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MDMA-assisted psychotherapy has shown potential as an effective treatment for post-traumatic stress disorder (PTSD). Preclinical studies involving rodents have demonstrated that MDMA can facilitate the extinction of fear memories. It has been noted that MDMA impacts oxytocin neurons and pro-inflammatory cytokines. Thus, the aim of this study was to explore the role of oxytocinergic signaling and neuroinflammatory markers in the therapeutic effects of MDMA. To achieve this, male rats were subjected to a model of PTSD involving exposure to shock and situational reminders. MDMA was microinjected into the medial prefrontal cortex (mPFC) before extinction training, followed by behavioral tests assessing activity levels, anxiety, and social function. Our findings indicate that MDMA treatment facilitated fear extinction and mitigated the shock-induced increase in freezing, as well as deficits in social behavior. Shock exposure led to altered expression of the gene coding for OXT-R and neuroinflammation in the mPFC and basolateral amygdala (BLA), which were restored by MDMA treatment. Importantly, the OXT-R antagonist L-368,899 prevented MDMA's therapeutic effects on extinction and freezing behavior. In conclusion, MDMA's therapeutic effects in the PTSD model are associated with alterations in OXT-R expression and neuroinflammation, and MDMA's effects on extinction and anxiety may be mediated by oxytocinergic signaling.
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Aging is associated with changes in cognitive and emotional function. Cannabidiol (CBD) has been reported to attenuate stress and anxiety in human and animal studies. In this study, we aimed to assess the therapeutic potential of CBD among middle-aged female rats exposed to social isolation (SI) and the potential involvement of brain-derived neurotrophic factor (BDNF) in these effects. Thirteen-month-old female rats were group-housed (GH) or exposed to social isolation (SI) and treated with vehicle or CBD (10 mg/kg). CBD restored the SI-induced immobility in the forced swim test and the SI-induced decrease in the expression of BDNF protein levels in the nucleus accumbens (NAc). CBD also increased the time that rats spent in the center in an open field, improved spatial training, and increased BDNF expression in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA). BDNF expression was found to be correlated with an antidepressant (in the NAc) and an anxiolytic (in the mPFC, BLA, NAc) phenotype, and with learning improvement in the PFC. Together, our results suggest that CBD may serve as a beneficial agent for wellbeing in old age and may help with age-related cognitive decline.
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Cannabidiol , Animales , Femenino , Ratas , Antidepresivos/farmacología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cannabidiol/farmacología , Cannabidiol/metabolismo , Núcleo Accumbens/metabolismo , Corteza Prefrontal/metabolismo , Aislamiento SocialRESUMEN
Environmental factors, including stress, that are experienced during early life (ELS) or adolescence are potential risk factors for the development of behavioral and mental disorders later in life. The endocannabinoid system plays a major role in the regulation of stress responses and emotional behavior, thereby acting as a mediator of stress vulnerability and resilience. Among the critical factors, which determine the magnitude and direction of long-term consequences of stress exposure is age, i.e., the maturity of brain circuits during stress exposure. Thus, the present study addressed the hypotheses that ELS and adolescent stress differentially affect the expression of regulatory elements of the endocannabinoid system, cannabinoid receptor 1 (CB1R) and fatty acid amide hydrolase (FAAH) in the medial prefrontal cortex (mPFC) of adult female rats. We also tested the hypothesis that the proposed gene expression changes are epigenetically modulated via altered DNA-methylation. The specific aims were to investigate if (i) ELS and adolescent stress as single stressors induce changes in CB1R and FAAH expression (ii) ELS exposure influences the effect of adolescent stress on CB1R and FAAH expression, and (iii) if the proposed gene expression changes are paralleled by changes of DNA methylation. The following experimental groups were investigated: (1) non-stressed controls (CON), (2) ELS exposure (ELS), (3) adolescent stress exposure (forced swimming; FS), (4) ELS + FS exposure. We found an up-regulation of CB1R expression in both single-stressor groups and a reduction back to control levels in the ELS + FS group. An up-regulation of FAAH expression was found only in the FS group. The data indicate that ELS, i.e., stress during a very immature stage of brain development, exerts a buffering programming effect on gene expression changes induced by adolescent stress. The detected gene expression changes were accompanied by altered DNA methylation patterns in the promoter region of these genes, specifically, a negative correlation of mean CB1R DNA methylation with gene expression was found. Our results also indicate that ELS induces a long-term "(re)programming" effect, characterized by CpG-site specific changes within the promoter regions of the two genes that influence gene expression changes in response to FS at adolescence.
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Cannabidiol (CBD) is a potential antidepressant agent. We examined the association between the antidepressant effects of CBD and alterations in brain microRNAs in the unpredictable chronic mild stress (UCMS) model for depression. UCMS male rats were injected with vehicle or CBD (10 mg/kg) and tested for immobility time in the forced swim test. Alterations in miRNAs (miR16, miR124, miR135a) and genes that encode for the 5HT1a receptor, the serotonergic transporter SERT, ß-catenin, and CB1 were examined. UCMS increased immobility time in a forced swim test (i.e., depressive-like behavior) and altered the expression of miRNAs and mRNA in the ventromedial prefrontal cortex (vmPFC), raphe nucleus, and nucleus accumbens. Importantly, CBD restored UCMS-induced upregulation in miR-16 and miR-135 in the vmPFC as well as the increase in immobility time. CBD also restored the UCMS-induced decrease in htr1a, the gene that encodes for the serotonergic 5HT1a receptor; using a pharmacological approach, we found that the 5HT1a receptor antagonist WAY100135 blocked the antidepressant-like effect of CBD on immobility time. Our findings suggest that the antidepressant effects of CBD in a rat model for depression are associated with alterations in miR-16 and miR-135 in the vmPFC and are mediated by the 5HT1a receptor.
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Cannabidiol , MicroARNs , Ratas , Masculino , Animales , Cannabidiol/farmacología , Cannabidiol/uso terapéutico , Cannabidiol/metabolismo , Depresión/tratamiento farmacológico , Depresión/genética , Antidepresivos/farmacología , Antidepresivos/uso terapéutico , Encéfalo/metabolismo , Corteza Prefrontal/metabolismo , MicroARNs/metabolismo , Receptor de Serotonina 5-HT1A/genética , Receptor de Serotonina 5-HT1A/metabolismo , Modelos Animales de EnfermedadRESUMEN
Early life stress (ELS) increases predisposition to depression. We compared the effects of treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597, and the selective serotonin reuptake inhibitor paroxetine, on ELS-induced depressive-like behavior and the expression of microRNAs (miRs) associated with depression in the medial prefrontal cortex (mPFC), hippocampal CA1 area, lateral habenula and dorsal raphe in rats. We also examined the mRNA expression of serotonergic (htr1a and slc6a4) and endocannabinoid (cnr1, cnr2 and faah) targets in the mPFC following ELS and pharmacological treatment. Adult males and females exposed to the 'Limited Bedding and Nesting' ELS paradigm demonstrated a depressive-like phenotype and late-adolescence URB597 treatment, but not paroxetine, reversed this phenotype. In the mPFC, ELS downregulated miR-16 in males and miR-135a in females and URB597 treatment restored this effect. In ELS females, the increase in cnr2 and decrease in faah mRNAs in the mPFC were reversed by URB597 treatment. We show for the first time that URB597 reversed ELS-induced mPFC downregulation in specific miRs and stress-related behaviors, suggesting a novel mechanism for the beneficial effects of FAAH inhibition. The differential effects of ELS and URB597 on males and females highlight the importance of developing sex-specific treatment approaches.
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Amidohidrolasas , MicroARNs , Estrés Psicológico , Animales , Femenino , Masculino , Ratas , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Benzamidas/farmacología , Benzamidas/uso terapéutico , Endocannabinoides/metabolismo , MicroARNs/genética , Estrés Psicológico/genética , Estrés Psicológico/metabolismoRESUMEN
Inhibition of fatty acid amide hydrolase (FAAH), which increases anandamide levels, has been suggested as a potential treatment for stress-related conditions. We examined whether the stress-preventing effects of the FAAH inhibitor URB597 on behavior are mediated via ß-catenin in the nucleus accumbens (NAc). Male rats were exposed to the shock and reminders model of PTSD and then treated with URB597 (0.4 mg/kg; i.p.). They were tested for anxiety- (freezing, startle response), depression-like behaviors (despair, social preference, anhedonia), and memory function (T-maze, social recognition). We also tested the involvement of the CB1 receptor (CB1r), ß-catenin, and metabotropic glutamate receptor subtype 5 (mGluR5) proteins. URB597 prevented the shock- and reminders-induced increase in anxiety- and depressive-like behaviors, as well as the impaired memory via the CB1r-dependent mechanism. In the NAc, viral-mediated ß-catenin overexpression restored the behavior of rats exposed to stress and normalized the alterations in protein levels in the NAc and the prefrontal cortex. Importantly, when NAc ß-catenin levels were downregulated by viral-mediated gene transfer, the therapeutic-like effects of URB597 were blocked. We suggest a potentially novel mechanism for the therapeutic-like effects of FAAH inhibition that is dependent on ß-catenin activation in the NAc in a PTSD rat model.
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Depression is characterized by continuous low mood and loss of interest or pleasure in enjoyable activities. First-line medications for mood disorders mostly target the monoaminergic system; however, many patients do not find relief with these medications, and those who do suffer from negative side effects and a discouragingly low rate of remission. Studies suggest that the endocannabinoid system (ECS) may be involved in the etiology of depression and that targeting the ECS has the potential to alleviate depression. ECS components (such as receptors, endocannabinoid ligands, and degrading enzymes) are key neuromodulators in motivation and cognition as well as in the regulation of stress and emotions. Studies in depressed patients and in animal models for depression have reported deficits in ECS components, which is motivating researchers to identify potential diagnostic and therapeutic biomarkers within the ECS. By understanding the effects of cannabinoids on ECS components in depression, we enhance our understanding of which brain targets they hit, what biological processes they alter, and eventually how to use this information to design better therapeutic options. In this article, we discuss the literature on the effects of cannabinoids on ECS components of specific depression-like behaviors and phenotypes in rodents and then describe the findings in depressed patients. A better understanding of the effects of cannabinoids on ECS components in depression may direct future research efforts to enhance diagnosis and treatment.
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Cannabinoides , Endocannabinoides , Animales , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Depresión/tratamiento farmacológico , Endocannabinoides/fisiología , Humanos , Trastornos del Humor/tratamiento farmacológicoRESUMEN
NMDA receptor blockade in rodents is commonly used to induce schizophrenia-like behavioral abnormalities, including cognitive deficits and social dysfunction. Aberrant glutamate and GABA transmission, particularly in adolescence, is implicated in these behavioral abnormalities. The endocannabinoid system modulates glutamate and GABA transmission, but the impact of endocannabinoid modulation on cognitive and social dysfunction is unclear. Here, we asked whether late-adolescence administration of the anandamide hydrolysis inhibitor URB597 can reverse behavioral deficits induced by early-adolescence administration of the NMDA receptor blocker MK-801. In parallel, we assessed the impact of MK-801 and URB597 on mRNA expression of glutamate and GABA markers. We found that URB597 prevented MK-801-induced novel object recognition deficits and social interaction abnormalities in adult rats, and reversed glutamate and GABA aberrations in the prelimbic PFC. URB597-mediated reversal of MK-801-induced social interaction deficits was mediated by the CB1 receptor, whereas the reversal of cognitive deficits was mediated by the CB2 receptor. This was paralleled by the reversal of CB1 and CB2 receptor expression abnormalities in the basolateral amygdala and prelimbic PFC, respectively. Together, our findings show that interfering with NMDA receptor function in early adolescence has a lasting impact on phenotypes resembling the negative symptoms and cognitive deficits of schizophrenia and on glutamate and GABA marker expression in the PFC. Prevention of behavioral and molecular abnormalities by late-adolescence URB597 via CB1 and CB2 receptors suggests that endocannabinoid stimulation may have therapeutic potential in addressing treatment-resistant symptoms.
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Maleato de Dizocilpina , Endocannabinoides , Animales , Ácidos Araquidónicos , Maleato de Dizocilpina/farmacología , Endocannabinoides/metabolismo , Endocannabinoides/farmacología , Expresión Génica , Glutamatos , Hidrólisis , Masculino , Alcamidas Poliinsaturadas , Ratas , Receptor Cannabinoide CB2/metabolismo , Receptores de N-Metil-D-Aspartato , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Long-lasting cognitive impairment is one of the most central negative consequences related to the exposure to cannabis during adolescence and particularly of Δ-9-tetrahydrocannabinol (THC). The aim of this study was to compare the protracted effects of adolescent versus late-adolescent chronic exposure to THC on short-term memory and plasticity and to examine whether rapamycin, a blocker of the mammalian target of rapamycin (mTOR) pathway, can restore THC-induced deficits in memory and plasticity. Male rats were injected with ascending doses of THC [2.5, 5, 10 mg/kg; intraperitoneally (i.p.)] during adolescence and late-adolescence (post-natal days 30-41 and 45-56, respectively), followed by daily injections of rapamycin (1 mg/kg, i.p.) during the first 10 days of cessation from THC. Thirty days after the last injection, rats were tested for short-term and working memory, anxiety-like behaviour, and plasticity in the pathways projecting from the ventral subiculum (vSub) of the hippocampus to the prefrontal cortex (PFC) and nucleus accumbens (NAc). THC exposure in adolescence, but not late-adolescence, was found to induce long-term deficits in object recognition short-term memory and synaptic plasticity in the hippocampal-accumbens pathway. Importantly, rapamycin rescued these persistent effects of THC administered during adolescence. Our findings show that some forms of memory and plasticity are sensitive to chronic THC administration during adolescence and that rapamycin administered during THC cessation may restore cognitive function and plasticity, thus potentially protecting against the possible long-term harmful effects of THC.
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Dronabinol , Alucinógenos , Animales , Dronabinol/farmacología , Hipocampo , Masculino , Corteza Prefrontal , Ratas , Sirolimus/farmacologíaRESUMEN
There have been growing concerns about the protracted effects of cannabis use in adolescents on emotion and cognition outcomes, motivated by evidence of growing cannabis use in adolescents, evidence linking cannabis use to various psychiatric disorders, and the increasingly perceived notion that cannabis is harmless. At the same time, studies suggest that cannabinoids may have therapeutic potential against the impacts of stress on the brain and behavior, and that young people sometimes use cannabinoids to alleviate feelings of depression and anxiety (i.e., "self-medication"). Exposure to early adverse life events may predispose individuals to developing psychopathology in adulthood, leading researchers to study the causality between early life factors and cognitive and emotional outcomes in rodent models and to probe the underlying mechanisms. In this review, we aim to better understand the long-term effects of cannabinoids administered in sensitive developmental periods (mainly adolescence) in rodent models of early life stress. We suggest that the effects of cannabinoids on emotional and cognitive function may vary between different sensitive developmental periods. This could potentially affect decisions regarding the use of cannabinoids in clinical settings during the early stages of development and could raise questions regarding educating the public as to potential risks associated with cannabis use.
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Cannabinoides/efectos adversos , Susceptibilidad a Enfermedades , Trastornos Psicóticos/etiología , Animales , Modelos Animales de Enfermedad , Humanos , Acontecimientos que Cambian la Vida , Trastornos Psicóticos/psicología , Medición de Riesgo , Factores de Riesgo , Roedores , Factores Sexuales , Estrés PsicológicoRESUMEN
Early-life stress (ELS) is associated with later onset of depression. Early cannabis use may be a risk factor that interacts with environmental factors to increase the risk of psychopathologies. We aimed to examine the long-term effects of ELS on depression- and anxiety-like behavior, and examine whether chronic fatty acid amide hydrolase (FAAH) inhibition during mid-adolescence could ameliorate or exacerbate ELS effects on behavior. Male and female rats were exposed to ELS during post-natal days (P) 7-14, injected with the FAAH inhibitor URB597 (0.4â¯mg/kg, i.p.) or vehicle for 2â¯weeks during mid-adolescence (P30-45) or late-adolescence (P45-60). Rats were tested in adulthood for behavior and alterations in CB1 receptors (CB1r) and glucocorticoid receptors (GRs) in the brains' stress circuit. ELS produced decreased social preference, impaired social recognition, increased learned helplessness and anxiety-like behavior. Administering URB597 during mid-adolescence did not prevent the deleterious long-term effects of ELS on behavior in males and females. When URB597 was administered during late-adolescence, it ameliorated ELS-induced depression- and anxiety-like behavior. Moreover, in males, ELS and URB597 decreased CB1r levels in the prefrontal cortex (PFC) and CA1 and GRs in the PFC and basolateral amygdala (BLA). In females, ELS and URB decreased CB1r in the BLA and GRs in the CA1 and BLA. The findings suggest that mid-adolescence, as opposed to late-adolescence, may not be a potential developmental period for chronic treatment with FAAH inhibitors and that sex-dependent alterations in CB1r and GRs expression in the BLA-PFC-CA1 circuit may contribute to the depressive behavioral phenotype.
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Amidohidrolasas , Depresión , Estrés Psicológico , Animales , Femenino , Masculino , Ratas , Endocannabinoides , Receptor Cannabinoide CB1RESUMEN
Early life stress (ELS) may increase predisposition to depression. Despite extensive research, there is still a lack of knowledge of how to optimally treat depression. We aimed to establish a role for the endocannabinoid (ECB) system within the hippocampal-nucleus accumbens (NAc) network as a possible effective target in combating the pathophysiological development of depression-like behavior and neuronal alterations that are precipitated by ELS. Male and female rats were exposed to ELS during post-natal days (P) 7-14, injected with the fatty acid amide hydrolase (FAAH) inhibitor URB597 or the monoacylglycerol lipase (MAGL) inhibitor JZL184 for 2 weeks during late-adolescence (P45-60). Rats were tested starting at P90 for depressive- and anxiety-like behaviors as well as social preference and recognition; alterations in FAAH and MAGL activity; the expression of brain-derived neurotrophic factor (BDNF); and plasticity in the hippocampal-NAc pathway. FAAH and MAGL inhibitors during late-adolescence prevented: (i) the long-term effects of ELS on depression- and anxiety-like behavior and the impairment in social behavior and neuronal plasticity in males and females; (ii) ELS-induced alterations in MAGL activity in males' hippocampus and females' hippocampus and NAc; and (iii) ELS-induced alterations in BDNF in males' hippocampus and NAc and females' hippocampus. Significant correlations were observed between alterations in MAGL and BDNF levels and the behavioral phenotype. The findings suggest that alterations in MAGL activity and BDNF expression in the hippocampal-NAc network contribute to the depressive-like behavioral phenotype in ELS males and females. Moreover, the study suggests FAAH and MAGL inhibitors as potential intervention drugs for depression.
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Antidepresivos/uso terapéutico , Benzamidas/uso terapéutico , Benzodioxoles/uso terapéutico , Carbamatos/uso terapéutico , Depresión/tratamiento farmacológico , Piperidinas/uso terapéutico , Interacción Social , Estrés Psicológico/tratamiento farmacológico , Factores de Edad , Animales , Depresión/etiología , Depresión/psicología , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Estrés Psicológico/complicaciones , Estrés Psicológico/psicología , Resultado del TratamientoRESUMEN
Post-traumatic stress disorder (PTSD) is a complex disorder that involves dysregulation of multiple neurobiological systems. The traumatic stressor plays a causal role in producing psychological dysfunction and the pattern of findings suggests that the hypothalamic-pituitary-adrenal (HPA) axis, which is instrumental for stress adaptation, is critically dysfunctional in PTSD. Given the lack of understanding of the basic mechanisms and underlying pathways that cause the disorder and its heterogeneity, PTSD poses challenges for treatment. Targeting the endocannabinoid (ECB) system to treat mental disorders, and PTSD in particular, has been the focus of research and interest in recent years. The ECB system modulates multiple functions, and drugs enhancing ECB signaling have shown promise as potential therapeutic agents in stress effects and other psychiatric and medical conditions. In this review, we focus on the interaction between the ECB-HPA systems in animal models for PTSD and in patients with PTSD. We summarize evidence supporting the use of cannabinoids in preventing and treating PTSD in preclinical and clinical studies. As the HPA system plays a key role in the mediation of the stress response and the pathophysiology of PTSD, we describe preclinical studies suggesting that enhancing ECB signaling is consistent with decreasing PTSD symptoms and dysfunction of the HPA axis. Overall, we suggest that a pharmacological treatment targeted at one system (e.g., HPA) may not be very effective because of the heterogeneity of the disorder. There are abnormalities across different neurotransmitter systems in the pathophysiology of PTSD and none of these systems function uniformly among all patients with PTSD. Hence, conceptually, enhancing ECB signaling may be a more effective avenue for pharmacological treatment.
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Cannabinoides/farmacología , Endocannabinoides/metabolismo , Trastornos por Estrés Postraumático/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/fisiopatología , Transducción de Señal/efectos de los fármacos , Trastornos por Estrés Postraumático/fisiopatologíaRESUMEN
Modulation of cannabinoid and neuropeptide Y (NPY) receptors may offer therapeutic benefits for post-traumatic stress disorder (PTSD). In this study, we aimed to investigate the functional interaction between these systems in the basolateral amygdala (BLA) in a rat model of PTSD. Rats were exposed to the shock and reminders model of PTSD and tested for hyper arousal/PTSD- and depression-like behaviors 3 weeks later. Immediately after shock exposure rats were microinjected into the BLA with URB597, a selective inhibitor of fatty acid amide hydrolase (FAAH) that increases the levels of the endocannabinoid anandamide or with the NPY1 receptor agonist Leu31,Pro34-NPY (Leu). Intra-BLA URB597 prevented the shock/reminders-induced PTSD- behaviors (extinction, startle) and depression-behaviors (despair, social impairments). These preventing effects of URB597 on PTSD- and depression-like behaviors were shown to be mostly mediated by cannabinoid CB1 and NPY1 receptors, as they were blocked when URB597 was co-administered with a low dose of a CB1 or NPY1 receptor antagonist. Similarly, intra-BLA Leu prevented development of all the behaviors. Interestingly, a CB1 antagonist prevented the effects of Leu on despair and social behavior, but not the effects on extinction and startle. Moreover, exposure to shock and reminders upregulated CB1 and NPY1 receptors in the BLA and infralimbic prefrontal cortex and this upregulation was restored to normal with intra-BLA URB597 or Leu. The findings suggest that the functional interaction between the eCB and NPY1 systems is complex and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid and NPY systems for stress-related diseases.
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Ácidos Araquidónicos/metabolismo , Complejo Nuclear Basolateral/metabolismo , Endocannabinoides/metabolismo , Neuropéptido Y/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Receptor Cannabinoide CB1/metabolismo , Receptores de Neuropéptido Y/metabolismo , Trastornos por Estrés Postraumático/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Amígdala del Cerebelo/metabolismo , Animales , Nivel de Alerta , Conducta Animal , Benzamidas/farmacología , Carbamatos/farmacología , Depresión/metabolismo , Depresión/fisiopatología , Modelos Animales de Enfermedad , Extinción Psicológica , Neuropéptido Y/análogos & derivados , Neuropéptido Y/farmacología , Ratas , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptores de Neuropéptido Y/agonistas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Reflejo de Sobresalto , Conducta Social , Trastornos por Estrés Postraumático/fisiopatologíaRESUMEN
Posttraumatic stress disorder (PTSD) is characterized by the reexperiencing of a traumatic event and is associated with slower extinction of fear responses. Impaired extinction of fearful associations to trauma-related cues may interfere with treatment response, and extinction deficits may be premorbid risk factors for the development of PTSD. We examined the effects of exposure to a severe footshock followed by situational reminders (SRs) on extinction, plasticity, and endocannabinoid (eCB) content and activity in the hippocampal CA1 area and basolateral amygdala (BLA). We also examined whether enhancing eCB signaling before extinction, using the fatty acid amide hydrolase (FAAH) inhibitor URB597, could prevent the shock/SRs-induced effects on fear response and plasticity. URB597 administered systemically (0.3 mg/kg) or locally into the CA1 or BLA (0.1 µg/side) prior to extinction decreased fear retrieval and this effect persisted throughout extinction training and did not recuperate during spontaneous recovery. A low dose of the CB1 receptor antagonist AM251 (0.3 mg/kg i.p. or 0.01 µg/0.5 µl intra-CA1 or intra-BLA) blocked these effects suggesting that the effects of URB597 were CB1 receptor-dependent. Exposure to shock and reminders induced behavioral metaplasticity with opposite effects on long-term potentiation (LTP) in the hippocampus (impairment) and the BLA (enhancement). URB597 was found to prevent the opposite shock/SR-induced metaplasticity in hippocampal and BLA-LTP. Exposure to shock and reminders might cause variation in endogenous cannabinoid levels that could affect fear-circuit function. Indeed, exposure to shock and SRs affected eCB content: increased 2-arachidonoyl-glycerol (2-AG) and N-arachidonylethanolamine (AEA) levels in the CA1, decreased serum and BLA AEA levels while shock exposure increased FAAH activity in the CA1 and BLA. FAAH inhibition before extinction abolished fear and modulated LTP in the hippocampus and amygdala, brain regions pertinent to emotional memory. The findings suggest that targeting the eCB system before extinction may be beneficial in fear memory attenuation and these effects may involve metaplasticity in the CA1 and BLA.
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Amígdala del Cerebelo/fisiología , Emociones/fisiología , Endocannabinoides/fisiología , Hipocampo/fisiología , Memoria/fisiología , Plasticidad Neuronal/fisiología , Amidohidrolasas , Animales , Benzamidas/administración & dosificación , Benzamidas/farmacología , Región CA1 Hipocampal/fisiología , Carbamatos/administración & dosificación , Carbamatos/farmacología , Electrochoque , Extinción Psicológica/efectos de los fármacos , Miedo/psicología , Potenciación a Largo Plazo/efectos de los fármacos , Masculino , Microinyecciones , Ratas , Ratas Sprague-DawleyRESUMEN
Chronic direct activation of cannabinoid CB1 receptors (CB1r) may lead to downregulation of CB1r which may in turn result in a depression-like phenotype in certain individuals. We examined the effects of chronic cannabinoid receptor activation before exposure to an emotional traumatic event on CB1r expression in the basolateral amygdala (BLA) and CA1 and on protracted anxiety- and depression-like behaviors. We used exposure to severe shock and situational reminders (SRs) in an inhibitory apparatus as a model for emotional trauma. Chronic treatment with the CB1/2 receptor agonist WIN55,212-2 (1.2â¯mg/kg, i.p.) before shock exposure had differential effects on depression- and anxiety-like behavioral measures depending on withdrawal periods. In the 24â¯hrs withdrawal condition, WIN55,212-2 enhanced fear retrieval and impaired extinction, increased anhedonia and despair, but had a therapeutic effect in the startle test. In the 10 days withdrawal condition, WIN55,212-2 enhanced fear retrieval and impaired extinction without preventing the shock/SR-induced negative effects on anhedonia or startle response, but had a therapeutic effect in the despair test. Chronic treatment with WIN55,212-2 was found to down regulate CB1r protein levels in the BLA in the 10 days withdrawal condition, and to upregulate CB1r protein levels in the 24â¯hrs condition. In the CA1, rats chronically injected with vehicle or WIN55,212-2 demonstrated downregulation of CB1r protein levels. Chronic exposure to cannabinoids prior to an emotional trauma may have deleterious effects on emotional function suggesting that direct CB1/2 receptor activation may not be an optimal way to manipulate the endocannabinoid system in stressful individuals.
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Benzoxazinas/farmacología , Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Emociones/efectos de los fármacos , Morfolinas/farmacología , Naftalenos/farmacología , Estrés Psicológico/metabolismo , Anhedonia/efectos de los fármacos , Anhedonia/fisiología , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Complejo Nuclear Basolateral/efectos de los fármacos , Complejo Nuclear Basolateral/metabolismo , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Depresión/tratamiento farmacológico , Depresión/metabolismo , Modelos Animales de Enfermedad , Emociones/fisiología , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Masculino , Psicotrópicos/farmacología , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismoRESUMEN
Activating the endocannabinoid system has become a major focus in the search for novel therapeutics for anxiety and deficits in fear extinction, two defining features of PTSD. We examined whether chronic treatment with the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.2, 0.3, 0.4â¯mg/kg, i.p.) or the CB1/2 receptor agonist WIN55,212-2 (0.25, 0.5â¯mg/kg, i.p.) injected for 3 weeks to rats exposed to the shock and reminders model of PTSD would attenuate post-stress symptoms and affect basolateral amygdala (BLA) and CA1 CB1 receptors. Exposure to shock and reminders enhanced acoustic startle response and impaired extinction. Rats exposed to shock and reminders and chronically treated with URB597 demonstrated normalized startle response and intact extinction kinetics. WIN55,212-2 only affected the startle response. The therapeutic effects of URB597 and WIN55,212-2 were found to be CB1 receptor dependent, as these effects were blocked when a low dose of the CB1 receptor antagonist AM251 (0.3â¯mg/kg, i.p. for 3 weeks) was co-administered. Moreover, URB597, but not WIN55,212-2, normalized the shock/reminders-induced upregulation in CB1 receptor levels in the BLA and CA1. One hour after the shock, N-arachidonoylethanolamine (AEA) was increased in the BLA and decreased in the CA1. Circulating 2-arachidonoylglycerol (2-AG) concentrations were decreased in shocked rats, with no significant effect in the BLA or CA1. FAAH activity was increased in the CA1 of shocked rats. Chronic cannabinoid treatment with URB597 can ameliorate PTSD-like symptoms suggesting FAAH inhibitors as a potentially effective therapeutic strategy for the treatment of disorders associated with inefficient fear coping.
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Amidohidrolasas/antagonistas & inhibidores , Benzamidas/administración & dosificación , Benzamidas/farmacología , Carbamatos/administración & dosificación , Carbamatos/farmacología , Trastornos por Estrés Postraumático/tratamiento farmacológico , Amidohidrolasas/metabolismo , Animales , Ácidos Araquidónicos/sangre , Complejo Nuclear Basolateral/metabolismo , Benzoxazinas/administración & dosificación , Benzoxazinas/farmacología , Región CA1 Hipocampal/metabolismo , Antagonistas de Receptores de Cannabinoides/farmacología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Endocannabinoides/sangre , Endocannabinoides/metabolismo , Extinción Psicológica/efectos de los fármacos , Glicéridos/sangre , Masculino , Morfolinas/administración & dosificación , Morfolinas/farmacología , Naftalenos/administración & dosificación , Naftalenos/farmacología , Piperidinas/farmacología , Alcamidas Poliinsaturadas , Pirazoles/farmacología , Ratas , Receptor Cannabinoide CB1/metabolismo , Receptor Cannabinoide CB2/fisiología , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiologíaRESUMEN
Posttraumatic stress disorder (PTSD) is a debilitating condition highly comorbid with depression. The endocannabinoid (eCB) system and brain-derived neurotrophic factor (BDNF) are suggestively involved in both disorders. We examined whether cannabinoids can prevent the long-term depressive-like symptoms induced by exposure to the shock and situational reminders (SRs) model of PTSD. The CB1/2 receptor agonist WIN55,212-2 (0.5â¯mg/kg; i.p.), the fatty acid hydrolase (FAAH) inhibitor URB597 (0.3â¯mg/kg, i.p.) or vehicle were administered 2â¯h after severe shock. Cannabinoids prevented the shock/SRs-induced alterations in social recognition memory, locomotion, passive coping, anxiety-like behavior, anhedonia, fear retrieval, fear extinction and startle response as well as the decrease in BDNF levels in the hippocampus and prefrontal cortex (PFC). Furthermore, significant correlations were found between depressive-like behaviors and BDNF levels in the brain. The findings suggest that cannabinoids may prevent both depressive- and PTSD-like symptoms following exposure to severe stress and that alterations in BDNF levels in the brains' fear circuit are involved in these effects.
Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/metabolismo , Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Depresión/prevención & control , Trastornos por Estrés Postraumático/tratamiento farmacológico , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Animales , Benzamidas/farmacología , Benzoxazinas/farmacología , Carbamatos/farmacología , Depresión/metabolismo , Modelos Animales de Enfermedad , Electrochoque , Inhibidores Enzimáticos , Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Morfolinas/farmacología , Naftalenos/farmacología , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas Sprague-Dawley , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/psicologíaRESUMEN
The locus coeruleus (LC)-amygdala circuit is implicated in playing a key role in responses to emotionally arousing stimuli and in the manifestation of post-traumatic stress disorder (PTSD). Here, we examined changes in gene expression of a number of important mediators of the LC-amygdala circuitry in the inhibition avoidance model of PTSD. After testing for basal acoustic startle response (ASR), rats were exposed to a severe footshock (1.5 mA for 10 s) in the inhibitory avoidance apparatus. They were given contextual situational reminders every 5 day for 25 days. Controls were treated identically but with the footshock inactivated. Animals were re-tested on second ASR and decapitated 1 h later. The shock group had enhanced hyperarousal and several changes in gene expression compared to controls. In the LC, mRNA levels of norepinephrine (NE) biosynthetic enzymes (TH, DBH), NE transporter (NET), NPY receptors (Y1R, Y2R), and CB1 receptor of endocannabinoid system were elevated. In the basolateral amygdala (BLA), there were marked reductions in gene expression for CB1, and especially Y1R, with rise for corticotropin-releasing hormone (CRH) system (CRH, CRH receptor 1), and no significant changes in the central amygdala. Our results suggest a fast forward mechanism in the LC-amygdala circuitry in the shock group.