BACKGROUND: Elevated brain levels of kynurenic acid (KYNA), a metabolite in the kynurenine pathway, are associated with cognitive dysfunctions, which are nowadays often considered as fundamental characteristics of several psychopathologies; however, the role of KYNA in mental illnesses, such as schizophrenia, is not fully elucidated. This study aimed to assess KYNA levels in the prefrontal cortex (PFC) of rats prenatally treated with methylazoxymethanol (MAM) acetate, i.e., a well-validated neurodevelopmental animal model of schizophrenia. The effects of an early pharmacological modulation of the endogenous cannabinoid system were also evaluated. METHODS: Pregnant Sprague-Dawley rats were treated with MAM (22 mg/kg, ip) or its vehicle at gestational day 17. Male offspring were treated with the cannabinoid CB1 receptor antagonist/inverse agonist AM251 (0.5 mg/kg/day, ip) or with the typical antipsychotic haloperidol (0.6 mg/kg/day, ip) from postnatal day (PND) 19 to PND39. The locomotor activity and cognitive performance were assessed in the novel object recognition test and the open field test in adulthood. KYNA levels in the PFC of prenatally MAM-treated rats were also assessed. RESULTS: A significant cognitive impairment was observed in prenatally MAM-treated rats (p < 0.01), which was associated with enhanced PFC KYNA levels (p < 0.05). The peripubertal AM251, but not haloperidol, treatment ameliorated the cognitive deficit (p < 0.05), by normalizing the PFC KYNA content in MAM rats. CONCLUSIONS: The present findings suggest that the cognitive deficit observed in MAM rats may be related to enhanced PFC KYNA levels which could be, in turn, mediated by the activation of cannabinoid CB1 receptor. These results further support the modulation of brain KYNA levels as a potential therapeutic strategy to ameliorate the cognitive dysfunctions in schizophrenia.

• Klíčová slova
• AM251, Haloperidol, Kynurenine Pathway, Novel object recognition test, Peripubertal treatment, Schizophrenia,
• MeSH
• antipsychotika farmakologie   MeSH
• haloperidol farmakologie   MeSH
• kognitivní dysfunkce metabolismus   farmakoterapie   MeSH
• krysa rodu Rattus MeSH
• kyselina kynurenová * metabolismus   MeSH
• methylazoxymethanolacetát * analogy a deriváty   MeSH
• modely nemocí na zvířatech MeSH
• piperidiny farmakologie   MeSH
• potkani Sprague-Dawley * MeSH
• prefrontální mozková kůra * metabolismus   účinky léků   MeSH
• pyrazoly farmakologie   MeSH
• receptor kanabinoidní CB1 metabolismus   MeSH
• schizofrenie * metabolismus   farmakoterapie   MeSH
• těhotenství MeSH
• zpožděný efekt prenatální expozice * 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
• Názvy látek
• AM 251 MeSH Prohlížeč
• antipsychotika MeSH
• haloperidol MeSH
• kyselina kynurenová * MeSH
• methylazoxymethanolacetát * MeSH
• piperidiny MeSH
• pyrazoly MeSH
• receptor kanabinoidní CB1 MeSH

Hypofunctioning of NMDA receptors, and the resulting shift in the balance between excitation and inhibition, is considered a key process in the pathophysiology of schizophrenia. One important manifestation of this phenomenon is changes in neural oscillations, those above 30 Hz (i.e., gamma-band oscillations), in particular. Although both preclinical and clinical studies observed increased gamma activity following acute administration of NMDA receptor antagonists, the relevance of this phenomenon has been recently questioned given the reduced gamma oscillations typically observed during sensory and cognitive tasks in schizophrenia. However, there is emerging, yet contradictory, evidence for increased spontaneous gamma-band activity (i.e., at rest or under baseline conditions). Here, we use the sub-chronic phencyclidine (PCP) rat model for schizophrenia, which has been argued to model the pathophysiology of schizophrenia more closely than acute NMDA antagonism, to investigate gamma oscillations (30-100 Hz) in the medial prefrontal cortex of anesthetized animals. While baseline gamma oscillations were not affected, oscillations induced by train stimulation of the posterior dorsal CA1 (pdCA1) field of the hippocampus were enhanced in PCP-treated animals (5 mg/kg, twice daily for 7 days, followed by a 7-day washout period). This effect was reversed by pharmacological enhancement of endocannabinoid levels via systemic administration of URB597 (0.3 mg/kg), an inhibitor of the catabolic enzyme of the endocannabinoid anandamide. Intriguingly, the pharmacological blockade of CB1 receptors by AM251 unmasked a reduced gamma oscillatory activity in PCP-treated animals. The findings are consistent with the observed effects of URB597 and AM251 on behavioral deficits reminiscent of the symptoms of schizophrenia and further validate the potential for cannabinoid-based drugs as a treatment for schizophrenia.

• Klíčová slova
• CB1 receptors, Endocannabinoids, Hippocampus, Prefrontal cortex, URB597,
• MeSH
• amidohydrolasy * antagonisté a inhibitory   metabolismus   MeSH
• antagonisté excitačních aminokyselin farmakologie   aplikace a dávkování   MeSH
• benzamidy * farmakologie   MeSH
• endokanabinoidy metabolismus   MeSH
• fencyklidin * farmakologie   MeSH
• gama rytmus EEG fyziologie   účinky léků   MeSH
• karbamáty * farmakologie   MeSH
• krysa rodu Rattus MeSH
• kyseliny arachidonové metabolismus   farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• piperidiny * farmakologie   MeSH
• polynenasycené alkamidy metabolismus   farmakologie   MeSH
• potkani Sprague-Dawley MeSH
• prefrontální mozková kůra účinky léků   metabolismus   patofyziologie   MeSH
• pyrazoly farmakologie   MeSH
• schizofrenie * patofyziologie   metabolismus   farmakoterapie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• AM 251 MeSH Prohlížeč
• amidohydrolasy * MeSH
• anandamide MeSH Prohlížeč
• antagonisté excitačních aminokyselin MeSH
• benzamidy * MeSH
• cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester MeSH Prohlížeč
• endokanabinoidy MeSH
• fatty-acid amide hydrolase MeSH Prohlížeč
• fencyklidin * MeSH
• karbamáty * MeSH
• kyseliny arachidonové MeSH
• piperidiny * MeSH
• polynenasycené alkamidy MeSH
• pyrazoly MeSH

Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ9-tetrahydrocannabinol (aTHC) may affect the impact of prenatal methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure in adult rats. We found that MAM and pTHC-exposed rats, when compared to the control group (CNT), were characterized by adult phenotype relevant to schizophrenia, including social withdrawal and cognitive impairment, as revealed by social interaction test and novel object recognition test, respectively. At the molecular level, we observed an increase in cannabinoid CB1 receptor (Cnr1) and/or dopamine D2/D3 receptor (Drd2, Drd3) gene expression in the prefrontal cortex of adult MAM or pTHC-exposed rats, which we attributed to changes in DNA methylation at key regulatory gene regions. Interestingly, aTHC treatment significantly impaired social behavior, but not cognitive performance in CNT groups. In pTHC rats, aTHC did not exacerbate the altered phenotype nor dopaminergic signaling, while it reversed cognitive deficit in MAM rats by modulating Drd2 and Drd3 gene expression. In conclusion, our results suggest that the effects of peripubertal THC exposure may depend on individual differences related to dopaminergic neurotransmission.

• Klíčová slova
• dopamine D2/D3 receptors, methylazoxymethanol acetate, psychopathology, Δ9-tetrahydrocannabinol,
• MeSH
• dopamin metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• prefrontální mozková kůra účinky léků   metabolismus   MeSH
• receptory dopaminu D3 metabolismus   MeSH
• schizofrenie * chemicky indukované   MeSH
• těhotenství MeSH
• tetrahydrokanabinol * toxicita   MeSH
• zpožděný efekt prenatální expozice * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• dopamin MeSH
• receptory dopaminu D3 MeSH
• tetrahydrokanabinol * MeSH

Neural components enabling flexible cognition and behavior are well-established, and depend mostly on proper intercommunication within the prefrontal cortex (PFC) and striatum. However, dense projections from the ventral hippocampus (vHPC) alter the functioning of the medial PFC (mPFC). Dysfunctional hippocampo-prefrontal connectivity negatively affects the integrity of flexible cognition, especially in patients with schizophrenia. In this study, we aimed to test the role of the vHPC and mPFC in a place avoidance task on a rotating arena using two spatial flexibility task variants - reversal learning and set-shifting. To achieve this, we inactivated each of these structures in adult male Long-Evans rats by performing bilateral local muscimol (a GABAA receptor agonist) injections. A significantly disrupted performance was observed in reversal learning in the vHPC-inactivated, but not in the mPFC-inactivated rats. These results confirm the notion that the vHPC participates in some forms of behavioral flexibility, especially when spatial cues are needed. It seems, rather unexpectedly, that the mPFC is not taxed in these flexibility tasks on a rotating arena.

• Klíčová slova
• Behavioral flexibility, Carousel, Muscimol, Prefrontal cortex, Rotating arena, Ventral hippocampus,
• MeSH
• hipokampus účinky léků   fyziologie   MeSH
• krysa rodu Rattus MeSH
• muscimol farmakologie   MeSH
• pozornost účinky léků   fyziologie   MeSH
• prefrontální mozková kůra účinky léků   fyziologie   MeSH
• prostorové vidění účinky léků   fyziologie   MeSH
• receptory GABA-A - agonisté farmakologie   MeSH
• reverzní učení účinky léků   fyziologie   MeSH
• učení vyhýbat se účinky léků   fyziologie   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
• muscimol MeSH
• receptory GABA-A - agonisté MeSH

Perinatal exposure to Δ9-tetrahydrocannabinol (THC) affects brain development and might increase the incidence of psychopathology later in life, which seems to be related to a dysregulation of endocannabinoid and/or dopaminergic systems. We here evaluated the transcriptional regulation of the genes encoding for the cannabinoid CB1 receptor (Cnr1) and the dopamine D2 receptor (Drd2) in perinatal THC-(pTHC) exposed male rats, focusing on the role of DNA methylation analyzed by pyrosequencing. Simultaneously, the molecular and behavioral abnormalities at two different time points (i.e., neonatal age and adulthood) and the potential preventive effect of peripubertal treatment with cannabidiol, a non-euphoric component of Cannabis, were assessed. The DRD2 methylation was also evaluated in a cohort of subjects with schizophrenia. We observed an increase in both Cnr1 and Drd2 mRNA levels selectively in the prefrontal cortex of adult pTHC-exposed rats with a consistent reduction in DNA methylation at the Drd2 regulatory region, paralleled by social withdrawal and cognitive impairment which were reversed by cannabidiol treatment. These adult abnormalities were preceded at neonatal age by delayed appearance of neonatal reflexes, higher Drd2 mRNA and lower 2-arachidonoylglycerol (2-AG) brain levels, which persisted till adulthood. Alterations of the epigenetic mark for DRD2 were also found in subjects with schizophrenia. Overall, reported data add further evidence to the dopamine-cannabinoid interaction in terms of DRD2 and CNR1 dysregulation which could be implicated in the pathogenesis of schizophrenia spectrum disorders, suggesting that cannabidiol treatment may normalize pTHC-induced psychopathology by modulating the altered dopaminergic activity.

• Klíčová slova
• Cannabidiol, Cannabinoid CB1 receptor, DNA methylation, Dopamine D2 receptor, Epigenetics, Schizophrenia, THC,
• MeSH
• chování zvířat účinky léků   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• maternofetální výměna látek MeSH
• messenger RNA metabolismus   MeSH
• metylace DNA účinky léků   MeSH
• potkani Sprague-Dawley MeSH
• prefrontální mozková kůra účinky léků   metabolismus   MeSH
• receptor kanabinoidní CB1 genetika   MeSH
• receptory dopaminu D2 genetika   MeSH
• regulace genové exprese účinky léků   MeSH
• schizofrenie genetika   MeSH
• těhotenství MeSH
• tetrahydrokanabinol farmakologie   MeSH
• zpožděný efekt prenatální expozice * MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• messenger RNA MeSH
• receptor kanabinoidní CB1 MeSH
• receptory dopaminu D2 MeSH
• tetrahydrokanabinol 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

BACKGROUND: The study evaluated the effectiveness of EEG alpha 1, alpha 2 and theta power, along with prefrontal theta cordance (PFC), frontal and occipital alpha 1, alpha 2 asymmetry (FAA1/2, OAA1/2) at baseline and their changes at week 1 in predicting response to antidepressants. METHOD: Resting-state EEG data were recorded from 103 depressive patients that were treated in average for 5.1 ± 0.9 weeks with SSRIs (n = 57) and SNRIs (n = 46). RESULTS: Fifty-five percent of patients (n = 56) responded to treatment (i.e.reduction of Montgomery-Åsberg Depression Rating Scale score ≥ 50%) and 45% (n = 47) of treated subjects did not reach positive treatment outcome. No differences in EEG baseline alpha and theta power or changes at week 1 for prefrontal, frontal, central, temporal and occipital regions were found between responders and non-responders. Both groups showed no differences at baseline PFC, FAA1/2 and OAA1/2 as well as change of FAA1/2 at week 1. The only parameters associated with treatment outcome were decrease of PFC in responders and increase of OAA1/2 at week 1 in non-responders. There was no influence of the used antidepressant classes on the results. The PFC change at week 1 (PFCC) (area under curve-AUC = 0.75) showed only a numerically higher predictive ability than OAA change in alpha 1 (OAA1C, AUC = 0.64)/alpha 2 (OAA2C, AUC = 0.63). A combined model, where OAA1C was added to PFCC (AUC = 0.79), did not significantly improve response prediction. CONCLUSION: Besides PFCC, we found that OAA1C/OAA2C might be another candidate for EEG predictors of antidepressant response.

• Klíčová slova
• Alpha asymmetry, Antidepressants, Depressive disorder, Prediction of treatment outcome, Prefrontal theta cordance, QEEG,
• MeSH
• alfa rytmus EEG * účinky léků   fyziologie   MeSH
• antidepresiva farmakologie   MeSH
• depresivní poruchy * farmakoterapie   patofyziologie   MeSH
• dospělí MeSH
• elektroencefalografie metody   MeSH
• hodnocení výsledků zdravotní péče * MeSH
• inhibitory zpětného vychytávání serotoninu a noradrenalinu farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• prefrontální mozková kůra * účinky léků   patofyziologie   MeSH
• prognóza MeSH
• selektivní inhibitory zpětného vychytávání serotoninu farmakologie   MeSH
• theta rytmus EEG * účinky léků   fyziologie   MeSH
• týlní lalok * účinky léků   patofyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antidepresiva MeSH
• inhibitory zpětného vychytávání serotoninu a noradrenalinu MeSH
• selektivní inhibitory zpětného vychytávání serotoninu MeSH

The hyperpolarization-activated cyclic-nucleotide-gated non-selective cation (HCN) channels play a potential role in the neurological basis underlying drug addiction. However, little is known about the role of HCN channels in methamphetamine (METH) abuse. In the present study, we examined the changes in working memory functions of METH re-exposed mice through Morris water maze test, and investigated the protein expression of HCN1 channels and potential mechanisms underlying the modulation of HCN channels by Western blotting analysis. Mice were injected with METH (1 mg/kg, i.p.) once per day for 6 consecutive days. After 5 days without METH, mice were re-exposed to METH at the same concentration. We found that METH re-exposure caused an enhancement of working memory, and a decrease in the HCN1 channels protein expression in both hippocampus and prefrontal cortex. The phosphorylated extracellular regulated protein kinase 1/2 (p-ERK1/2), an important regulator of HCN channels, was also obviously reduced in hippocampus and prefrontal cortex of mice with METH re-exposure. Meanwhile, acute METH exposure did not affect the working memory function and the protein expressions of HCN1 channels and p-ERK1/2. Overall, our data firstly showed the aberrant protein expression of HCN1 channels in METH re-exposed mice with enhanced working memory, which was probably related to the down-regulation of p-ERK1/2 protein expression.

• MeSH
• down regulace účinky léků   fyziologie   MeSH
• draslíkové kanály biosyntéza   MeSH
• hipokampus účinky léků   metabolismus   MeSH
• hyperpolarizační iontové kanály řízené cyklickými nukleotidy antagonisté a inhibitory   biosyntéza   MeSH
• krátkodobá paměť účinky léků   fyziologie   MeSH
• lokomoce účinky léků   fyziologie   MeSH
• methamfetamin aplikace a dávkování   toxicita   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• náhodné rozdělení MeSH
• prefrontální mozková kůra účinky léků   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• draslíkové kanály MeSH
• Hcn1 protein, mouse MeSH Prohlížeč
• hyperpolarizační iontové kanály řízené cyklickými nukleotidy MeSH
• methamfetamin MeSH

There are a number of clinically effective treatments for stress-associated psychiatric diseases, including major depressive disorder (MDD). Nonetheless, many patients exhibit resistance to first-line interventions calling for novel interventions based on pathological mechanisms. Accumulating evidence implicates altered glutamate signaling in MDD pathophysiology, suggesting that modulation of glutamate signaling cascades may offer novel therapeutic potential. Here we report that JHU-083, our recently developed prodrug of the glutaminase inhibitor 6-diazo-5-oxo-L-norleucine (DON) ameliorates social avoidance and anhedonia-like behaviors in mice subjected to chronic social defeat stress (CSDS). JHU-083 normalized CSDS-induced increases in glutaminase activity specifically in microglia-enriched CD11b+ cells isolated from the prefrontal cortex and hippocampus. JHU-083 treatment also reverses the CSDS-induced inflammatory activation of CD11b+ cells. These results support the importance of altered glutamate signaling in the behavioral abnormalities observed in the CSDS model, and identify glutaminase in microglia-enriched CD11b+ cells as a pharmacotherapeutic target implicated in the pathophysiology of stress-associated psychiatric conditions such as MDD.

