RESUMEN
Neural activity within the ventromedial prefrontal cortex (vmPFC) is a critical determinant of stressor-induced anxiety. Pharmacological activation of the vmPFC during stress protects against stress-induced social anxiety suggesting that altering the excitatory/inhibitory (E/I) tone in the vmPFC may promote stress resilience. E/I balance is maintained, in part, by endogenous cannabinoid (eCB) signaling with the calcium dependent retrograde release of 2-arachidonoylglycerol (2-AG) suppressing presynaptic neurotransmitter release. We hypothesized that raising 2-AG levels, via inhibition of its degradation enzyme monoacylglycerol lipase (MAGL) with KML29, would shift vmPFC E/I balance and promote resilience. In acute slice experiments, bath application of KML29 (100 nM) augmented evoked excitatory neurotransmission as evidenced by a left-shift in fEPSP I/O curve, and decreased sIPSC amplitude. In whole-cell recordings, KML29 increased resting membrane potential but reduced the after depolarization, bursting rate, membrane time constant and slow after hyperpolarization. Intra-vmPFC administration of KML29 (200ng/0.5µL/hemisphere) prior to inescapable stress (IS) exposure (25, 5s tail shocks) prevented stress induced anxiety as measured by juvenile social exploration 24 h after stressor exposure. Conversely, systemic administration of KML29 (40 mg/kg, i.p.) 2 h before IS exacerbated stress induced anxiety. MAGL inhibition in the vmPFC may promote resilience by augmenting the output of neurons that project to brainstem and limbic structures that mediate stress responses.
Asunto(s)
Potenciales Postsinápticos Excitadores/fisiología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/metabolismo , Corteza Prefrontal/enzimología , Estrés Psicológico/enzimología , Estrés Psicológico/psicología , Animales , Benzodioxoles/farmacología , Benzodioxoles/uso terapéutico , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Masculino , Técnicas de Cultivo de Órganos , Piperidinas/farmacología , Piperidinas/uso terapéutico , Corteza Prefrontal/efectos de los fármacos , Pirazoles/farmacología , Pirazoles/uso terapéutico , Ratas , Ratas Endogámicas F344 , Estrés Psicológico/tratamiento farmacológicoRESUMEN
The probability of suffering the mood disorder depression is up to 30% in women and 15% in men during their life span. Pharmacological options for depression are limited: conventional antidepressants have low efficacy and a delayed onset of action (several weeks). Here we investigate the antidepressant actions of inhibitors of monoacylglycerol lipase (MAGL), the major degradative enzyme of the endocannabinoid 2-arachidonoylglycerol. A low-dose of MAGL inhibitors produces antidepressant effects on acute stress-exposed mice, through glutamatergic synaptic long-term depression (LTD), without significant effects on chronic corticosterone-exposed mice. In contrast, a high-dose of MAGL inhibitors produces pro- or antidepressant effects on acute stress- or chronic corticosterone-exposed mice, respectively, through GABAergic synaptic disinhibition. In the hippocampus, in vivo inhibition of MAGL induces a CB1 cannabinoid receptor (CB1R)-dependent suppression of inhibitory GABAergic synapses and an in vivo LTD of excitatory glutamatergic synapses. LTD induction requires CB1R in astroglial cells (but not in GABAergic or glutamatergic neurons) and postsynaptic glutamate receptors. The conventional antidepressant fluoxetine produces rapid or delayed antidepressant effects in acute stress- or chronic corticosterone-exposed mice, respectively. We propose that depression-like behavior of animals in response to acute stress is the normal behavioral response, and thus, MAGL inhibitors, which produce antidepressant effects in chronic corticosterone-exposed animals through GABAergic synaptic disinhibition, represent a new class of rapidly-acting and long-lasting antidepressants.
