Active allothetic avoidance task (AAPA) could be a useful tool to study cognitive deficit of schizofrenia. In this task two different reference frames are created. The subject should distinguish which oriental frame is relevant for navigation and is proper for the solution of the task. This ability is called cognitive coordination. It is proved that the process of cognitive coordination is impaired in schizophrenic individuals, which comes to light in a Stroop test. Schizophrenia-like behavior can be modelled on the rats by a non-competitive NMDA receptor antagonist dizocipline (MK-801). The aim of these thesis was to study the existence of alternative strategies and the influence of different habituation on the performance of rats within AAPA. Furthermore, we have been studying the influence of MK-801 at a dose of 0.15mg / kg on the cognitive coordination in this task. We have found that the rats are able to learn AAPA task after pre-training without distal orientation cues, using relatively efficient alternative strategies. In these alternative strategies the idiothetic navigation is applied. The performance of rats in AAPA task is influenced by different conditions during habituation. We have proved that MK-801 at this dosage has no effect on cognitive performance of the rats in AAPA task, but...

Die vorliegende Arbeit beschäftigt sich mit dem Einfluss der NMDA-Rezeptorantagonisten, Memantin, MK-801, CGS und Ifenprodil auf die hypoxieinduzierte Zellschädigung an kortikalen Zellen der Ratte. Außerdem wurde der Einfluss von subtoxischen Konzentrationen von NMDA sowie von Roscovitin, einem Hemmer Cyclin-abhängiger Kinasen, auf die hypoxiebedingte Zellschädigung untersucht. Ziel dieser Arbeit war es, die neuroprotektive Wirkung dieser Substanzen zu erfassen. Zur Untersuchung der hypoxischen Schädigung wurden zwei 48-Well-Zellkulturplatten mit 15 Tage alten kortikalen Zellen der Ratte verwendet. Eine Kulturplatte wurde für vier Stunden mit HEPES(N-2-Hydroxyethylpiperazine-N’-2-Ethansulfonsäure)-Puffer (ohne Glucose) unter hypoxischen Bedingungen inkubiert. Die zweite Platte, mit glukorisiertem HEPES-Puffer, wurde für vier Stunden unter normoxischen Bedingungen inkubiert. Der HEPES-Puffer wurde nach vier Stunden entfernt, die Kulturplatten mit Dulbecco’s Modified Eagle Medium (DMEM) gewaschen und mit diesem Medium für 24 Stunden unter normoxischen Bedingungen inkubiert. Anschließend wurde das Medium ent¬fernt, durch NMDA, Memantin, Roscovitin, CGS und Ifenprodil ersetzt und die Ansätze für weitere 24 Stunden unter normoxischen Bedingungen inkubiert. Zur Beurteilung der Zellschädigung wurden der Aktivitätsanstieg der Laktat-Dehydrogenase (LDH), die Freisetzung freier Sauerstoffradikale und die Steigerung der Caspase-Aktivität bestimmt. Während die Bestimmung der LDH-Aktivität und die Freisetzung der freien Sauer¬stoff¬radikale nekrotische Veränderungen der Zellen charakterisiert, zeigt eine Zunahme der Caspase-Aktivität apoptotische Vorgänge an. LDH ist ein stabiles zytoplasmatisches Enzym, das in fast allen Körperzellen vorkommt. Beim Absterben der Zelle wird das Enzym durch die Schädigung der Plasmamembran aus der Zelle freigesetzt, so dass es zu einem Anstieg der LDH-Aktivität proportional zur Anzahl der toten Zellen kommt. Diese Aktivität wurde spektrophotometrisch mit einem Mikrotiterplatten-Lesegerät bestimmt. Die Ergebnisse des LDH-Tests zeigen, dass nach der 24-stündigen Behandlung der Zellen mit MK-801 die LDH-Aktivität um 11%, bei Roscovitin um 13%, bei Memantin (5 µM) um 56%, bei Memantin (0,5 µM) um 52% und mit NMDA (5 µM) um 44% signifikant vermindert wurde. Bei einer hypoxiebedingten Schädigung kortikaler Zellen kommt es auch zur Bildung freier Sauer¬stoff¬radikale. 2’,7’-Dichlorfluorescein Diacetat (2’,7’-H2DCF-DA) wird von den Zellen auf¬ge¬nommen und intrazellulär mit Sauerstoff- und Stickstoffspezies zum Fluoreszenz¬farb-stoff 2’,7’-Dichlorodihydrofluorescein (DCF) deacetyliert. DCF verbleibt dabei in den Zellen, so dass die Messung der Fluoreszenz der Zellen als Maß für intrazelluläre Oxidationsprozesse verwendet werden kann. Die DCF-Fluoreszenz-Änderung wurde mittels eines Fluorimeters gemessen und die daraus resultierenden Daten mit einer im Fluorimeter integrierten Software bearbeitet. Die Ergebnisse zeigen, dass die Freisetzung der freien Sauerstoffradikale, der hypoxiegeschädigten Zellen, signifikant durch Ifenprodil (10 µM) um 119%, Memantin (50 µM) um 88% und NMDA (5 µM) um 134% reduziert wurde. Die hypoxieinduzierte Zellmembranschädigung führt desweiteren zu einem Anstieg der Caspase-Aktivität. Mit Hilfe des Apo-One Homogeneous Caspase-3/7-Assays (Promega) wurde die Aktivität der Caspasen 3 und 7 fluorimetrisch bestimmt. Um die unterschiedliche Zelldichte in den Kulturschalen zu berücksichtigen, wurde eine Proteinbestimmung nach der Bicinchoninsäure-Methode (Smith et al. 1985) durchgeführt. Einen protektiven Effekt auf die Zellschädigung zeigen Memantin und NMDA in Bezug auf die Beeinflussung dieser Caspase-Aktivität. Der hypoxiebedingte Anstieg der Caspase-3-Aktivität konnte nach 24-stündiger Inkubation mit Memantin (5 µM) um 24%, mit Memantin (0,5 µM) um 28% und mit NMDA (5 µM) um 24% vermindert werden. CGS hat in diesen Versuchen keinen protektiven Einfluss auf die hypoxie¬induzierte Zellschädigung. Diese Arbeit zeigt, dass die Applikation niedriger NMDA-Konzentrationen neuroprotektive Effekte auf die Entwicklung der hypoxischen Schädigung von kortikalen Zellen der Ratte hat. Darüber hinaus wird vermutet, dass NMDA sogar einen trophischen Effekt auf das Über-leben der kortikalen Neurone ausübt. Dieser schützende Mechanismus von NMDA scheint denselben, wenn nicht sogar einen größeren protektiven Effekt wie Memantin zu induzieren. Um die Therapiemöglichkeiten der zerebralen Hypoxie durch neuroprotektive Medikamente zu optimieren, wären jedoch weitergehende Untersuchungen besonders als In-vivo-Modelle wünschenswert.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Excessive formation of reactive oxygen species (ROS) and disruption of glutamate uptake have been hypothesized as key mechanisms contributing to quinolinic acid (QA)- induced toxicity. Thus, here we investigate if the use of diphenyl diselenide (PhSe)2, guanosine (GUO) and MK-801, alone or in combination, could protect rat brain slices from QA-induced toxicity. QA (1 mM) increased ROS formation, thiobarbituric acid reactive substances (TBARS) and decreased cell viability after 2 h of exposure. (PhSe)2 (1 μM) protected against this ROS formation in the cortex and the striatum and also prevented decreases in cell viability induced by QA. (PhSe)2 (5 μM) prevented ROS formation in the hippocampus. GUO (10 and 100 μM) blocked the increase in ROS formation caused by QA and MK-801 (20 and 100 μM) abolished the pro-oxidant effect of QA. When the non effective concentrations were used in combination produced a decrease in ROS formation, mainly (PhSe)2 + GUO and (PhSe)2 + GUO + MK-801. These results demonstrate that this combination could be effective to avoid toxic effects caused by high concentrations of QA. Furthermore, the data