Significant portion of OCD patients fail to attain a treatment response. Utilizing the complementary knowledge from human multimodal neuroimaging and animal model (quinpirole sensitization) we aim to remediate the major knowledge gaps in OCD and elucidate role of glutamate, brain structure-function linking, and neurochemical interactions within neuronal circuits of OCD. We will primarily focus on the anterior cingulate (ACC) identified as a candidate region for OCD development by our previous studies. In a group of 40 non-medicated patients (and control subjects) we will assess the morphometry, connectivity, and glutamate in the ACC and other brain areas. The human neuroimaging results will be interpreted using animal model complementing our heuristic framework by data not measurable in humans. Animal part then aims at testing neurochemical interactions (microdialysis), functional connectivity (qEEG) and immediate-early gene imaging. Our results will contribute to OCD neurobiology elucidation and outline novel therapies based on regional neurostimulation and glutamate modulation.

Významná část pacientů s OCD nedosáhne uspokojivé léčebné odpovědi. Využitím komplementárních informací z humánního zobrazení mozku a animálního modelu (senzitizace quinpirolem) cílíme na hlavní nedostatky v poznání OCD a objasníme roli glutamátu, vztah strukturálních a funkčních změn mozku a neurochemické interakce v neuronálních okruzích OCD. Primárně se pak zaměříme na přední cingulum (ACC), které jsme v předchozích studiích identifikovali jako kandidátní region pro rozvoj OCD. Ve skupině 40 nemedikovaných OCD pacientů (a zdravých kontrol) provedeme hodnocení morfometrie, konektivity a hladiny glutamátu v ACC a dalších oblastí mozku. Humánní neurozobrazovací výsledky budeme interpretovat s využitím animálního modelu, který doplní náš heuristický rámec o data, která nejsou měřitelná u lidí. Animální část bude hodnotit neurochemické interakce (microdialýza), funkční konektivitu (qEEG) a expresi časných genů. Naše výsledky přispějí k pochopení neurobiologie OCD a naznačí nové možnosti léčby založené na regionální neurostimulaci a modulaci glutamátu.

• MeSH
• chinpyrol MeSH
• cingulární gyrus patofyziologie   MeSH
• elektroencefalografie MeSH
• glutamin MeSH
• kontrolní skupiny MeSH
• kyselina glutamová MeSH
• magnetická rezonanční spektroskopie MeSH
• magnetická rezonanční tomografie MeSH
• modely nemocí na zvířatech MeSH
• neuroplasticita MeSH
• neurotransmiterové látky MeSH
• obsedantně kompulzivní porucha patofyziologie   MeSH
• okamžité časné geny MeSH
• translační biomedicínský výzkum MeSH

• Konspekt
• Patologie. Klinická medicína
• NLK Obory
• neurologie
• psychiatrie
• biochemie
• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Obsessive-compulsive disorder (OCD) is a chronic psychiatric illness and 1 of the most common anxiety disorders with the prevalence of 3%. Although its pathogenesis remains unclear, the traditional model focused on alternations in the serotonin system. Selective serotonin reuptake inhibitors provide the most effective treatment; however, as much as 40-60% of patients do not respond to antidepressants therapy. Thus, attention has shifted towards other neurotransmitter systems and related neuroanatomical structures. Recently, there is extensive evidence showing a key role of glutamate pathways abnormalities within the cortico-striatal-thalamo-cortical circuitry and temporal lobes in OCD pathogenesis. In this review, we link together the existent neuroanatomical, neurophysiological, and neuropsychological evidence to argue for potential benefits of adjuvant treatment with glutamatergic agents, especially memantine. By a targeted de-excitation effect on the glutamatergic system in the temporal lobes and connected brain regions, memantine might further alleviate OCD symptoms. This effect should be even more pronounced in certain subtypes of patients with specific cognitive deficits and maladaptive compensatory memory processes (e.g., checkers).

• MeSH
• glutamátové receptory metabolismus   MeSH
• kognitivní poruchy etiologie   MeSH
• kyselina glutamová metabolismus   MeSH
• látky působící na systém excitačních aminokyselin terapeutické užití   MeSH
• lidé MeSH
• mozek účinky léků   metabolismus   MeSH
• neuropsychologické testy MeSH
• obsedantně kompulzivní porucha komplikace   farmakoterapie   metabolismus   patologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Latent toxoplasmosis, the life-long presence of dormant stages of Toxoplasma in immunoprivileged organs and of anamnestic IgG antibodies in blood, affects about 30% of humans. Infected subjects have an increased incidence of various disorders, including schizophrenia. Several studies, as well as the character of toxoplasmosis-associated disturbance of neurotransmitters, suggest that toxoplasmosis could also play an etiological role in Obsessive-Compulsive Disorder (OCD). METHODS: The aim of the present cross-sectional study performed on a population of 7471 volunteers was to confirm the association between toxoplasmosis and OCD, and toxoplasmosis and psychological symptoms of OCD estimated by the standard Obsessive-Compulsive Inventory-Revised (OCI-R). RESULTS: Incidence of OCD was 2.18% (n=39) in men and 2.28% (n=83) in women. Subjects with toxoplasmosis had about a 2.5 times higher odds of OCD and about a 2.7 times higher odds of learning disabilities. The incidence of 18 other neuropsychiatric disorders did not differ between Toxoplasma-infected and Toxoplasma-free subjects. The infected subjects, even the OCD-free subjects, scored higher on the OCI-R. LIMITATIONS: Examined subjects provided the information about their toxoplasmosis and OCD statuses themselves, which could result in underrating the strength of observed associations. CONCLUSIONS: The results confirmed earlier reports of the association between toxoplasmosis and OCD. They also support recent claims that latent toxoplasmosis is in fact a serious disease with many impacts on quality of life of patients.

• MeSH
• dospělí MeSH
• kočky MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• neparametrická statistika MeSH
• obsedantně kompulzivní porucha diagnóza   parazitologie   psychologie   MeSH
• průřezové studie MeSH
• schizofrenie diagnóza   parazitologie   MeSH
• Toxoplasma MeSH
• toxoplazmóza komplikace   přenos   MeSH
• zvířata MeSH
• Check Tag
• dospělí MeSH
• kočky MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články 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.

• 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

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.

• MeSH
• chinpyrol škodlivé účinky   MeSH
• chování zvířat MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• neurobehaviorální symptomy MeSH
• obsedantně kompulzivní porucha * patofyziologie   MeSH
• reprodukovatelnost výsledků * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH