RESUMO
RATIONALE: The endocannabinoid system plays an important role in the organization of panic-like defensive behavior. Threatening situations stimulate brain areas, such as the dorsomedial hypothalamus (DMH). However, there is a lack of studies addressing the role of the DMH endocannabinoid system in panic-like responses. OBJECTIVES: We aimed to verify which mechanisms underlie anandamide-mediated responses in the DMH. METHODS: To test the hypothesis that the anandamide produces panicolytic-like effects, we treated mice with intra-DMH microinjections of vehicle or increasing doses of anandamide (0.5, 5, or 50 pmol) and then performed confrontation with the South American snake Epicrates cenchria assisi. RESULTS: Intra-DMH anandamide treatment yielded a U-shaped dose-response curve with no effect of the lowest (0.5 pmol) or the highest (50 pmol) dose and significant inhibition of panic-like responses at the intermediate (5 pmol) dose. In addition, this panicolytic-like effect was prevented by pretreatment of the DMH with the CB1 receptor antagonist AM251 (100 pmol). However, pretreatment of the DMH with the TRPV1 receptor antagonist 6-iodo-nordihydrocapsaicin (3 nmol) restored the panicolytic-like effect of the highest dose of anandamide. Immunohistochemistry revealed that CB1 receptors were present primarily on axonal fibers, while TRPV1 receptors were found almost exclusively surrounding the perikarya in DMH. CONCLUSIONS: The present results suggest that anandamide exerts a panicolytic-like effect in the DMH by activation of CB1 receptors and that TRPV1 receptors are related to the lack of effect of the highest dose of anandamide.
Assuntos
Ácidos Araquidônicos/administração & dosagem , Agonistas de Receptores de Canabinoides/administração & dosagem , Núcleo Hipotalâmico Dorsomedial/metabolismo , Endocanabinoides/administração & dosagem , Pânico/fisiologia , Alcamidas Poli-Insaturadas/administração & dosagem , Receptor CB1 de Canabinoide/biossíntese , Canais de Cátion TRPV/biossíntese , Animais , Boidae , Brasil , Núcleo Hipotalâmico Dorsomedial/efeitos dos fármacos , Relação Dose-Resposta a Droga , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pânico/efeitos dos fármacos , Piperidinas/administração & dosagem , Pirazóis/administração & dosagem , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Canais de Cátion TRPV/antagonistas & inibidoresRESUMO
Drug dependence seems to involve a learning and memory process. Since learning and memory depend on protein synthesis, drug dependence may depend on protein synthesis, too. Drug-induced reward is a crucial effect for the development of drug-dependence. We used chloramphenicol (CAP, a protein synthesis inhibitor), to evaluate its effects on amphetamine (amph)-seeking behavior, on CB1R expression and on protein synthesis in general, in specific areas of the brain. Two groups of Wistar adult male rats were subjected to amph-induced conditioned place preference (CPP). Rats in group 1 received amph and were kept in the chamber for 30min. Once this period elapsed, they received a subcutaneous injection of saline (veh) and were returned to their home-cage. Rats in group 2 were also treated with amph but received CAP (150mg/kgsc) instead of saline. Once CPP was evaluated rats were sacrificed and the prefrontal cortex (PFC), the nucleus accumbens (NAcc) and the hippocampus (Hipp) were isolated and prepared for CB1R Western blot analysis. A vivarium reared group of rats was added as a non-experimentally manipulated control group. Results indicate that group 1 developed CPP while increasing CB1R expression in the NAcc. Group 2 did not develop CPP, had lower CB1R expression in the PFC and lacked the CB1R increase in the NAcc observed in the amph+veh group. These results support the notion that among the underlying mechanisms for amph-seeking reward is an increase in CB1R, further supporting an interaction between dopamine/endocannabinoids in CPP learning.
Assuntos
Anfetamina/antagonistas & inibidores , Anfetamina/farmacologia , Estimulantes do Sistema Nervoso Central/antagonistas & inibidores , Estimulantes do Sistema Nervoso Central/farmacologia , Cloranfenicol/farmacologia , Condicionamento Operante/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Inibidores da Síntese de Proteínas/farmacologia , Receptor CB1 de Canabinoide/biossíntese , Receptor CB1 de Canabinoide/efeitos dos fármacos , Animais , Masculino , Memória/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
The pathophysiology associated with increased prevalence of depression in diabetics is not completely understood, although studies have pointed the endocannabinoid system as a possible target. Then, we aimed to investigate the role of this system in the pathophysiology of depression associated with diabetes. For this, diabetic (DBT) male Wistar rats were intraperitoneally treated with cannabinoid CB1 (AM251, 1mg/kg) or CB2 (AM630, 1mg/kg) receptor antagonists followed by anandamide (AEA, 0.005mg/kg) and then submitted to the forced swimming test (FST). Oxidative stress parameters, CB1 receptor expression and serotonin (5-HT) and noradrenaline levels in the hippocampus (HIP) and prefrontal cortex (PFC) were also performed. It was observed that DBT animals presented a more pronounced depressive-like behavior and increase of CB1 receptor expression in the HIP. AEA treatment induced a significant improvement in the depressive-like behavior, which was reversed by the CB1 antagonist AM251, without affecting the hyperglycemia or weight gain. AEA was also able to restore the elevated CB1 expression and also to elevate the reduced level of 5-HT in the HIP from DBT animals. In addition, AEA restored the elevated noradrenaline levels in the PFC and induced a neuroprotective effect by restoring the decreased reduced glutathione and increased lipid hydroperoxides levels along with the decreased superoxide dismutase activity observed in HIP or PFC. Together, our data suggest that in depression associated with diabetes, the endocannabinoid anandamide has a potential to induce neuroadaptative changes able to improve the depressive-like response by its action as a CB1 receptor agonist.
Assuntos
Ácidos Araquidônicos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Depressão/tratamento farmacológico , Depressão/etiologia , Diabetes Mellitus Experimental/psicologia , Endocanabinoides/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Alcamidas Poli-Insaturadas/uso terapêutico , Receptor CB1 de Canabinoide/efeitos dos fármacos , Animais , Indóis/farmacologia , Masculino , Norepinefrina/metabolismo , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/biossíntese , Serotonina/metabolismo , Natação/psicologiaRESUMO
The endocannabinoid system, composed of cannabinoid receptors, endocannabinoids, and synthesis and degradation enzymes, is present since early stages of brain development. During this period, the endocannabinoid system is involved in the regulation of neural progenitor proliferation and specification as well as the migration and differentiation of pyramidal neurons and interneurons. Marijuana consumption during pregnancy represents a serious risk in relation to the fetal brain development since Δ(9) -tetrahidrocannabinol, the main active compound of cannabis, can reach the fetus through placenta and hemato-encephalic barrier. Cohort studies performed on children and adolescents of mothers who consumed marijuana during pregnancy reported cognitive and comportamental abnormalities. In the present study, we examined the expression of the cannabinoid receptor CB1 R during corticogenesis in radially and tangentially migrating post-mitotic neurons. We found that prenatal exposure to WIN impaired tangential and radial migration of post-mitotic neurons in the dorsal pallium. In addition, we described alterations of two transcription factors associated with proliferating and newly post-mitotic glutamatergic cells in the dorsal pallium, Tbr1 and Tbr2, and disruption in the number of Cajal-Retzius cells. The present results contribute to the knowledge of neurobiological substrates that determine neuro-comportamental changes that will persist through post-natal life.
Assuntos
Benzoxazinas/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Córtex Cerebral/citologia , Endocanabinoides/fisiologia , Morfolinas/farmacologia , Naftalenos/farmacologia , Neurônios/efeitos dos fármacos , Receptor CB1 de Canabinoide/fisiologia , Animais , Apoptose/efeitos dos fármacos , Moléculas de Adesão Celular Neuronais/análise , Divisão Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/embriologia , Proteínas do Domínio Duplacortina , Proteínas da Matriz Extracelular/análise , Feminino , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologia , Ácido Glutâmico/fisiologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/embriologia , Interneurônios/citologia , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Proteínas Associadas aos Microtúbulos/análise , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Neurônios/fisiologia , Neuropeptídeos/análise , Gravidez , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/biossíntese , Proteína Reelina , Serina Endopeptidases/análise , Proteínas com Domínio T/metabolismo , Transcrição GênicaRESUMO
BACKGROUND: There is a close relationship between the endocannabinoid system and alcoholism. This study investigated possible differential expression of cannabinoid receptors CB1 (CB1R) and CB2 (CB2R) in an outbred mice strain displaying behavioral variability to ethanol (EtOH)-induced locomotor sensitization. METHODS: Male adult Swiss mice treated chronically with EtOH (2 g/kg, i.p., daily for 21 days) were classified as "EtOH_High" or "EtOH_Low" according to their locomotor activity after the 21st EtOH injection. A control group was similarly injected with saline. Temporal analysis of CB1R and CB2R immunoreactivity was performed in 3 different occasions: (i) at the end of chronic EtOH treatment, (ii) on the fifth day of EtOH withdrawal, and (iii) after EtOH challenge. RESULTS: Overall, no differences were seen between experimental groups regarding the CB1R at the end of acquisition. However, there were decreases in CB2R in the prefrontal cortex and the hippocampus in EtOH_Low mice. On the fifth day of withdrawal, only EtOH_High mice presented increase in CB1R. Nonetheless, CB2R up-regulation was observed in both EtOH_High and EtOH_Low mice. EtOH challenge counteracted CB1R and CBR2 up-regulation, mainly in the EtOH_High, in structures related to emotionality, such as prefrontal cortex, ventral tegmental area, amygdala, striatum, and hippocampus. CONCLUSIONS: There are different patterns of cannabinoid receptor expression during locomotor sensitization paradigm, at both temporal and behavioral perspectives. We hypothesize that CB2R down-regulation might be related to resilience to develop locomotor sensitization, while CB1R up-regulation relates to withdrawal aspects in sensitized mice.
Assuntos
Etanol/administração & dosagem , Regulação da Expressão Gênica , Atividade Motora/efeitos dos fármacos , Receptor CB1 de Canabinoide/biossíntese , Receptor CB2 de Canabinoide/biossíntese , Animais , Animais não Endogâmicos , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Atividade Motora/fisiologia , Distribuição Aleatória , Receptor CB1 de Canabinoide/genética , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
The central nervous system control of food intake has been extensively studied, hence, several neurotransmitter systems regulating this function are now clearly identified, for example, the endocannabinoid and serotoninergic systems. The former stimulates feeding while the latter inhibits it. Oleamide (Ole) is a cannabimimetic molecule affecting both systems. In this work, we tested the orexigenic and anorectic potential of Ole when administered into the nucleus accumbens shell (NAcS), a brain region that has been related to the orexigenic effects of cannabinoids. Additionally, we tested if Ole administered into this nucleus affects the activity of the hypothalamic nuclei involved in feeding behaviour, just as other cannabinoids do. We found a hyperphagic effect of Ole that is mediated through CB1 activation. The combination of Ole and the CB1 antagonist, AM251, produced a hypophagia that was fully blocked by SB212084, a 5-HT2C receptor antagonist. We also show that blockade of 5-HT2C and 5-HT2A receptors in the NAcS stimulates food intake. Finally, the combination of Ole and AM251 activates hypothalamic nuclei, an effect also blocked by SB242084. In conclusion, we show, for the first time, that Ole administered into the NAcS has a dual effect on feeding behaviour, acting through cannabinoid and serotonin receptors. These effects probably result from a downstream interaction with the hypothalamus.
Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Ácidos Oleicos/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia , Aminopiridinas/farmacologia , Animais , Comportamento Alimentar/fisiologia , Hiperfagia/induzido quimicamente , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Indóis/farmacologia , Ketanserina/farmacologia , Masculino , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ácidos Oleicos/administração & dosagem , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/biossíntese , Receptor 5-HT2A de Serotonina/metabolismo , Receptor 5-HT2C de Serotonina/metabolismoRESUMO
Accumulating evidence indicates that the endocannabinoid system plays an essential role in the development and maturation of the central nervous system. Studies also have demonstrated that neural systems that regulate behavioral responses can be influenced by exercise during development. Exercise and endogenous cannabinoid activity have independently been shown to regulate brain plasticity, hence demonstrating a promising field of the endocannabinoid-exercise interaction. In order to investigate whether physical exercise during development would promote changes the brain endocannabinoid system, we investigated the cannabinoid receptor type 1 (CB1) expression in the brain of rats trained during the adolescent period. The results showed that an aerobic exercise program performed during adolescence significantly reduced the CB1 receptor expression in the striatum and hippocampal formation. These findings suggest an important link between the endocannabinoid system and physical training in adolescence.
Assuntos
Química Encefálica/fisiologia , Condicionamento Físico Animal/fisiologia , Receptor CB1 de Canabinoide/biossíntese , Envelhecimento/fisiologia , Animais , Western Blotting , Peso Corporal/fisiologia , Encéfalo/crescimento & desenvolvimento , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/metabolismo , Corpo Estriado/anatomia & histologia , Corpo Estriado/metabolismo , Hipocampo/anatomia & histologia , Hipocampo/metabolismo , Imuno-Histoquímica , Masculino , Ratos , Ratos WistarRESUMO
RATIONALE: One of the adaptive abilities of the brain is the generation of a strategy to optimize acquisition of information, i.e., learning. In this study, we explored the role of environmental conditions (the light-dark cycle) and of the endocannabinoid anandamide in rats to select a strategy to solve the Barnes maze (BM). OBJECTIVES: To determine the effects of manipulating the cannabinergic system on a spatial task in relation to the light-dark cycle. MATERIALS AND METHODS: Rats received an intrahippocampal or intrastriatal administration of anandamide, AM251, or their combination at two different points of the light-dark cycle (1300 and 0100 hours), and their performance in the BM was evaluated. In addition, we determined the expression of the cannabinoid 1 receptor (CB1R) in the hippocampus and striatum throughout the light-dark cycle. RESULTS: Results indicate that rats solved the BM by using a spatial strategy during the light phase and a procedural (serial) strategy during the dark phase of the cycle. CB1R expression varied in the hippocampus, being higher at 1300 hours and lower at 0100 hours, whereas its expression remained unchanged in the striatum. CONCLUSIONS: Changes in the brain, which include changes in the endocannabinoid system, prompt it to use different strategies (spatial and procedural, or others not evaluated in this study) to cope with the environmental demands. These cerebral changes are adaptive responses to the light-dark cycle.
Assuntos
Ácidos Araquidônicos/farmacologia , Moduladores de Receptores de Canabinoides/farmacologia , Endocanabinoides , Aprendizagem em Labirinto/efeitos dos fármacos , Orientação/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Animais , Ácidos Araquidônicos/administração & dosagem , Western Blotting , Ritmo Circadiano/efeitos dos fármacos , Escuridão , Hipocampo/fisiologia , Imuno-Histoquímica , Luz , Masculino , Microinjeções , Neostriado/fisiologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/administração & dosagem , Pirazóis/administração & dosagem , Pirazóis/farmacologia , RNA/biossíntese , RNA/isolamento & purificação , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
In the present study, we examined whether cannabinoid receptor expression and the effects of receptor stimulation vary as a function of gonadal status in a peripheral tissue, namely the male rat parotid gland. Four groups of male rats were studied: gonadal intact, castrated, castrated testosterone (1 mg/100 g bodyweight) treated and gonadal intact testosterone treated. 2. The results showed that the density of CB(1) receptors decreased after castration and that receptor density was restored to control values after testosterone treatment. This decrement was associated with a decrease of anandamide (10(-10) to 10(-5) mol/L)-induced cAMP accumulation and amylase release without changes in the anandamide-induced inhibition of Na(+)/K(+)-ATPase activity. 3. Castration did not modify either the subtype of cannabinoid receptor involved in the actions of anandamide or drug affinity for the receptor. 4. The mechanism underlying anandamide-induced cAMP accumulation, amylase release and inhibition of Na(+)/K(+)-ATPase activity, namely through the activation of adenylyl cyclase, was the same in control and castrated rats. 5. Basal cAMP accumulation, amylase release and Na(+)/K(+)-ATPase activity were not altered by castration. 6. Castration had no effect on the concentration of total protein. 7. It can be concluded that CB(1) cannabinoid receptor expression is regulated by testosterone in male rat parotid gland and this has functional implications for cAMP accumulation and amylase release.