obtained in the ROS formation and cellular viability assays suggest different pathways in amelioration of QA toxicity present in the neurodegenerative process. / A formação excessiva de espécies reativas de oxigênio (ROS) e alterações na captação de glutamato têm sido associadas como mecanismos chave que contribuem para toxicidade induzida pelo ácido quinolínico (AQ). Assim, nós investigamos se a utilização do disseleneto de difenila (PhSe)2, guanosina (GUO) e MK-801, isoladamente ou em combinação, podem proteger as fatias de regiões cerebrais de ratos da toxicidade induzida por AQ. AQ (1 mM) aumentou a formação de ROS, substâncias reativas ao ácido tiobarbitúrico (TBARS) e diminuiu a viabilidade celular após 2h de exposição. (PhSe)2 (1 μM) protegeu contra esta formação de ROS no córtex e no estriado e além disso preveniu a diminuição da viabilidade celular induzida pelo AQ. (PhSe)2 (5 μM) preveniu a formação de ROS no hipocampo. GUO (10 e 100 μM) bloqueou o aumento na formação de ROS causada pelo AQ e MK-801 (20 e 100 μM) aboliu o efeito pró-oxidante do AQ. Quando as concentrações não-efetivas foram usadas em combinação produziram uma diminuição na formação de ROS, principalmente (PhSe)2 + GUO e (PhSe)2 + GUO + MK-801. Estes resultados demonstram que esta combinação pode ser eficaz para evitar os efeitos tóxicos provocados por concentrações elevadas do AQ. Além disso, os dados obtidos nos ensaios de formação de ROS e viabilidade celular sugerem diferentes vias de atuação na melhora da toxicidade induzida pelo AQ presente no processo neurodegenerativo.

Glutamatergic receptors are targets for many L-glutamate structure analogues, which cause neurotoxicity. This study investigated the actions of two dicarboxylic compounds, the first had cyclic framework and rigid structure, and the other had an acyclic framework and flexible structure, on the glutamatergic neurotransmission, oxidative damage and behavior in mice. The first compound evaluated was D,L-cis-2,3-pyrrolidine dicarboxylate (D,L-cis-2,3-PDC), a new glutamate analogue. D,L-cis-2,3-PDC reduced sodium-independent [3H]-L-glutamate binding by 50% in lysed membrane preparations and had no effect on sodium-dependent glutamate binding. Intracerebroventricular administration (ICV) of D,L-cis-2,3-PDC (7.5 - 25 nmol/ 5μl) induced dose-dependent tonic-clonic convulsions. The co-administration of MK-801 (7 nmol/ 2.5 μl; ICV), a noncompetitive NMDA receptor antagonist, with D,L-cis-2,3-PDC (16.5 nmol/ 2.5 μl; ICV) fully protected the animals against D,L-cis-2,3-PDC-induced convulsions, while the co-administration of DNQX (10 nmol/ 2.5 μl; ICV), a AMPA and KA receptors antagonist, increased the latency to convulsion and did not alter the percentage of animals that had convulsions. These results suggest that D,L-cis-2,3-PDC-induced effects are mediated predominantly by NMDA receptors activation. The second compound studied was succinate, the accumulating substrate in succinate dehydrogenase (SDH) deficiencies and SDH inhibitor intoxication. Adult male mice received an ICV injection of succinate (0.7, 1.0 and 1.7 μmol/ 5 μl) or 0.9% NaCl (5 μl) and had their exploratory behavior assessed in an open field for 10 min. Succinate (0.7 and 1.0 μmol/ 5 μl) decreased locomotor activity behavior and increased thiobarbituric acid reactive substances (TBARS) and protein carbonylation in the forebrain. Conversely, 1.7 μmol of succinate did not alter locomotor activity or oxidative damage parameters. The involvement of NMDA receptors in the succinate-induced increase of total protein carbonylation content and exploratory behavior inhibition was assessed by co-administrating MK-801 (7 nmol/ 2.5 μl, ICV) with succinate (1 μmol/ 2.5 μl, ICV). The co-administration of MK-801 protected against succinate-induced increase of total protein carbonylation and decrease of locomotor activity. These results suggest the involvement of NMDA receptors in these effects of succinate, which may of particular relevance for succinate-accumulating conditions, such as SDH inhibitors intoxication and inherited SDH deficiencies. / Os receptores glutamatérgicos são alvos da ação de muitas neurotoxinas análogas ao L-glutamato. Neste estudo foram investigadas as ações de dois compostos dicarboxílicos, um de cadeia cíclica e estrutura rígida e o outro de cadeia acíclica e estrutura flexível, sobre a neurotransmissão glutamatérgica, dano oxidativo e comportamento em roedores. No primeiro trabalho foi investigado se o D,L-cis-2,3-dicarboxilato de pirrolidina (D,L-cis-2,3-PDC) altera a ligação de [3H]-L-glutamato em membranas plasmáticas de córtex de ratos adultos e se os receptores N-metil-D-aspartato (NMDA) estão envolvidos nas convulsões induzidas por este composto. O D,L-cis-2,3-PDC reduziu a ligação de [3H]-L-glutamato Na+-independente em 50% nas preparações de membranas rompidas e não apresentou efeito sobre a ligação de [3H]-L-glutamato Na+-dependente. A administração intracerebroventricular (ICV) de D,L-cis-2,3-PDC (7,5; 25 nmol/ 5 μl) induziu convulsões generalizadas do tipo tônico-clônica nos camundongos, de uma maneira dose-dependente. A co-administração de MK-801 (7 nmol/ 2,5 μl; ICV), um antagonista não-competitivo dos receptores NMDA, com D,L-cis-2,3-PDC (16,5 nmol/ 2,5 μl; ICV), protegeu totalmente os animais das convulsões induzidas por D,L-cis-2,3-PDC, enquanto que a co-administração de DNQX (10 nmol/ 2,5 μl; ICV), um antagonista dos receptores AMPA e KA, aumentou a latência das convulsões, mas não alterou a percentagem de animais que tiveram convulsões. Estes resultados sugerem que os efeitos induzidos por D,L-cis-2,3-PDC são mediados principalmente pela ativação dos receptores NMDA. No segundo estudo, foi investigado se o sucinato, substrato que se acumula nas deficiências da enzima sucinato desidrogenase (SDH) e nas intoxicações por inibidores da SDH, causa lipoperoxidação e carbonilação protéica, e se os receptores NMDA estão envolvidos no dano oxidativo induzido por sucinato. Camundongos machos adultos receberam uma injeção ICV de sucinato (0,7; 1,0; 1,7 μmol/ 5 μl) ou 0,9 % de NaCl (5 μl) e seu comportamento foi analisado em um campo aberto por 10 minutos. Sucinato (0,7; 1,0 μmol/ 5 μl) diminuiu a atividade locomotora e aumentou as substâncias que reagem ao ácido tiobarbitúrico (TBARS) e carbonilação protéica no cérebro. Por outro lado, 1,7 μmol de sucinato não alterou a atividade locomotora ou os parâmetros de dano oxidativo. O envolvimento dos receptores NMDA no aumento induzido por sucinato do conteúdo de carbonilação protéica e da inibição do comportamento exploratório foi avaliado pela co-administração de MK-801 (7nmol/ 2,5 μl, ICV) com sucinato (1 μmol/ 2,5 μl, ICV). A co-administração de MK801 protegeu contra o aumento induzido por sucinato da carbonilação protéica e na diminuição da atividade locomotora. Esses resultados sugerem o envolvimento dos receptores NMDA nesses efeitos do sucinato, os quais são de grande relevância nas condições em que acumula sucinato, tais como as intoxicações com inibidores da SDH e deficiências dessa enzima causadas por erros inatos do metabolismo.

Non-competitive antagonists of NMDA receptors can induce psychomimetic effects - they can cause schizophrenia-like behavior in healthy volunteers. MK-801 is such an agent. It is often used to model schizophrenia-like behavior in experimental animals. On the other hand, non-competitive antagonists of NMDA receptors show antidepressant effects both in patients suffering from depression and in animal models. Currently, cognitive deficit is considered to be a crucial symptom of the schizophrenia. Cognitive coordination is a process distinguishing irrelevant and relevant stimuli. A disruption of this process could play a pivotal role in cognitive deficit in schizophrenia. Active Allothetic Place Avoidance task (AAPA) could be a useful tool to study this phenomenon. In this task an animal has to distinguish between two spatial (reference) frames, whereas one of them is irrelevant and the other is relevant. The aims of my diploma thesis were: to study 1) behavioral strategies of laboratory rats in AAPA task and 2) effect of MK-801 on behavioral strategies and cognitive efficiency of rats in this task. The rats demonstrated two different strategies in the AAPA task. The first strategy was an active avoidance of an aversive sector; the second one was "freezing" with minimal active movement on the arena. Application...

Primary polydipsia, excessive drinking without known medical cause, continues to occur with a significant prevalence in psychiatric populations. While the etiology of polydipsia remains unknown, the fact that it is significantly associated with a diagnosis of schizophrenia has led some to postulate that the two may share common neurological pathophysiologies. Animal models of schizophrenia-like symptoms have focused on modeling the core behavioral and neurochemical features of the illness, like cognitive deficits and enhanced dopamine transmission. Here, we used three well-established models, including repeated amphetamine treatment, subchronic MK-801 (an N-methyl-D-aspartate [NMDA]-receptor antagonist), and post-weaning social isolation. We also examined a “double-hit” model, combining NMDA-receptor antagonism and social isolation. We paired these models to test the hypothesis that drinking will be enhanced in a paradigm of excessive drinking in the rat. In rodents, non-physiologic drinking can be induced by intermittent presentation of food (e.g., one sugar-pellet a minute) in the presence of a drinking spout to a hungry animal, termed schedule-induced polydipsia (SIP). Animals pretreated with pharmacological or non-pharmacological models of schizophrenia-like symptoms showed significantly increased SIP, The “double hit” model did not further increase drinking above that of either social isolation or MK-801 treatment alone. A moderate amount of spontaneous polydipsia in the homecage of MK-801-treated rats was also observed and resulted in one death secondary to excessive drinking, a phenomenon also found in inpatients with schizophrenia. Following repeated treatment with AMPH, there was some evidence that over time, animals learned to drink increased amounts independently of the scheduled food presentation. This evidence suggests that the excessive drinking behavior observed in polydipsia associated with schizophrenia may have a learned component. In summary, animal models of schizophrenia-like symptoms augmented SIP behavior, showing that polydipsia associated with schizophrenia may be modeled in rodents. As each model has been shown to modify dopamine transmission to some degree, the evidence suggests augmented SIP may reflect changes in dopamine transmission and dopamine may be the common link between polydipsia and schizophrenia. Further research is necessary to fully elucidate the mechanisms underlying SIP, polydipsia and schizophrenia. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2012-10-31 17:43:18.34

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The noncompetitive NMDA receptor antagonist ketamine produces rapid and sustained antidepressant effects in patients suffering from major depressive disorder. However, abuse liability is a concern. To further evaluate the relationship between antidepressant-like and abuse-related effects of NMDA receptor antagonists, this study evaluated the effects of ketamine, MK-801, and phencyclidine in male Sprague-Dawley rats responding under two procedures that have been used to assess antidepressant-like effects [differential-reinforcement-of-low-rate (DRL) 72 s schedule of food reinforcement] and abuse-related drug effects [intracranial self-stimulation (ICSS)]. Under DRL 72 s, ketamine produced an antidepressant-like effect by increasing reinforcers, decreasing responses, and producing a rightward shift in the peak location of the interresponse time (IRT) distributions. Phencyclidine produced a modest antidepressant-like effect by increasing reinforcers and decreasing responses, but did not shift the IRT distributions. In contrast, MK-801 produced a psychostimulant-like effect by decreasing reinforcers, increasing responses, and producing a leftward shift in the peak location of the IRT distributions. The antidepressant-like effects of ketamine on the DRL 72 s procedure do not appear to be mediated by inhibiting the reuptake of serotonin via serotonin transporters or antagonism of 5-HT2 receptors. Additionally, the dissociable effects of ketamine and MK-801 in the DRL 72 s procedure may be mediated by 5-HT2 receptors. Following acute administration, ketamine produced only dose- and time-dependent depression of ICSS and failed to produce an abuse-related facilitation of ICSS at any dose or pretreatment time. Repeated dosing with ketamine produced dose-dependent tolerance to the rate-decreasing effects of ketamine but failed to unmask expression of ICSS facilitation. Termination of ketamine treatment failed to produce withdrawal-associated decreases in ICSS. In contrast, MK-801 and phencyclidine effects produced dose- and time-dependent facilitation of ICSS by MK-801. Taken together, our findings provide further evidence that expression of these antidepressant-like and abuse-related effects of ketamine, phencyclidine, and MK-801 may be related to NMDA receptor affinity.

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Zebrafish can be used to model complex human behavioral traits such as learning and memory. This study aims to establish a protocol for evaluating the object recognition memory or object location tasks in zebrafish. We evaluated novel object recognition memory and analyzed the exploration time of novel and familiar objects in the training and test sessions. There was a preference of the animal to explore the new object in comparison to the familiar object (61% of exploration time). We also evaluated the object location task and measured the exploration time of each object in the familiar and novel object locations. There was a preference of the animal to explore the object in the novel location in comparison to the object in the familiar location (63% of exploration time). We also evaluated the effect of the non-competitive NMDA receptor antagonist MK-801 on the object recognition and object location memory in zebrafish. In this regimen treatment, control (water only) and treated animals (5 ?M MK-801) presented a significant preference in exploring the familiar object in comparison to the new object (66 and 68% of exploration time, respectively); however, 10 ?M MK-801-treated animals did not show differences in the exploration time of the objects. In the object location task, the animals treated with the 5 or 10 ?M MK-801 did not show a significant preference for the familiar or novel location whereas the control group had a higher preference in exploring the object in the familiar location (64% of exploration time). Therefore, it is possible to suggest that 5 ?M MK-801 impaired the memory formation in an object location task, which is in agreement with previous studies demonstrating the cognitive deficit induced by MK-801 treatment in aversive and spatial memory. Considering the different responses of the control group between original task and in the regimen treatment, we evaluated the impact of habituation on cortisol levels of animals in three different protocols: 1) habituated at the experiment apparatus for 3 days (Condition 1 ? C1), 2) habituated at the experiment apparatus for 3 days plus treatment tank exposure at fourth day (Condition 2 - C2), 3) habituated at the treatment tank exposure and experiment apparatus for 3 days and exposed to treatment tank again at fourth day (Condition 3 ? C3). The results showed higher levels of cortisol in animals submitted to C2 and C3 conditions compared to animals submitted to C1. These results demonstrated that the animals submitted to treatment tank exposure have a different performance in object recognition and object location memory due to stress responses. Therefore, these tasks are prone to evaluate memory in physiological and pathological conditions, but its use is limited to perform pharmacological studies due to sensitivity to stress caused by manipulation. / A mem?ria permite que os animais possam adaptar e modificar seu comportamento diante de novas experi?ncias. Uma s?rie de fatores pode resultar num d?ficit de mem?ria como: doen?as neurodegenerativas, altera??es decorrentes de intoxica??es e uso de f?rmacos. O peixe-zebra vem sendo usado para modelar caracter?sticas comportamentais humanas complexas, como o aprendizado e mem?ria. Este estudo tem como objetivo estabelecer um protocolo para avaliar tarefas de mem?ria de reconhecimento de objetos ou de localiza??o de objetos no peixe-zebra. N?s avaliamos a mem?ria de reconhecimento de objeto novo e analisamos o tempo de explora??o de objetos novos e familiares nas sess?es de treino e teste. Houve uma prefer?ncia do animal em explorar o novo objeto em compara??o com o objeto familiar (61% do tempo de explora??o). Tamb?m avaliamos a tarefa de localiza??o de objeto e medimos o tempo de explora??o de cada objeto nos locais familiares e novos. Houve uma prefer?ncia do animal para explorar o objeto na localiza??o nova em compara??o com o objeto na localiza??o familiar (63% do tempo de explora??o). Tamb?m avaliamos o efeito do antagonista n?o competitivo do receptor NMDA MK-801 na mem?ria de reconhecimento de objeto novo e na localiza??o de objeto em peixe-zebra. Neste tratamento, o controle (somente ?gua) e os animais tratados (MK-801 5 ?M) apresentaram uma prefer?ncia significativa na explora??o do objeto familiar em compara??o com o novo objeto (66 e 68% do tempo de explora??o, respectivamente); no entanto, animais tratados com MK-801 10 ?M n?o mostraram diferen?as no tempo de explora??o dos objetos. Na tarefa de localiza??o de objeto, os animais tratados com MK-801 5 ou 10 ?M n?o mostraram prefer?ncia significativa pelo objeto na localiza??o familiar ou nova, enquanto que o grupo controle teve uma prefer?ncia maior em explorar o objeto na localiza??o familiar (64% de tempo de explora??o). Portanto, sugere-se que o MK-801 5 ?M prejudicou a forma??o da mem?ria em uma tarefa de localiza??o de objeto, o que est? de acordo com estudos pr?vios, demonstrando o d?ficit cognitivo induzido pelo MK-801 em mem?rias aversivas ou espaciais. Considerando as diferentes respostas do grupo controle entre a tarefa original e no tratamento, avaliamos o impacto da habitua??o nos n?veis de cortisol dos animais em tr?s protocolos diferentes: 1) habituado ao aparato experimental por 3 dias (Condi??o 1 - C1) 2) habituado ao aparato experimental por 3 dias mais a exposi??o ao aqu?rio de tratamento no quarto dia (Condi??o 2 - C2), 3) habituado na exposi??o ao aqu?rio de tratamento e no aparato experimental por 3 dias e exposto ao aqu?rio de tratamento novamente no quarto dia (Condi??o 3 - C3). Os resultados mostraram n?veis mais elevados de cortisol em animais submetidos a condi??es C2 e C3 em compara??o com animais submetidos a C1. Esses resultados demonstraram que os animais submetidos ? exposi??o ao aqu?rio de tratamento apresentam desempenho diferente nas tarefas de mem?ria de reconhecimento de objetos e de localiza??o do objeto devido ao estresse. Portanto, essas tarefas s?o adequadas para avaliar a mem?ria em condi??es fisiol?gicas e patol?gicas, mas seu uso ? limitado em estudos farmacol?gicos devido ? sensibilidade ao estresse causado pela manipula??o.

Previous research has shown that cannabidiol (CBD), a non-psychoactive compound in the hemp plant Cannabis sativa, may be useful in treating drug craving, one of the hallmarks of drug addiction. However, the neural mechanism by which CBD attenuates craving is poorly understood. Studies from other laboratories have shown that neuroplastic changes associated with brain NMDA glutamate systems may at least partially serve as a neural mechanism for craving. In the current study, the noncompetitive NMDA receptor antagonist MK-801 maleate was used to induce locomotor sensitization, a form of NMDA glutamate-mediated neuroplasticity, in mice to test the sensitization-attenuating potential of CBD. Separate groups of mice (N=8) received either CBD (1.0 mg/kg, i.p.) or saline thirty minutes prior to an intraperitoneal injection of MK-801 (0.5 mg/kg, i.p.) or saline and tested for locomotor performance in an open field (Induction Trial). Seventy-two hours later all mice, regardless of drug pretreatment, were tested for locomotor activity following a second administration (0.5 mg/kg, i.p.) of MK-801 (Sensitization Trial). Results revealed a significant difference across groups for the Induction Trial, with groups receiving SAL-MK801 and CBD-MK801 significantly more active than SAL-SAL and CBD-SAL groups. Pretreatment with CBD had no effect on the locomotor activating effects of MK-801 during the Sensitization Trial with similar levels of locomotor performance across drug groups. Possibilities for the lack of CBD effects are discussed, as well as implications and future research directions.