Asunto(s)
Benzodioxoles/metabolismo , Depresión/metabolismo , Piperidinas/metabolismo , Animales , Antidepresivos/farmacología , Ácidos Araquidónicos , Benzodioxoles/uso terapéutico , Región CA1 Hipocampal/metabolismo , Depresión/tratamiento farmacológico , Endocannabinoides/metabolismo , Endocannabinoides/uso terapéutico , Neuronas GABAérgicas/metabolismo , Hipocampo/metabolismo , Depresión Sináptica a Largo Plazo/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Monoacilglicerol Lipasas/antagonistas & inhibidores , Monoacilglicerol Lipasas/metabolismo , Neuronas/metabolismo , Piperidinas/uso terapéutico , Receptor Cannabinoide CB1/metabolismo , Sinapsis/metabolismoRESUMEN
A large body of evidence has been brought forward connecting developmental immune activation to abnormal fear and anxiety levels. Anxiety disorders have extremely high lifetime prevalence, yet susceptibility factors that contribute to their emergence are poorly understood. In this research we investigated whether an inflammatory insult early in life can alter the response to fear conditioning in adulthood. Fear learning and extinction are important and adaptive behaviors, mediated largely by the amygdala and its interconnectivity with cortico-limbic circuits. Male and female rat pups were given LPS (100µg/kg i.p.) or saline at postnatal day 14; LPS activated cFos expression in the central amygdala 2.5h after exposure, but not the basal or lateral nuclei. When tested in adulthood, acquisition of an auditory cued or contextual learned fear memory was largely unaffected as was the extinction of fear to a conditioned context. However, we detected a deficit in auditory fear extinction in male and female rats that experienced early-life inflammation, such that there is a significant delay in fear extinction processes resulting in more sustained fear behaviors in response to a conditioned cue. This response was specific to extinction training and did not persist into extinction recall. The effect could not be explained by differences in pain threshold (unaltered) or in baseline anxiety, which was elevated in adolescent females only and unaltered in adolescent males and adult males and females. This research provides further evidence for the involvement of the immune system during development in the shaping of fear and anxiety related behaviors.
Asunto(s)
Extinción Psicológica/efectos de los fármacos , Miedo/fisiología , Estrés Psicológico/inmunología , Adaptación Psicológica , Amígdala del Cerebelo/efectos de los fármacos , Animales , Ansiedad/metabolismo , Trastornos de Ansiedad , Condicionamiento Clásico/fisiología , Condicionamiento Psicológico/fisiología , Señales (Psicología) , Femenino , Inflamación , Aprendizaje , Lipopolisacáridos/farmacología , Masculino , Recuerdo Mental/fisiología , Ratas , Ratas Sprague-Dawley , RoedoresRESUMEN
Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function. The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence. We investigated the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS. To test this, multiple cohorts of Sprague Dawley rats were injected with LPS on P14. In adolescence, rats were subjected to behavioral testing in a reciprocal social interaction paradigm as well as the open field. We quantified eCB levels in the amygdala of P14 and adolescent animals (anandamide and 2-arachidonoylglycerol) as well as adolescent amygdaloid cannabinoid receptor 1 (CB1) binding site density and the hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which metabolizes the eCB anandamide. Additionally, we examined the impact of FAAH inhibition on alterations in social behavior. Our results indicate that P14 LPS decreases adolescent social behavior (play and social non-play) in males and females at P40. This behavioral alteration is accompanied by decreased CB1 binding, increased anandamide levels and increased FAAH activity. Oral administration of the FAAH inhibitor PF-04457845 (1mg/kg) prior to the social interaction task normalizes LPS-induced alterations in social behavior, while not affecting social behavior in the control group. Infusion of 10ng PF-04457845 into the basolateral amygdala normalized social behavior in LPS injected females. These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Ácidos Araquidónicos/metabolismo , Conducta Animal , Endocannabinoides/metabolismo , Inflamación/psicología , Alcamidas Poliinsaturadas/metabolismo , Conducta Social , Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/metabolismo , Animales , Femenino , Glicéridos/metabolismo , Inflamación/inducido químicamente , Lipopolisacáridos , Masculino , Piridazinas/administración & dosificación , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/metabolismo , Transducción de Señal , Urea/administración & dosificación , Urea/análogos & derivadosRESUMEN
UNLABELLED: Women of child-bearing age are the population group at highest risk for depression. In pregnant women, fluoxetine (Flx) is the most widely prescribed selective serotonin reuptake inhibitor (SSRI) used for the treatment of depression. While maternal stress, depression, and Flx exposure have been shown to effect neurodevelopment of the offspring, separately, combined effects of maternal stress and Flx exposure have not been extensively examined. The present study investigated the effects of prenatal maternal stress and perinatal exposure to the SSRI Flx on the behavior of male mice as adults. METHODS: C57BL/6 dams exposed to chronic unpredictable stress from embryonic (E) day 4 to E18 and non-stressed dams were administered Flx (25 mg/kg/d) in the drinking water from E15 to postnatal day 12. A separate control group consisted of animals that were not exposed to stress or Flx. At 12 days of age, brain levels of serotonin were assessed in the male offspring. At two months of age, the male offspring of mothers exposed to prenatal stress (PS), perinatal Flx, PS and Flx, or neither PS or Flx, went through a comprehensive behavioral test battery. At the end of testing brain-derived neurotropic factor (BDNF) levels were assessed in the frontal cortex of the offspring. RESULTS: Maternal behavior was not altered by either stress or Flx treatment. Treatment of the mother with Flx led to detectible Flx and NorFlx levels and lead to a decrease in serotonin levels in pup brains. In the adult male offspring, while perinatal exposure to Flx increased aggressive behavior, prenatal maternal stress decreased aggressive behavior. Interestingly, the combined effects of stress and Flx normalized aggressive behavior. Furthermore, perinatal Flx treatment led to a decrease in anxiety-like behavior in male offspring. PS led to hyperactivity and a decrease in BDNF levels in the frontal cortex regardless of Flx exposure. Neither maternal stress or Flx altered offspring performance in tests of cognitive abilities, memory, sensorimotor information processing, or risk assessment behaviors. These results demonstrate that maternal exposure to stress and Flx have a number of sustained effects on the male offspring.
Asunto(s)
Conducta Animal , Encéfalo/efectos de los fármacos , Fluoxetina/toxicidad , Efectos Tardíos de la Exposición Prenatal , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidad , Estrés Psicológico , Agresión/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Masculino , Conducta Materna/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , EmbarazoRESUMEN
It has previously been shown in rats that acute administration of delta-9-tetrahydrocannabinol (THC) exerts a dose-dependent effect on simple locomotor activity, with low doses of THC causing hyper-locomotion and high doses causing hypo-locomotion. However the effect of acute THC administration on cortical movement representations (motor maps) and skilled learned movements is completely unknown. It is important to determine the effects of THC on motor maps and skilled learned behaviors because behaviors like driving place people at a heightened risk. Three doses of THC were used in the current study: 0.2mg/kg, 1.0mg/kg and 2.5mg/kg representing the approximate range of the low to high levels of available THC one would consume from recreational use of cannabis. Acute peripheral administration of THC to drug naïve rats resulted in dose-dependent alterations in motor map expression using high resolution short duration intracortical microstimulation (SD-ICMS). THC at 0.2mg/kg decreased movement thresholds and increased motor map size, while 1.0mg/kg had the opposite effect, and 2.5mg/kg had an even more dramatic effect. Deriving complex movement maps using long duration (LD)-ICMS at 1.0mg/kg resulted in fewer complex movements. Dosages of 1.0mg/kg and 2.5mg/kg THC reduced the number of reach attempts but did not affect percentage of success or the kinetics of reaching on the single pellet skilled reaching task. Rats that received 2.5mg/kg THC did show an increase in latency of forelimb removal on the bar task, while dose-dependent effects of THC on unskilled locomotor activity using the rotorod and horizontal ladder tasks were not observed. Rats may be employing compensatory strategies after receiving THC, which may account for the robust changes in motor map expression but moderate effects on behavior.
Asunto(s)
Dronabinol/farmacología , Actividad Motora/efectos de los fármacos , Corteza Motora/efectos de los fármacos , Psicotrópicos/farmacología , Animales , Estimulación Eléctrica , Miembro Anterior , Masculino , Ratas , Ratas Long-EvansRESUMEN
The developing brain undergoes substantial maturation into adulthood and the development of specific neural structures occurs on differing timelines. Transient imbalances between developmental trajectories of corticolimbic structures, which are known to contribute to regulation over fear learning and anxiety, can leave an individual susceptible to mental illness, particularly anxiety disorders. There is a substantial body of literature indicating that the endocannabinoid (eCB) system critically regulates stress responsivity and emotional behavior throughout the life span, making this system a novel therapeutic target for stress- and anxiety-related disorders. During early life and adolescence, corticolimbic eCB signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that eCB signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic eCB signaling, such as stress or cannabinoid exposure, could serve as a neural substrate contributing to alterations to the normative developmental trajectory of neural structures governing emotional behavior and fear learning. In this review, we first introduce the components of the eCB system and discuss clinical and rodent models showing eCB regulation of fear learning and anxiety in adulthood. Next, we highlight distinct fear learning and regulation profiles throughout development and discuss the ontogeny of the eCB system in the central nervous system, and models of pharmacological augmentation of eCB signaling during development in the context of fear learning and anxiety.
Asunto(s)
Ansiedad/metabolismo , Encéfalo/crecimiento & desarrollo , Endocannabinoides/metabolismo , Miedo , Aprendizaje , Animales , Encéfalo/metabolismo , Encéfalo/fisiología , Humanos , NeurogénesisRESUMEN
The endocannabinoid (eCB) system regulates emotion, stress, memory and cognition through the cannabinoid type 1 (CB1 ) receptor. To test the role of CB1 signaling in social anxiety and memory, we utilized a genetic knockout (KO) and a pharmacological approach. Specifically, we assessed the effects of a constitutive KO of CB1 receptors (CB1 KOs) and systemic administration of a CB1 antagonist (AM251; 5 mg/kg) on social anxiety in a social investigation paradigm and social memory in a social discrimination test. Results showed that when compared with wild-type (WT) and vehicle-treated animals, CB1 KOs and WT animals that received an acute dose of AM251 displayed anxiety-like behaviors toward a novel male conspecific. When compared with WT animals, KOs showed both active and passive defensive coping behaviors, i.e. elevated avoidance, freezing and risk-assessment behaviors, all consistent with an anxiety-like profile. Animals that received acute doses of AM251 also showed an anxiety-like profile when compared with vehicle-treated animals, yet did not show an active coping strategy, i.e. changes in risk-assessment behaviors. In the social discrimination test, CB1 KOs and animals that received the CB1 antagonist showed enhanced levels of social memory relative to their respective controls. These results clearly implicate CB1 receptors in the regulation of social anxiety, memory and arousal. The elevated arousal/anxiety resulting from either total CB1 deletion or an acute CB1 blockade may promote enhanced social discrimination/memory. These findings may emphasize the role of the eCB system in anxiety and memory to affect social behavior.
Asunto(s)
Ansiedad/genética , Memoria , Receptor Cannabinoide CB1/genética , Adaptación Psicológica , Animales , Ansiedad/metabolismo , Nivel de Alerta , Reacción Cataléptica de Congelación , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Discriminación SocialRESUMEN
SETTING: Three district hospitals in KwaZulu-Natal, South Africa, with specialized drug-resistant tuberculosis (TB) wards. OBJECTIVE: To increase understanding of the implementation of occupational health (OH) and infection control (IC) guidelines for the prevention and control of TB among health care workers (HCWs). DESIGN: An operational cross-sectional study conducted between July and September 2011, consisting of interviews with OH and IC nurses and chart review of OH medical records. RESULTS: Although general national and provincial OH policies are in place, no specific OH policies exist for hospital settings. Two of three hospitals had a full-time OH nurse and all had a full-time IC nurse. All hospitals offered TB symptom screening; however, only 19% of HCWs were screened in 2010. TB incidence among HCWs was 1958 per 100 000 population in 2010. All hospitals offered HIV counseling and testing; however, only 22% of staff were tested across sites. Two hospitals offered isoniazid preventive therapy to HIV-positive staff and reassigned these staff to low TB risk areas. CONCLUSIONS: While OH policies and procedures are in place, implementation of these policies and procedures is inconsistent. This potentially places HCWs at risk of acquiring TB. These findings support the need for strengthening OH and IC services to prevent TB.
RESUMEN
Chronic stress is known to modulate cannabinoid CB1 receptor binding densities in corticolimbic structures, in a region-dependent manner; however, the ontogeny of these changes and the degree to which they recover following exposure to stress have yet to be determined. To this extent, we examined both the immediate and sustained effects (following a 40-day recovery period) of a repeated restraint stress paradigm (30-min restraint/day for 10 days) on CB1 receptor binding in the prefrontal cortex (PFC), hippocampus and amygdala in both adolescent (stress onset at post-natal day [PND] 35) and adult (stress onset at PND 75) male Sprague-Dawley rats. Consistent with previous reports, we found that repeated stress in adult rats resulted in an increase in CB1 receptor binding in the PFC, a reduction in CB1 receptor binding in the hippocampus and no effect in the amygdala. Interestingly, adolescent rats exposed to repeated restraint stress did not show any change in hippocampal CB1 receptor density, but exhibited an upregulation of CB1 receptor binding in both the PFC and amygdala. In adults, a 40-day recovery period resulted in a normalization of CB1 receptor binding in the PFC, and surprisingly a pronounced upregulation of CB1 receptor binding in the hippocampus, possibly indicative of a rebound effect. Adolescents similarly exhibited this rebound increase in hippocampal CB1 receptor binding, despite a lack in immediate downregulation following repeated restraint. Of particular interest, adolescents exposed to stress were found to have a sustained downregulation of prefrontocortical CB1 receptors in adulthood, which may relate to some of the reported sustained behavioral effects of stress in adolescence. Collectively, these data indicate that the effects of chronic stress on cannabinoid CB1 receptor binding are modulated by the age of stress exposure and period of recovery following the cessation of stress.
Asunto(s)
Sistema Límbico/metabolismo , Corteza Prefrontal/metabolismo , Receptor Cannabinoide CB1/antagonistas & inhibidores , Receptor Cannabinoide CB1/metabolismo , Estrés Psicológico/metabolismo , Factores de Edad , Animales , Regulación hacia Abajo/fisiología , Masculino , Unión Proteica/fisiología , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/biosíntesis , Estrés Psicológico/psicología , Factores de TiempoRESUMEN
Hyperactivation of the amygdala following chronic stress is believed to be one of the primary mechanisms underlying the increased propensity for anxiety-like behaviors and pathological states; however, the mechanisms by which chronic stress modulates amygdalar function are not well characterized. The aim of the current study was to determine the extent to which the endocannabinoid (eCB) system, which is known to regulate emotional behavior and neuroplasticity, contributes to changes in amygdalar structure and function following chronic stress. To examine the hypothesis, we have exposed C57/Bl6 mice to chronic restraint stress, which results in an increase in fatty acid amide hydrolase (FAAH) activity and a reduction in the concentration of the eCB N-arachidonylethanolamine (AEA) within the amygdala. Chronic restraint stress also increased dendritic arborization, complexity and spine density of pyramidal neurons in the basolateral nucleus of the amygdala (BLA) and increased anxiety-like behavior in wild-type mice. All of the stress-induced changes in amygdalar structure and function were absent in mice deficient in FAAH. Further, the anti-anxiety effect of FAAH deletion was recapitulated in rats treated orally with a novel pharmacological inhibitor of FAAH, JNJ5003 (50 mg per kg per day), during exposure to chronic stress. These studies suggest that FAAH is required for chronic stress to induce hyperactivity and structural remodeling of the amygdala. Collectively, these studies indicate that FAAH-mediated decreases in AEA occur following chronic stress and that this loss of AEA signaling is functionally relevant to the effects of chronic stress. These data support the hypothesis that inhibition of FAAH has therapeutic potential in the treatment of anxiety disorders, possibly by maintaining normal amygdalar function in the face of chronic stress.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Amidohidrolasas/fisiología , Amígdala del Cerebelo/patología , Ansiedad/prevención & control , Estrés Psicológico/enzimología , Amidohidrolasas/deficiencia , Amidohidrolasas/genética , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/enzimología , Ansiedad/etiología , Ácidos Araquidónicos , Enfermedad Crónica , Ciclohexanoles/farmacología , Dendritas/ultraestructura , Evaluación Preclínica de Medicamentos , Endocannabinoides/deficiencia , Endocannabinoides/metabolismo , Conducta Exploratoria/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Alcamidas Poliinsaturadas , Células Piramidales/patología , Ratas , Ratas Sprague-Dawley , Receptor Cannabinoide CB1/agonistas , Receptor Cannabinoide CB1/fisiología , Restricción Física/efectos adversos , Estrés Psicológico/complicaciones , Estrés Psicológico/patología , Estrés Psicológico/fisiopatologíaRESUMEN
Accumulating evidence has revealed that dysregulation of the endocannabinoid system could contribute to the development of major depression. Studies carried out post-mortem in depressed suicide victims have revealed increased CB(1) receptor binding site density in the prefrontal cortex (PFC). Accordingly, exposure of rodents to chronic unpredictable stress (CUS) results in phenotypic changes that mirror those of human depression, including increased CB(1) receptor binding site density in the PFC. Our goal in these studies was to examine the effects of CUS on the density of CB(1) receptor binding sites in the rodent medial PFC and to explore the role of this alteration in the behavioral changes invoked by CUS. Rodents exposed to CUS exhibited increased CB(1) receptor maximal binding site density (B(max)) within the ventromedial PFC, but not the dorsomedial PFC. To determine whether this change in the ventromedial PFC is an adaptive response, or alternatively, a consequence of chronic stress that contributes to the adoption of passive coping, we examined whether local CB(1) receptor blockade within the ventromedial PFC following CUS would significantly alter behaviors in the forced swim test (FST). CUS exposure significantly increased passive coping in the FST, and this was further augmented by discrete ventromedial PFC microinfusions of the CB(1) receptor antagonist AM251 prior to swim stress. Moreover, local CB(1) receptor blockade reduced active coping responses in CUS-exposed rats. These findings suggest that the increase in CB(1) receptor B(max) observed in the ventromedial PFC of rodents exposed to CUS maintains proactive coping strategies following chronic stress exposure.
Asunto(s)
Corteza Prefrontal/metabolismo , Receptor Cannabinoide CB1/metabolismo , Estrés Psicológico/patología , Regulación hacia Arriba , Adaptación Psicológica , Analgésicos/farmacocinética , Animales , Señales (Psicología) , Ciclohexanoles/farmacocinética , Modelos Animales de Enfermedad , Masculino , Unión Proteica , Ratas , Ratas Sprague-Dawley , Natación/psicología , Tritio/farmacocinéticaRESUMEN
This article is part of a Special Issue entitled:Stress, Emotional Behavior, and the Endocannabinoid System.
Asunto(s)
Moduladores de Receptores de Cannabinoides/fisiología , Emociones/fisiología , Endocannabinoides , Estrés Psicológico/fisiopatología , Animales , Conducta Animal/fisiología , HumanosRESUMEN
The hypothalamic-pituitary-adrenal (HPA) axis regulates the outflow of glucocorticoid hormones under basal conditions and in response to stress. Within the last decade, a large body of evidence has mounted indicating that the endocannabinoid system is involved in the central regulation of the stress response; however, the specific role endocannabinoid signaling plays in phases of HPA axis regulation, and the neural sites of action mediating this regulation, were not mapped out until recently. This review aims to collapse the current state of knowledge regarding the role of the endocannabinoid system in the regulation of the HPA axis to put together a working model of how and where endocannabinoids act within the brain to regulate outflow of the HPA axis. Specifically, we discuss the role of the endocannabinoid system in the regulation of the HPA axis under basal conditions, activation in response to acute stress, and glucocorticoid-mediated negative feedback. Interestingly, there appears to be some anatomical specificity to the role of the endocannabinoid system in each phase of HPA axis regulation, as well as distinct roles of both anandamide and 2-arachidonoylglycerol in these phases. Overall, the current level of information indicates that endocannabinoid signaling acts to suppress HPA axis activity through concerted actions within the prefrontal cortex, amygdala, and hypothalamus.
Asunto(s)
Moduladores de Receptores de Cannabinoides/metabolismo , Endocannabinoides , Retroalimentación Fisiológica/fisiología , Glucocorticoides/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Transducción de Señal/fisiología , Animales , Humanos , Estrés Psicológico/metabolismoRESUMEN
Limbic endocannabinoid signaling is known to be sensitive to chronic stress; however, studies investigating the impact of prolonged exposure to glucocorticoid hormones have been limited by the concurrent exposure to the stress of daily injections. The present study was designed to examine the effects of a noninvasive approach to alter plasma corticosterone (CORT) on the endocannabinoid system. More precisely, we explored the effects of a 4-week exposure to CORT dissolved in the drinking water of mice (100 µg/ml) and measured cannabinoid CB(1) receptor binding, endocannabinoid content, activity of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH), and mRNA expression of both the CB(1) receptor and FAAH in both the hippocampus and amygdala. Our data demonstrate that CORT decreases CB(1) receptor binding site density in both the hippocampus and amygdala and also reduced anandamide (AEA) content and increased FAAH activity within both structures. These changes in both CB(1) receptor binding and FAAH activity were not accompanied by changes in mRNA expression of either the CB(1) receptor or FAAH in either brain region. Interestingly, our CORT delivery regimen significantly increased 2-AG concentrations within the hippocampus, but not the amygdala. Collectively, these data demonstrate that the confounder of injection stress is sufficient to conceal the ability of protracted exposure to glucocorticoids to reduce CB(1) receptor density and augment AEA metabolism within limbic structures.
Asunto(s)
Moduladores de Receptores de Cannabinoides/metabolismo , Corticosterona/farmacología , Endocannabinoides , Sistema Límbico/efectos de los fármacos , Receptor Cannabinoide CB1/metabolismo , Transducción de Señal/efectos de los fármacos , Amidohidrolasas/metabolismo , Animales , Sistema Límbico/metabolismo , Masculino , Ratones , Transducción de Señal/fisiologíaRESUMEN
BACKGROUND: Preclinical research has suggested that the endocannabinoid system may be involved in the etiology and/or treatment of depression; however, there are no published studies examining circulating endocannabinoid content in patients with clinical depression. METHODS: This study examined the endocannabinoids (anandamide; AEA) and 2-arachidonylglycerol (2-AG) in serum from ambulatory, medication-free female patients diagnosed with minor or major depression, and in controls matched for demographic characteristics. RESULTS: Serum 2-AG content was significantly decreased in patients diagnosed with major depression, and this decrease was correlated significantly and negatively with duration of the depressive episode, such that 2-AG content was progressively lower the longer the depressive episode. While AEA was not associated with major depression PER SE, a strong negative correlation was found between serum AEA content and Hamilton ratings for cognitive and somatic anxiety, suggesting that AEA content may relate to the anxiety dimension of affective disorders. In subjects with minor depression, serum AEA was significantly elevated, with 2-AG content demonstrating a similar, but statistically insignificant trend. DISCUSSION: These are the first clinical data to indicate that the endocannabinoid system may be disturbed in affective disease, and suggest that future research is required to determine the relevance of these changes with respect to disease manifestation and pharmacotherapy.
Asunto(s)
Moduladores de Receptores de Cannabinoides/sangre , Trastorno Depresivo/sangre , Endocannabinoides , Adulto , Ansiedad/sangre , Ansiedad/psicología , Ácidos Araquidónicos/sangre , Cromatografía Líquida de Alta Presión , Trastorno Depresivo/psicología , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/psicología , Femenino , Glicéridos/sangre , Humanos , Espectrometría de Masas , Alcamidas Poliinsaturadas/sangre , Escalas de Valoración PsiquiátricaRESUMEN
With advances in basic and clinical neuroscience, many gaps have appeared in the traditional monoamine theory of depression that have led to reformulation of the hypotheses concerning the neurobiology of depression. The more recent hypotheses suggest that melancholic depression is characterized by central glucocorticoid resistance that results in hypercortisolemia, which in turn leads to down-regulation of neurotrophins and subsequent neurodegeneration. Examining the neurobiology of depression from this perspective suggests that the endocannabinoid system may play a role in the etiology of melancholic depression. Specifically, pharmacological and genetic blockade of the cannabinoid CB1 receptor induces a phenotypic state that is analogous to melancholic depression, including symptoms such as reduced food intake, heightened anxiety, increased arousal and wakefulness, deficits in extinction of aversive memories and supersensitivity to stress. These similarities between melancholic depression and an endocannabinoid deficiency become more interesting in light of recent findings that endocannabinoid activity is down-regulated by chronic stress and possibly increased by some antidepressant regimens. We propose that an endocannabinoid deficiency may underlie some of the symptoms of melancholic depression, and that enhancement of this system may ultimately be a novel form of pharmacotherapy for treatment-resistant depression.
Asunto(s)
Moduladores de Receptores de Cannabinoides/fisiología , Depresión/fisiopatología , Endocannabinoides , Animales , Antidepresivos/uso terapéutico , Moduladores de Receptores de Cannabinoides/deficiencia , Depresión/etiología , Depresión/terapia , Ejercicio Físico/fisiología , Humanos , Receptor Cannabinoide CB1/fisiologíaRESUMEN
BACKGROUND: Oxygen (O(2)) homeostasis is central to myocardial tissue functioning, and increased O(2) demand is thought to be satisfied by a vasodilatory mechanism that results in increased blood and O(2) delivery. We applied blood oxygenation level-dependent (BOLD) MRI in conjunction with vasodilatory stress to index the ability to augment intramyocardial oxygenation in hypertensive hypertrophy, the primary cause of heart failure. METHODS AND RESULTS: Nine healthy controls and 10 hypertensive subjects with moderate-to-severe hypertrophy underwent imaging on a 1.5 T clinical scanner. The dipyridamole-induced change in the apparent transverse relaxation rate, R2*, which correlates with hemoglobin oxygenation, was -5.4+/-2.2 s(-1) (95% CI, -4.0 to -6.8 s(-1)) in controls compared with -1.7+/-1.4 s(-1) (95% CI, -0.8 to -2.6 s(-1)) in hypertensive patients (P=0.0003). CONCLUSIONS: Patients with hypertensive hypertrophy demonstrate an impaired ability to increase intramyocardial oxygenation during vasodilatory stress, as indexed by BOLD MRI. The capacity to image vascular function with BOLD MRI may advance the understanding of the development of ventricular dysfunction in hypertension.
Asunto(s)
Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Oxígeno/sangre , Vasodilatación , Adulto , Circulación Coronaria/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiopatología , Dipiridamol/administración & dosificación , Femenino , Humanos , Hipertensión/sangre , Hipertensión/complicaciones , Hipertrofia Ventricular Izquierda/sangre , Hipertrofia Ventricular Izquierda/etiología , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Vasodilatación/efectos de los fármacos , Vasodilatadores/administración & dosificaciónRESUMEN
An in-depth cardiovascular risk factor assessment was carried out in a sample of 205 Korean American elderly in Maryland, consisting of 75 males and 130 females aged 60 to 89 years (mean age = 69.9 +/- 6.5 years). Six risk factors were assessed in each participant: high blood pressure, current smoking, high blood cholesterol, overweight, sedentary lifestyle, and diabetes. The findings of this cross-sectional study suggested that high blood pressure was the leading cardiovascular disease risk factor among Korean American elderly (71%), followed by high blood cholesterol (53%), overweight (43%), sedentary life style (24%), diabetes (18%), and smoking (7%). Two thirds of the sample had multiple cardiovascular disease risk factors. The pattern of prevalence and risk factors that was observed was consistent with the distribution of multiple risk factors in that the combination of high blood pressure, high blood cholesterol, and overweight was most common in Korean American elderly (62%). These findings indicate that culturally relevant and salient strategies are needed to reduce multiple risk factors in this population.
Asunto(s)
Anciano/estadística & datos numéricos , Asiático/estadística & datos numéricos , Enfermedades Cardiovasculares/etnología , Enfermedades Cardiovasculares/etiología , Anciano de 80 o más Años , Baltimore/epidemiología , Estudios Transversales , Complicaciones de la Diabetes , Diabetes Mellitus/etnología , Femenino , Encuestas Epidemiológicas , Humanos , Hipercolesterolemia/complicaciones , Hipercolesterolemia/etnología , Hipertensión/complicaciones , Hipertensión/etnología , Corea (Geográfico)/etnología , Masculino , Obesidad/complicaciones , Obesidad/etnología , Vigilancia de la Población , Prevalencia , Medición de Riesgo , Factores de Riesgo , Fumar/efectos adversos , Fumar/etnologíaRESUMEN
OBJECTIVES: To describe the prevalence of obesity, associated factors, and current approaches to weight in an inner city African-American community. DESIGN: In-home survey by community health interviewers. SETTING: Baltimore, Maryland. PARTICIPANTS: 2196 community residents identified in a probability sample of census blocks. MAIN OUTCOME MEASURES: Self-reported height and weight and calculated Body Mass Index (BMI), category of BMI, and stated weight goals. RESULTS: Sixty percent of participants were overweight (BMI> or =25 kg/m2), and 31% were obese (BMI> or =30 kg/m2). In multivariate analysis, women, those earning $15,000-30,000, and those aged 45-60 were more likely to be obese; less likely to be obese were smokers, daily drinkers, and those with "good" or "excellent" health. Sixty-one percent of obese participants reported trying to lose weight, while 36% of normal weight participants were trying to gain weight. Of those trying to lose weight, 35% were using recommended approaches, and 26% received "the professional help they needed to control their weight." CONCLUSIONS: Although obesity was prevalent, few were using recommended weight loss strategies and a significant minority of normal weight participants were trying to gain weight, indicating a need for improved weight management and obesity prevention in the African-American community.