereas A-843277 was ineffective. In the FST, SB-699551-A was ineffective and A-843277 reduced immobility, but only at the highest dose. In the amphetamine-induced and phencyclidine-induced hyperlocomotion test, both compounds were ineffective. SB-699551-A showed an anxiolytic-like property in the ultrasonic vocalization test; however, this compound has a sedative effect. A-843277 showed an antidepressant-like property in the FST, but its immobility-reducing effect may also be a consequence of abdominal irritation. Consequently, further investigations are required to define the therapeutic potential of 5-HT5A receptor ligands in anxiety, depression and schizophrenia models.

Assessment of the effects of NS11394 and L-838417, α2/3 subunit-selective GABA(A) [corrected] receptor-positive allosteric modulators, in tests for pain, anxiety, memory and motor function.

The aim of the present paper was to study the effects of GABAA receptor-positive modulators (L-838417 and NS11394) showing a preference for α2/3 subunits of the GABAA receptor, in models of pain, anxiety, learning, memory and motor function. These compounds have been suggested to have a favourable therapeutic profile over nonselective compounds such as diazepam. In this study, we tested both compounds for their effects in rat models of formalin-induced pain, spinal nerve-ligation-induced mechanical allodynia, plus maze, open field, rotarod, balance beam walking, contextual fear conditioning and Morris water maze. Both compounds exerted analgesic, but no anxiolytic effects. However, they induced motor side-effects, and learning and memory impairment at similar doses. Therefore, the anxiolytic effect and the lack of side-effects of these compounds, as described in the literature, could not be confirmed in the present study.

Discovery of cariprazine (RGH-188): a novel antipsychotic acting on dopamine D3/D2 receptors.

Medicinal chemistry optimization of an impurity isolated during the scale-up synthesis of a pyridylsulfonamide type dopamine D(3)/D(2) compound (1) led to a series of new piperazine derivatives having affinity to both dopamine D(3) and D(2) receptors. Several members of this group showed excellent pharmacokinetic and pharmacodynamic properties as demonstrated by outstanding activities in different antipsychotic tests. The most promising representative, 2m (cariprazine) had good absorption, excellent brain penetration and advantageous safety profile. Based on its successful clinical development we are looking forward to the NDA filing of cariprazine in 2012.

Corrigendum: Intracerebroventricularly Injected Streptozotocin Exerts Subtle Effects on the Cognitive Performance of Long-Evans Rats.

[This corrects the article DOI: 10.3389/fphar.2021.662173.].

Introduction of a pharmacological neurovascular uncoupling model in rats based on results of mice.

Our aim was to establish a pharmacologically induced neurovascular uncoupling (NVU) method in rats as a model of human cognitive decline. Pharmacologically induced NVU with subsequent neurological and cognitive defects was described in mice, but not in rats so far. We used 32 male Hannover Wistar rats. NVU was induced by intraperitoneal administration of a pharmacological "cocktail" consisting of N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH, a specific inhibitor of epoxyeicosatrienoic acid-producing epoxidases, 5 mg kg-1), L-NG-nitroarginine methyl ester (L-NAME, a nitric oxide synthase inhibitor, 10 mg kg-1) and indomethacin (a nonselective inhibitor of cyclooxygenases, 1 mg kg-1) and injected twice daily for 8 consecutive days. Cognitive performance was tested in the Morris water-maze and fear-conditioning assays. We also monitored blood pressure. In a terminal operation a laser Doppler probe was used to detect changes in blood-flow (CBF) in the barrel cortex while the contralateral whisker pad was stimulated. Brain and small intestine tissue samples were collected post mortem and examined for prostaglandin E2 (PGE2) level. Animals treated with the "cocktail" showed no impairment in their performance in any of the cognitive tasks. They had higher blood pressure and showed cca. 50% decrease in CBF. Intestinal bleeding and ulcers were found in some animals with significantly decreased levels of PGE2 in the brain and small intestine. Although we could evoke NVU by the applied mixture of pharmacons, it also induced adverse side effects such as hypertension and intestinal malformations while the treatment did not cause cognitive impairment. Thus, further refinements are still required for the development of an applicable model.

Performance of the intracerebroventricularly injected streptozotocin Alzheimer's disease model in a translationally relevant, aged and experienced rat population.

The intracerebroventricularly (icv) injected streptozotocin (STZ) induced brain state is a widely used model of sporadic Alzheimer-disease (AD). However, data have been generated in young, naive albino rats. We postulate that the translationally most relevant animal population of an AD model should be that of aged rats with substantial learning history. The objective of the study was thus to probe the model in old rats with knowledge in various cognitive domains. Long-Evans rats of 23 and 10 months age with acquired knowledge in five-choice serial reaction time task (5-CSRTT), a cooperation task, Morris water-maze (MWM) and "pot-jumping" exercise were treated with 3 × 1.5 mg/kg icv. STZ and their performance were followed for 3 months in the above and additional behavioral assays. Both STZ-treated age groups showed significant impairment in the MWM (spatial learning) and novel object recognition test (recognition memory) but not in passive avoidance and fear conditioning paradigms (fear memory). In young STZ treated rats, significant differences were also found in the 5CSRTT (attention) and pot jumping test (procedural learning) while in old rats a significant increase in hippocampal phospho-tau/tau protein ratio was observed. No significant difference was found in the cooperation (social cognition) and pairwise discrimination (visual memory) assays and hippocampal ß-amyloid levels. STZ treated old animals showed impulsivity-like behavior in several tests. Our results partly coincide with partly deviate from those published on young, albino, unexperienced rats. Beside the age, strain and experience level of the animals differences can also be attributed to the increased dose of STZ, and the applied food restriction regime. The observed cognitive and non-cognitive activity pattern of icv. STZ in aged experienced rats call for more extensive studies with the STZ model to further strengthen and specify its translational validity.