Perinatal testosterone, or its metabolite estradiol, organize the brain toward a male phenotype. Male rodents with insufficient testosterone during this period fail to display sexual behavior and partner preference for receptive females in adulthood. However, cohabitation with non-reproductive conspecifics under the influence of a D2 agonist facilitates the expression of conditioned partner preference via Pavlovian learning in gonadally intact male rats. In the present experiment, three groups of neonatal PD1 males (N = 12/group) were either gonadectomized (GDX), sham-GDX, or left intact and evaluated for social preferences and sexual behaviors as adults. We then examined whether the effects of GDX could be reversed by conditioning the males via cohabitation with receptive females under the effects of the D2 agonist quinpirole (QNP) or saline, along with the size of some brain regions, such as the sexually dimorphic nucleus of the preoptic area (SDN-POA), suprachiasmatic nucleus (SCN), posterior dorsal medial amygdala (MeApd) and ventromedial hypothalamus (VMH). Results indicated that neonatal GDX resulted in the elimination of male-typical sexual behavior, an increase in same-sex social preference, and a reduction of the area of the SDN-POA. However, GDX-QNP males that underwent exposure to receptive females in adulthood increased their social preference for females and recovered the size in the SDN-POA. Although neonatal GDX impairs sexual behavior and disrupts partner preference and brain dimorphism in adult male rats, Pavlovian conditioning under enhanced D2 agonism ameliorates the effects on social preference and restores brain dimorphism in the SDN-POA without testosterone.

• MeSH
• area praeoptica * metabolismus   MeSH
• chinpyrol farmakologie   MeSH
• kastrace MeSH
• krysa rodu rattus MeSH
• mozek MeSH
• pohlavní dimorfismus * MeSH
• těhotenství MeSH
• testosteron farmakologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články 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.

• MeSH
• antagonisté dopaminu D2 farmakologie   MeSH
• chinpyrol farmakologie   MeSH
• cingulární gyrus účinky léků   fyziologie   MeSH
• hipokampus účinky léků   fyziologie   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
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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

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.

• 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

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

Dopamine-mediated neurotransmission is widely studied with respect to motivation, motor activity and cognitive processes. The aim of the present study was to evaluate the role of D2 receptors in the behavior of rats in the active allothetic place avoidance (AAPA) task. D2 receptor agonist quinpirole and antagonist sulpiride were administered intraperitoneally 20min prior to behavioral testing. Administration of quinpirole led to dose-dependent increase of locomotion; the spatial efficiency was spared across the dose range studied (0.05-1.0mg/kg). In contrast, sulpiride decreased locomotor activity at a dose not influencing spatial efficiency (60mg/kg); the highest dose of sulpiride (100mg/kg) caused a deficit in both locomotor and spatial behaviors. The results suggest a relatively lesser importance of D2 receptors for spatial efficiency in the AAPA task, with a predominant influence of D2 receptor ligands on motor activity.

• MeSH
• agonisté dopaminu farmakologie   MeSH
• analýza rozptylu MeSH
• antagonisté dopaminu farmakologie   MeSH
• chinpyrol farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• financování organizované MeSH
• krysa rodu rattus MeSH
• lokomoce účinky léků   MeSH
• potkani Long-Evans MeSH
• prostorové chování účinky léků   MeSH
• receptory dopaminu D2 fyziologie   MeSH
• sulpirid farmakologie   MeSH
• učení vyhýbat se účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH