We designed a behavioral task called One-Trial Trace Escape Reaction (OTTER), in which rats incidentally associate two temporally discontinuous stimuli: a neutral acoustic cue (CS) with an aversive stimulus (US) which occurs two seconds later (CS-2s-US sequence). Rats are first habituated to two similar environmental contexts (A and B), each consisting of an interconnected dark and light chamber. Next, rats experience the CS-2s-US sequence in the dark chamber of one of the contexts (either A or B); the US is terminated immediately after a rat escapes into the light chamber. The CS-2s-US sequence is presented only once to ensure the incidental acquisition of the association. The recall is tested 24 h later when rats are presented with only the CS in the alternate context (B or A), and their behavioral response is observed. Our results show that 59% of the rats responded to the CS by escaping to the light chamber, although they experienced only one CS-2s-US pairing. The OTTER task offers a flexible high throughput tool to study memory acquired incidentally after a single experience. Incidental one-trial acquisition of association between temporally discontinuous events may be one of the essential components of episodic memory formation.

• MeSH
• krysa rodu Rattus MeSH
• rozpomínání MeSH
• strach fyziologie   MeSH
• úniková reakce MeSH
• vydry * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Maternal immune activation has been identified as a significant risk factor for schizophrenia. Using rodent models, past work has demonstrated various behavioral and brain impairments in offspring after immune-activating events. We applied 5 mg/kg of poly(I:C) on gestation day 9 to pregnant mouse dams, whose offspring were then stressed during puberty. We show impairments in attentional set-shifting in a T-maze, and a decreased number of parvalbumin-positive interneurons in the hippocampus as a result of peripubertal stress specifically in females.

• Klíčová slova
• Behavioral tests, Cognitive deficit, Immunochallenge, Interneurons, Maternal immune activation, Mouse, Poly(I:C), Prenatal infection, Schizophrenia,
• MeSH
• chování zvířat fyziologie   MeSH
• exekutivní funkce fyziologie   MeSH
• hipokampus cytologie   MeSH
• infekční komplikace v těhotenství * chemicky indukované   imunologie   MeSH
• interneurony cytologie   MeSH
• kognitivní dysfunkce etiologie   patologie   patofyziologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• poly I-C aplikace a dávkování   MeSH
• pozornost fyziologie   MeSH
• psychický stres komplikace   patologie   patofyziologie   MeSH
• schizofrenie etiologie   imunologie   patologie   patofyziologie   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice chemicky indukované   patologie   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• poly I-C MeSH

Quinpirole (QNP) sensitization is a well-established model of stereotypical checking relevant to obsessive-compulsive disorder. Previously, we found that QNP-treated rats display deficits in hippocampus-dependent tasks. The present study explores the expression of immediate early genes (IEG) during QNP-induced stereotypical checking in the hippocampus, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and medial prefrontal cortex (mPFC). Adult male rats were injected with QNP (0.5 mg/mL/kg; n = 15) or saline (n = 14) daily for 10 days and exposed to an arena enriched with two objects. Visits to the objects and the corners of the arena were recorded. QNP-treated rats developed an idiosyncratic pattern of visits that persisted across experimental days. On day 11, rats were exposed to the arena twice for 5 min and sacrificed. The expression of IEGs Arc and Homer1a was determined using cellular compartment analysis of temporal activity by fluorescence in situ hybridization. IEG-positive nuclei were counted in the CA1 area of the hippocampus, ACC, OFC, and mPFC. We found significantly fewer IEG-positive nuclei in the CA1 in QNP-treated rats compared to controls. The overlap between IEG expressing neurons was comparable between the groups. We did not observe significant differences in IEG expression between QNP treated and control rats in ACC, OFC, and mPFC. In conclusion, treatment of rats with quinpirole decreases plasticity-related activity in the hippocampus during stereotypical checking.

• Klíčová slova
• Arc, Homer1, hippocampus, obsessive-compulsive disorder, quinpirole, stereotypical checking,
• MeSH
• antagonisté dopaminu D2 farmakologie   MeSH
• chinpyrol farmakologie   MeSH
• cingulární gyrus účinky léků   fyziologie   MeSH
• hipokampus účinky léků   fyziologie   MeSH
• krysa rodu Rattus MeSH
• neurony účinky léků   metabolismus   MeSH
• neuroplasticita účinky léků   fyziologie   MeSH
• okamžité časné geny MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Long-Evans MeSH
• prefrontální mozková kůra účinky léků   fyziologie   MeSH
• receptory dopaminu D2 metabolismus   MeSH
• receptory dopaminu D3 antagonisté a inhibitory   MeSH
• regulace genové exprese účinky léků   MeSH
• stereotypní chování účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antagonisté dopaminu D2 MeSH
• chinpyrol MeSH
• receptory dopaminu D2 MeSH
• receptory dopaminu D3 MeSH

RATIONALE: Chronic quinpirole (QNP) sensitization is an established animal model relevant to obsessive-compulsive disorder (OCD) that has been previously shown to induce several OCD-like behavioral patterns, such as compulsive-like checking and increased locomotion. OBJECTIVES: In current study we explored the effect of antiglutamatergic drugs, memantine and riluzole, on cognitive and behavioral performance of QNP sensitized rats. METHODS: During habituation phase, the rats (N = 56) were injected with QNP (0.25 mg/kg) or saline solution (every other day up to 10 injections) and placed into rotating arena without foot shocks for 50-min exploration. Active place avoidance task in rotating arena with unmarked to-be-avoided shock sector was used during acquisition phase. Rats were injected with memantine (1 mg/kg or 5 mg/kg), riluzole (1 mg/kg or 5 mg/kg) or saline solution 30 min before the trial and with QNP (0.25 mg/kg) or saline right before they were placed inside the rotating arena with 60° unmarked shock sector. Locomotion and number of entrances into the shock sector were recorded. RESULTS: QNP sensitization led to a robust deficit in place learning. However, neither memantine nor riluzole did reverse or alleviate the deficit induced by QNP. Contrarily, memantine significantly aggravated QNP induced deficit. CONCLUSIONS: The exacerbation of cognitive deficit following antiglutamatergic agents could be mediated by decreased glutamate concentration in nucleus accumbens and decreased hippocampal activation in the QNP sensitization model.

• Klíčová slova
• Active allothetic place avoidance task, Memantine, Obsessive-compulsive disorder, Quinpirole, Riluzole,
• MeSH
• agonisté dopaminu farmakologie   MeSH
• antagonisté excitačních aminokyselin farmakologie   MeSH
• chinpyrol farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• kognice účinky léků   MeSH
• krysa rodu Rattus MeSH
• memantin farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• obsedantně kompulzivní porucha * MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Long-Evans MeSH
• riluzol farmakologie   MeSH
• učení účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté dopaminu MeSH
• antagonisté excitačních aminokyselin MeSH
• chinpyrol MeSH
• memantin MeSH
• riluzol MeSH

[This corrects the article on p. 42 in vol. 9, PMID: 29487522.].

• Klíčová slova
• animal model, behavior, chronic treatment, dizocilpine, rats, schizophrenia, western blot,
• Publikační typ
• časopisecké články MeSH
• tisková chyba MeSH

The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These results support the face validity, but not construct validity of this model. We suggest that chronic treatment of adolescent and adult rats does not constitute a plausible animal model of schizophrenia.

• Klíčová slova
• animal model, behavior, chronic treatment, dizocilpine, rats, schizophrenia, western blot,
• Publikační typ
• časopisecké články MeSH

Adult neurogenesis in the dentate gyrus adds a substantial number of new functional neurons to the hippocampus network in rodents. To date, however, the function of these new granule cells remains unclear. We conducted an experiment to assess the contribution of adult neurogenesis in the dentate gyrus to acquisition and reversal learning in a task that predominantly requires generalization of a rule. Young adult male Long-Evans rats were repeatedly administered either a cytostatic temozolomide or saline for a period of four weeks (3 injections per week). Post treatment, animals were injected with bromodeoxyuridine to quantify adult neurogenesis in the dentate gyrus. For behavioral assessment we used hippocampus-dependent active place avoidance with reversal in a Carousel maze. Animals first learned to avoid a 60° sector on the rotating arena. Afterwards, sector was relocated to the opposite side of the rotating arena (reversal). The administration of temozolomide significantly improved the reversal performance compared to saline-treated rats. Our results suggest a significant, level-dependent, improvement of reversal learning in animals with reduced adult neurogenesis in hippocampus.

• Klíčová slova
• Active avoidance, Adult neurogenesis, Discrimination, Generalization, Hippocampus, Reversal,
• MeSH
• antitumorózní látky alkylující farmakologie   MeSH
• dakarbazin analogy a deriváty   farmakologie   MeSH
• gyrus dentatus účinky léků   MeSH
• krysa rodu Rattus MeSH
• neurogeneze účinky léků   MeSH
• neurony účinky léků   MeSH
• potkani Long-Evans MeSH
• prostorové učení účinky léků   MeSH
• reverzní učení účinky léků   MeSH
• temozolomid MeSH
• učení vyhýbat se účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky alkylující MeSH
• dakarbazin MeSH
• temozolomid MeSH

Quinpirole (QNP) sensitization is one of the commonly used animal models of obsessive-compulsive disorder (OCD). We have previously shown that QNP-sensitized animals display a robust cognitive flexibility deficit in an active place avoidance task with reversal in Carousel maze. This is in line with numerous human studies showing deficits in cognitive flexibility in OCD patients. Here we explored the effect of clomipramine, an effective OCD drug that attenuates compulsive checking in QNP, on sensitized rats in acquisition and reversal performances in an active place avoidance task. We found that the addition of clomipramine to QNP-sensitization impairs acquisition learning to a degree that reversal learning could not be tested. In a hippocampal-independent two-way active avoidance task clomipramine did not have an effect on acquisition learning in QNP-treated rats; suggesting that the detrimental effect of clomipramine is hippocampus based. We also tested the effect of risperidone in QNP-sensitized animals, which is not effective in OCD treatment. Risperidone also marginally impaired acquisition learning of QNP-sensitized animals, but not reversal. Moreover, we explored the effect of the augmentation of clomipramine treatment with risperidone in QNP-sensitized rats- a common step in treating SRI-unresponsive OCD patients. Only under this treatment regime animals were unimpaired in both acquisition and reversal learning. Augmentation of SRI with neuroleptics therefore could be beneficial for improving cognitive flexibility, and possibly be considered a first line of treatment in patients with reduced cognitive flexibility.

• Klíčová slova
• Animal model, Antidepressant, Antipsychotics, Obsessive-compulsive disorder, Quinpirole, Rat,
• MeSH
• agonisté dopaminu toxicita   MeSH
• analýza rozptylu MeSH
• antagonisté serotoninu farmakologie   MeSH
• bludiště - učení účinky léků   MeSH
• chinpyrol toxicita   MeSH
• elektrický šok MeSH
• hipokampus účinky léků   fyziologie   MeSH
• klomipramin terapeutické užití   MeSH
• krysa rodu Rattus MeSH
• lokomoce účinky léků   MeSH
• modely nemocí na zvířatech MeSH
• obsedantně kompulzivní porucha chemicky indukované   farmakoterapie   MeSH
• potkani Long-Evans MeSH
• risperidon farmakologie   MeSH
• selektivní inhibitory zpětného vychytávání serotoninu terapeutické užití   MeSH
• učení vyhýbat se účinky léků   MeSH
• úniková reakce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• agonisté dopaminu MeSH
• antagonisté serotoninu MeSH
• chinpyrol MeSH
• klomipramin MeSH
• risperidon MeSH
• selektivní inhibitory zpětného vychytávání serotoninu MeSH

Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with 1-3% prevalence. OCD is characterized by recurrent thoughts (obsessions) and repetitive behaviors (compulsions). The pathophysiology of OCD remains unclear, stressing the importance of pre-clinical studies. The aim of this article is to critically review a proposed animal model of OCD that is characterized by the induction of compulsive checking and behavioral sensitization to the D2/D3 dopamine agonist quinpirole. Changes in this model have been reported at the level of brain structures, neurotransmitter systems and other neurophysiological aspects. In this review, we consider these alterations in relation to the clinical manifestations in OCD, with the aim to discuss and evaluate axes of validity of this model. Our analysis shows that some axes of validity of quinpirole sensitization model (QSM) are strongly supported by clinical findings, such as behavioral phenomenology or roles of brain structures. Evidence on predictive validity is contradictory and ambiguous. It is concluded that this model is useful in the context of searching for the underlying pathophysiological basis of the disorder because of the relatively strong biological similarities with OCD.

• Klíčová slova
• OCD, animal model, brain circuits, human, quinpirole, rat,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Dopamine plays a role in generating flexible adaptive responses in changing environments. Chronic administration of D2-like agonist quinpirole (QNP) induces behavioral sensitization and stereotypical behaviors reminiscent of obsessive-compulsive disorder (OCD). Some of these symptoms persist even after QNP discontinuation. In QNP-sensitization, perseverative behavior has often been implicated. To test the effect of QNP-sensitization on reversal learning and its association with perseveration we selected an aversively motivated hippocampus-dependent task, active place avoidance on a Carousel. Performance was measured as the number of entrances into a to-be-avoided sector (errors). We tested separately QNP-sensitized rats in QNP-drugged and QNP-undrugged state in acquisition and reversal tasks on the Carousel. In acquisition learning there were no significant differences between groups and their respective controls. In reversal, QNP-sensitized drugged rats showed a robust but transient increase in number of errors compared to controls. QNP-sensitized rats in an undrugged state were not overtly different from the control animals but displayed an altered learning manifested by more errors at the beginning compensated by quicker learning in the second session compared to control animals. Importantly, performance was not associated with perseveration in neither QNP-sensitized drugged nor QNP-sensitized undrugged animals. The present results show that chronic QNP treatment induces robust reversal learning deficit only when the substance is continuously administered, and suggest that QNP animal model of OCD is also feasible model of cognitive alterations in this disorder.

• Klíčová slova
• behavior, cognitive coordination, flexibility, obsessive–compulsive disorder, quinpirole, rat, reversal,
• Publikační typ
• časopisecké články MeSH