RESUMO
Newly conducted research suggests that metabolic disorders, like diabetes and obesity, play a significant role as risk factors for psychiatric disorders. This connection presents a potential avenue for creating novel antidepressant medications by repurposing drugs originally developed to address antidiabetic conditions. Earlier investigations have shown that GLP-1 (Glucagon-like Peptide-1) analogs exhibit neuroprotective qualities in various models of neurological diseases, encompassing conditions such as Alzheimer's disease, Parkinson's disease, and stroke. Moreover, GLP-1 analogs have demonstrated the capability to enhance neurogenesis, a process recognized for its significance in memory formation and the cognitive and emotional aspects of information processing. Nonetheless, whether semaglutide holds efficacy as both an antidepressant and anxiolytic agent remains uncertain. To address this, our study focused on a mouse model of depression linked to type 2 diabetes induced by a High Fat Diet (HFD). In this model, we administered semaglutide (0.05 mg/Kg intraperitoneally) on a weekly basis to evaluate its potential as a therapeutic option for depression and anxiety. Diabetic mice had higher blood glucose, lipidic profile, and insulin resistance. Moreover, mice fed HFD showed higher serum interleukin (IL)-1ß and lipopolysaccharide (LPS) associated with impaired humor and cognition. The analysis of behavioral responses revealed that the administration of semaglutide effectively mitigated depressive- and anxiety-like behaviors, concurrently demonstrating an enhancement in cognitive function. Additionally, semaglutide treatment protected synaptic plasticity and reversed the hippocampal neuroinflammation induced by HFD fed, improving activation of the insulin pathway, demonstrating the protective effects of semaglutide. We also found that semaglutide treatment decreased astrogliosis and microgliosis in the dentate gyrus region of the hippocampus. In addition, semaglutide prevented the DM2-induced impairments of pro-opiomelanocortin (POMC), and G-protein-coupled receptor 43 (GPR43) and simultaneously increased the NeuN + and Glucagon-like Peptide-1 receptor (GLP-1R+) neurons in the hippocampus. Our data also showed that semaglutide increased the serotonin (5-HT) and serotonin transporter (5-HTT) and glutamatergic receptors in the hippocampus. At last, semaglutide changed the gut microbiota profile (increasing Bacterioidetes, Bacteroides acidifaciens, and Blautia coccoides) and decreased leaky gut, improving the gut-brain axis. Taken together, semaglutide has the potential to act as a therapeutic tool for depression and anxiety.
Assuntos
Ansiedade , Eixo Encéfalo-Intestino , Disfunção Cognitiva , Depressão , Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Peptídeos Semelhantes ao Glucagon , Camundongos Endogâmicos C57BL , Animais , Peptídeos Semelhantes ao Glucagon/farmacologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/psicologia , Diabetes Mellitus Tipo 2/metabolismo , Camundongos , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Depressão/tratamento farmacológico , Depressão/psicologia , Depressão/metabolismo , Masculino , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Ansiedade/etiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Eixo Encéfalo-Intestino/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Antidepressivos/farmacologia , Antidepressivos/uso terapêuticoRESUMO
Protectin DX (PDX), a specialized pro-resolving lipid mediator, presents potential therapeutic applications across various medical conditions due to its anti-inflammatory and antioxidant properties. Since type-1 diabetes mellitus (T1DM) is a disease with an inflammatory and oxidative profile, exploring the use of PDX in addressing T1DM and its associated comorbidities, including diabetic neuropathic pain, depression, and anxiety becomes urgent. Thus, in the current study, after 2 weeks of T1DM induction with streptozotocin (60 mg/kg) in Wistar rats, PDX (1, 3, and 10 ng/animal; i.p. injection of 200 µl/animal) was administered specifically on days 14, 15, 18, 21, 24, and 27 after T1DM induction. We investigated the PDX's effectiveness in alleviating neuropathic pain (mechanical allodynia; experiment 1), anxiety-like and depressive-like behaviors (experiment 2). Also, we studied whether the PDX treatment would induce antioxidant effects in the blood plasma, hippocampus, and prefrontal cortex (experiment 3), brain areas involved in the modulation of emotions. For evaluating mechanical allodynia, animals were repeatedly submitted to the Von Frey test; while for studying anxiety-like responses, animals were submitted to the elevated plus maze (day 26) and open field (day 28) tests. To analyze depressive-like behaviors, the animals were tested in the modified forced swimming test (day 28) immediately after the open field test. Our data demonstrated that PDX consistently increased the mechanical threshold throughout the study at the two highest doses, indicative of antinociceptive effect. Concerning depressive-like and anxiety-like behavior, all PDX doses effectively prevented these behaviors when compared to vehicle-treated T1DM rats. The PDX treatment significantly protected against the increased oxidative stress parameters in blood plasma and in hippocampus and prefrontal cortex. Interestingly, treated animals presented improvement on diabetes-related parameters by promoting weight gain and reducing hyperglycemia in T1DM rats. These findings suggest that PDX improved diabetic neuropathic pain, and induced antidepressant-like and anxiolytic-like effects, in addition to improving parameters related to the diabetic condition. It is worth noting that PDX also presented a protective action demonstrated by its antioxidant effects. To conclude, our findings suggest PDX treatment may be a promising candidate for improving the diabetic condition per se along with highly disabling comorbidities such as diabetic neuropathic pain and emotional disturbances associated with T1DM.
Assuntos
Ansiedade , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Ácidos Docosa-Hexaenoicos , Ratos Wistar , Animais , Masculino , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/psicologia , Ratos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/psicologia , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Depressão/tratamento farmacológico , Depressão/etiologia , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Hiperalgesia/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Neuropatias Diabéticas/tratamento farmacológicoRESUMO
Gestational diabetes (GD) has a negative impact on neurodevelopment, resulting in cognitive and neurological deficiencies. Oxidative stress (OS) has been reported in the brain of the first-generation offspring of GD rats. OS has been strongly associated with neurodegenerative diseases. In this work, we determined the effect of GD on the cognitive behavior, oxidative stress and metabolism of second-generation offspring. GD was induced with streptozotocin (STZ) in pregnant rats to obtain first-generation offspring (F1), next female F1 rats were mated with control males to obtain second-generation offspring (F2). Two and six-month-old F2 males and females were employed. Anxious-type behavior, spatial learning and spatial working memory were evaluated. In cerebral cortex and hippocampus, the oxidative stress and serum biochemical parameters were measured. Male F2 GD offspring presented the highest level of anxiety-type behavior, whilst females had the lowest level of anxiety-type behavior at juvenile age. In short-term memory, adult females presented deficiencies. The offspring F2 GD females presented modifications in oxidative stress biomarkers in the cerebral cortex as lipid-peroxidation, oxidized glutathione and catalase activity. We also observed metabolic disturbances, particularly in the lipid and insulin levels of male and female F2 GD offspring. Our results suggest a transgenerational effect of GD on metabolism, anxiety-like behavior, and spatial working memory.
Assuntos
Ansiedade/etiologia , Comportamento Animal/fisiologia , Fenômenos Fisiológicos da Nutrição Materna , Estresse Oxidativo/fisiologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Animais , Biomarcadores , Córtex Cerebral/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/psicologia , Diabetes Gestacional/metabolismo , Diabetes Gestacional/psicologia , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Peroxidação de Lipídeos/fisiologia , Masculino , Memória de Curto Prazo/fisiologia , Gravidez , Ratos , Aprendizagem Espacial/fisiologia , EstreptozocinaRESUMO
Cannabidiol (CBD), a phytocannabinoid compound, presents antidepressant and anxiolytic-like effects in the type-1 diabetes mellitus(DM1) animal model. Although the underlying mechanism remains unknown, the type-1A serotonin receptor (5-HT1A) and cannabinoids type-1 (CB1) and type-2 (CB2) receptors seem to play a central role in mediating the beneficial effects on emotional responses. We aimed to study the involvement of these receptors on an antidepressant- and anxiolytic-like effects of CBD and on some parameters of the diabetic condition itself. After 2 weeks of the DM1 induction in male Wistar rats by streptozotocin (60 mg/kg; i.p.), animals were treated continuously for 2-weeks with the 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg, i.p.), CB1 antagonist AM251 (1 mg/kg i.p.) or CB2 antagonist AM630 (1 mg/kg i.p.) before the injection of CBD (30 mg/kg, i.p.) or vehicle (VEH, i.p.) and then, they were submitted to the elevated plus-maze and forced swimming tests. Our findings show the continuous treatment with CBD improved all parameters evaluated in these diabetic animals. The previous treatment with the antagonists - 5-HT1A, CB1, or CB2 - blocked the CBD-induced antidepressant-like effect whereas only the blockade of 5-HT1A or CB1 receptors was able to inhibit the CBD-induced anxiolytic-like effect. Regarding glycemic control, only the blockade of CB2 was able to inhibit the beneficial effect of CBD in reducing the glycemia of diabetic animals. These findings indicated a therapeutic potential for CBD in the treatment of depression/anxiety associated with diabetes pointing out a complex intrinsic mechanism in which 5-HT1A, CB1, and/or CB2 receptors are differently recruited.
Assuntos
Ansiolíticos/uso terapêutico , Antidepressivos/uso terapêutico , Canabidiol/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Animais , Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Canabidiol/farmacologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor 5-HT1A de Serotonina/metabolismoRESUMO
RATIONALE: Studies point out a higher prevalence of posttraumatic stress disorder (PTSD) in individuals with diabetes mellitus. It is known that glucocorticoid (GR) and mineralocorticoid (MR) receptors are implicated in fear memory processes and PTSD. However, there is no preclinical studies addressing the involvement of these receptors on abnormal fear memories related to diabetic condition. OBJECTIVES: By inducing a contextual conditioned fear memory, we generate a suitable condition to investigate the extinction and the generalization of the fear memory in streptozotocin-induced diabetic (DBT) rats alongside the expression of the cytosolic and nuclear GR and MR in the hippocampus (HIP) and prefrontal cortex (PFC). Moreover, we investigated the involvement of the MR or GR on the acquisition of fear memory extinction and on the generalization of this fear memory. When appropriate, anxiety-related behavior was evaluated. METHODS: Male Wistar rats received one injection of steptozotocin (i.p.) to induce diabetes. After 4 weeks, the animals (DBTs and non-DBTs) were subjected to a conditioned contextual fear protocol. RESULTS: The expression of MR and GR in the HIP and PFC was similar among all the groups. The single injection of MR agonist was able to facilitate the acquisition of the impaired fear memory extinction in DBTs animals together with the impairment of its generalization. However, the GR antagonism impaired only the generalization of this fear memory which was blocked by the previous injection of the MR antagonist. All treatments were able to exert anxiolytic-like effects. CONCLUSIONS: The results indicate that MR activation in DBT animals disrupts the overconsolidation of aversive memory, without discarding the involvement of emotional behavior in these processes.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Extinção Psicológica/fisiologia , Medo/fisiologia , Generalização Psicológica/fisiologia , Memória/fisiologia , Receptores de Mineralocorticoides/metabolismo , Animais , Diabetes Mellitus Experimental/psicologia , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/psicologia , Fludrocortisona/farmacologia , Generalização Psicológica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Memória/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , Receptores de Mineralocorticoides/agonistasRESUMO
The physiopathology of anxiety or depression related to diabetes is still poorly understood. The treatment with antidepressant drugs is a huge challenge due to theirs adherence low rate and many adverse effects. Thus, the seeking for a better treatment for these associated diseases is of utmost importance. Given that the oxidative stress in different tissues occurs in diabetes and anxiety or depression as well, the antioxidant gallic acid becomes an interesting compound to be investigated. Thus, the effects of long-term treatment with gallic acid (0, 10, 20 and 40 mg/kg; gavage) were evaluated in diabetic (DBT) animals submitted to the elevated plus-maze (EPM), the light-dark transition (LDT) tests and modified forced swim test (mFST). Also, indirect parameters of oxidative stress, lipid peroxidation (LPO) and reduced glutathione (GSH) levels were evaluated in the hippocampus (HIP) and prefrontal cortex (PFC). The results showed that DBT animals presented a decrease in the spent time in the open arms, in the end arm exploration and head dips when evaluated in the EPM test; moreover, a decrease in the spent time in the lit compartment of LDT test was observed, suggesting an anxiogenic-like behavior. During the mFST, an increase in the mean counts of immobility and a decrease in the mean counts of swimming and climbing were observed, indicating a depressive-like behavior. These aversive behaviors were more pronounced when compared to normoglycemic (NGL) animals and streptozotocin-treated animals that not become DBT. In addition, DBT rats showed an increase in the oxidative stress parameters in the HIP and PFC that was reversed by the gallic acid treatment (lowest dose - 10 mg/kg), i.e., the treatment decreased the elevated LPO levels and increased the reduced GSH in the HIP and PFC. Also, gallic acid treatment was able to produce an anxiolytic-like effect in the EPM and LDT tests, but not antidepressant-like effect in the FST. Taken together, the results suggest that the antioxidant/neuroprotective effect of gallic acid treatment in HIP and PFC of DBT animals may be essential to the anxiolytic-like effect.
Assuntos
Ansiolíticos/farmacologia , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/psicologia , Ácido Gálico/farmacologia , Animais , Ansiolíticos/administração & dosagem , Antidepressivos/administração & dosagem , Antioxidantes/administração & dosagem , Ansiedade/etiologia , Ansiedade/fisiopatologia , Comportamento Animal/efeitos dos fármacos , Depressão/etiologia , Depressão/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Modelos Animais de Doenças , Fluoxetina/administração & dosagem , Fluoxetina/farmacologia , Ácido Gálico/administração & dosagem , Glutationa/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hiperglicemia/tratamento farmacológico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Wistar , EstreptozocinaRESUMO
Depression associated with diabetes has been described as a highly debilitating comorbidity. Due to its complex and multifactorial mechanisms, the treatment of depression associated with diabetes represents a clinical challenge. Cannabidiol (CBD), the non-psychotomimetic compound derived from Cannabis sativa, has been pointed out as a promising compound for the treatment of several psychiatric disorders. Here, we evaluated the potential antidepressant-like effect of acute or sub-chronic treatment with CBD in diabetic rats using the modified forced swimming test (mFST). Also, to better understand the functionality of the endocannabinoid system in diabetic animals we also evaluated the effect of URB597, a fatty acid amide hydrolase inhibitor. Four weeks after the treatment with streptozotocin (60â¯mg/kg; i.p.; diabetic group-DBT) or citrate buffer (i.p.; normoglycemic group-NGL), DBT animals received an acute intraperitoneal injection of CBD (0, 0.3, 3, 10, 30 or 60â¯mg/kg), 1â¯h before the mFST, or URB597 (0, 0.1, 0.3 or 1â¯mg/kg) 2â¯h before the mFST. In another set of experiments, animals were sub-chronically treated with CBD (0, 0.3, 3, 30 or 60â¯mg/kg i.p.), 24, 5 and 1â¯h before the mFST or URB597 (0, 0.1, 0.3 or 1â¯mg/kg i.p.) 24, 5 and 2â¯h before the mFST. The NGL group was acutely treated with CBD (0, 30â¯mg/kg i.p.) or URB597 (0, 0.3â¯mg/kg; i.p.). Acute treatment with either CBD or URB induced an antidepressant-like effect in NGL rats, but not in DBT rats. However, sub-chronic treatment with CBD (only at a dose of 30â¯mg/kg), but not with URB597, induced a mild antidepressant-like effect in DBT animals. Neither body weight nor blood glucose levels were altered by treatments. Considering the importance of the endocannabinoid system to the mechanism of action of many antidepressant drugs, the mild antidepressant-like effect of the sub-chronic treatment with CBD, but not with URB597 does not invalidate the importance of deepening the studies involving the endocannabinoid system particularly in DBT animals.
Assuntos
Antidepressivos/administração & dosagem , Benzamidas/administração & dosagem , Canabidiol/administração & dosagem , Carbamatos/administração & dosagem , Depressão/tratamento farmacológico , Diabetes Mellitus Experimental/tratamento farmacológico , Animais , Depressão/sangue , Depressão/psicologia , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/psicologia , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Wistar , Natação/psicologiaRESUMO
It is known that diabetic (DBT) animals present dysregulation on the serotonergic system in several brain areas associated with anxiety-like responses. The aim of this study was to investigate the involvement of 5-HT1A receptors on dorsal periaqueductal gray (dPAG) in the behavioral response related to panic disorder in type-1 DBT animals. For this, the escape response by electric stimulation (ES) of dPAG in DBT and normoglycemic (NGL) animals was assessed. Both NGL and DBT animals were exposed to an open-field test (OFT) 28 days after DBT confirmation. The current threshold to induce escape behavior in DBT animals was reduced compared with NGL animals. No impairment in locomotor activity was observed when DBT animals were compared with NGL animals. An intra-dPAG injection of the 5-HT1A receptor agonist (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) increased the [INCREMENT] threshold in both DBT and NGL, suggesting a panicolytic-like effect. DBT animals presented a more pronounced panicolytic-like response compared with NGL as a higher [INCREMENT] threshold was observed after 8-OH-DPAT treatment, which could be a consequence of the increased expression of the 5-HT1A receptor in the dPAG from DBT animals. Our results are in line with the proposal that a deficiency in serotonergic modulation of the dPAG is involved in triggering the panic attack and the 5-HT1A receptors might be essential for the panicolytic-like response.
Assuntos
Pânico/fisiologia , Substância Cinzenta Periaquedutal/fisiopatologia , Neurônios Serotoninérgicos/metabolismo , Animais , Ansiedade/metabolismo , Diabetes Mellitus Experimental/psicologia , Modelos Animais de Doenças , Reação de Fuga/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
The present study investigated the protective effect of quercetin (Querc) on memory, anxiety-like behavior and impairment of ectonucleotidases and acetylcholinesterase (AChE) activities in brain of streptozotocin-induced diabetic rats (STZ-diabetes). The type 1 diabetes mellitus was induced by an intraperitoneal injection of 70mg/kg of streptozotocin (STZ), diluted in 0.1M sodium-citrate buffer (pH 4.5). Querc was dissolved in 25% ethanol and administered by gavage at the doses of 5, 25 and 50mg/kg once a day during 40days. The animals were distributed in eight groups of ten animals as follows: vehicle, Querc 5mg/kg, Querc 25mg/kg, Querc 50mg/kg, diabetes, diabetes plus Querc 5mg/kg, diabetes plus Querc 25mg/kg and diabetes plus Querc 50mg/kg. Querc was able to prevent the impairment of memory and the anxiogenic-like behavior induced by STZ-diabetes. In addition, Querc prevents the decrease in the NTPDase and increase in the adenosine deaminase (ADA) activities in SN from cerebral cortex of STZ-diabetes. STZ-diabetes increased the AChE activity in SN from cerebral cortex and hippocampus. Querc 50mg/kg was more effective to prevent the increase in AChE activity in the brain of STZ-diabetes. Querc also prevented an increase in the malondialdehyde levels in all the brain structures. In conclusion, the present findings showed that Querc could prevent the impairment of the enzymes that regulate the purinergic and cholinergic extracellular signaling and improve the memory and anxiety-like behavior induced by STZ-diabetes.
Assuntos
5'-Nucleotidase/metabolismo , Acetilcolinesterase/metabolismo , Adenosina Desaminase/metabolismo , Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Memória/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Quercetina/farmacologia , Animais , Ansiedade/induzido quimicamente , Ansiedade/enzimologia , Ansiedade/psicologia , Encéfalo/enzimologia , Encéfalo/fisiopatologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/enzimologia , Diabetes Mellitus Experimental/psicologia , Diabetes Mellitus Tipo 1/induzido quimicamente , Diabetes Mellitus Tipo 1/enzimologia , Diabetes Mellitus Tipo 1/psicologia , Relação Dose-Resposta a Droga , Proteínas Ligadas por GPI/metabolismo , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/enzimologia , Transtornos da Memória/psicologia , Atividade Motora/efeitos dos fármacos , Ratos Wistar , EstreptozocinaRESUMO
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.