• MeSH
• antigeny CD11b * MeSH
• chování zvířat účinky léků   MeSH
• deprese etiologie   prevence a kontrola   MeSH
• diazooxonorleucin * farmakologie   MeSH
• glutaminasa účinky léků   MeSH
• hipokampus účinky léků   imunologie   metabolismus   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• prefrontální mozková kůra účinky léků   imunologie   metabolismus   MeSH
• prekurzory léčiv * farmakologie   MeSH
• psychický stres komplikace   MeSH
• signální transdukce MeSH
• zánět farmakoterapie   imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• antigeny CD11b * MeSH
• diazooxonorleucin * MeSH
• glutaminasa MeSH
• Itgam protein, mouse MeSH Prohlížeč
• prekurzory léčiv * MeSH

Chronic methamphetamine (meth) abuse often turns into a compulsive drug-taking disorder accompanied by persistent cognitive deficits and re-occurring psychosis. Possible common neurobiological substrates underlying meth-induced deficits and schizophrenia remain poorly understood. Serotonin 2A (5-HT2A) and metabotropic glutamate 2 (mGlu2) receptors co-regulate psychosis-like behaviors and cognitive function in animals. Therefore, in the present study we examined the effects of chronic exposure to three different drugs known to produce persistent deficits in sensorimotor gating and cognition [meth, phencyclidine (PCP) and MK-801] on the expression of 5-HT2A and mGlu2 within the rat medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and perirhinal cortex (PRh). Adult male rats underwent 14 days of: (a) meth self-administration (6 h/day), (b) phencyclidine (PCP; 5 mg/kg, twice/day) administration, or (c) MK-801 (0.3 mg/kg, twice/day) administration. Seven days after the discontinuation of drug administration, tissues of interest were collected for protein expression analysis. We found that despite different pharmacological mechanism of action, chronic meth, PCP, and MK-801 similarly dysregulated 5-HT2A and mGlu2, as indicated by an increase in the 5-HT2A/mGlu2 expression ratio in the mPFC (all three tested drugs), PRh (meth and PCP), and dHPC (MK-801 only). Complementary changes in G-protein expression (increase in Gαq and decrease in Gαi) were also observed in the mPFC of meth animals. Finally, we found that 5-HT2A/mGlu2 cooperation can be mediated in part by the formation of the receptor heteromer in some, but not all cortical regions. In summary, these data suggest that a shift towards increased availability (and G-protein coupling) of cortical 5-HT2A vs. mGlu2 receptors may represent a common neurobiological mechanism underlying the emergence of psychosis and cognitive deficits observed in subjects with meth use disorder and schizophrenia.

• Klíčová slova
• 5-HT2A, Heterocomplex, MK-801, Methamphetamine, Phencyclidine, mGlu2,
• MeSH
• dizocilpinmaleát farmakologie   MeSH
• fencyklidin farmakologie   MeSH
• imunoprecipitace MeSH
• krysa rodu Rattus MeSH
• methamfetamin aplikace a dávkování   farmakologie   MeSH
• perirhinální mozková kůra účinky léků   metabolismus   MeSH
• potkani Long-Evans MeSH
• potkani Wistar MeSH
• prefrontální mozková kůra účinky léků   metabolismus   MeSH
• protilátky imunologie   MeSH
• receptor serotoninový 5-HT2A imunologie   metabolismus   MeSH
• receptory metabotropního glutamátu metabolismus   MeSH
• reprodukovatelnost výsledků 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
• srovnávací studie MeSH
• Názvy látek
• dizocilpinmaleát MeSH
• fencyklidin MeSH
• metabotropic glutamate receptor 2 MeSH Prohlížeč
• methamfetamin MeSH
• protilátky MeSH
• receptor serotoninový 5-HT2A MeSH
• receptory metabotropního glutamátu MeSH