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Abstract

Estrogen administration elicits anxiolytic and antidepressant-like effects in female rats; however, the mechanism of this effect is unknown. Fatty acid amide hydrolase (FAAH), the enzyme which degrades the endocannabinoid anandamide, has been shown to be regulated by estrogen. Thus, we examined if the anxiolytic and antidepressant effects of estrogen implicated the endocannabinoid system. In the first experiment, ovariectomized female rats were administered a single injection of 17beta-estradiol (10 microg) or oil, and 48 h later were given an injection of the cannabinoid CB1 receptor antagonist AM251 (1 mg/kg) or vehicle. One hour after AM251 or vehicle administration, subjects were tested in either the open field test (OFT), elevated plus maze (EPM) or the forced swim test (FST). Estradiol treatment resulted in a significant increase in open arm entries in the EPM and time spent in the center quadrant of the OFT, which were reversed by co-treatment with AM251, suggesting that endocannabinoids are integral to the anxiolytic effects of estrogen. No significant effects of estradiol or AM251 were seen in the FST. In the second experiment, administration of the FAAH inhibitor URB597 (0.1 and 0.3 mg/kg) increased open arm entries in the EPM and time spent in the center quadrant in the OFT as well as significantly reduced immobility in the FST. Collectively, these data demonstrate that estrogen may elicit changes in emotional behavior through an endocannabinoid mechanism, and suggest that inhibition of FAAH represents a therapeutic target for anxiety and depression in women.

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... The 'emotionality' in P70 females rats was probed with behavioural tests [65] . Only the open field test resulted in sufficient alteration of time spent in the centre by 10 μg estradiol -from 22 to 34 s that was prevented by 1 mg/kg AM 251. ...
... Changes in immobility and struggling times were concluded to be non significant that proves a need for the departure from statistics and back to basic discoveries with the 'n-of-one' experiment [66] . Respective values after estradiol were 65 vs. 108 and 101 vs. 150 s [65] . At least the SEM values of immobility time were similar at 20 vs. 26 s. ...
... At least the SEM values of immobility time were similar at 20 vs. 26 s. Therefore, the 'potential importance of endocannabinoid signaling in emotional behavior in females' [65] specifically is not plausible. ...
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Since the reward center is considered to be the area tegmentalis ventralis of the hypothalamus, logically its neurons could mainly be responsible for addiction. However, the literature asserts that almost any neurons of CNS can respond to one or another addictive compound. Obviously not only addictive nicotine, but also alcohol, amphetamine, cannabis, cocaine, heroin and morphine may influence dopaminergic cells alone in VTA. Moreover, paradoxically some of these drugs ameliorate symptoms, counterbalance syndromes, cure diseases and improve health, not only those related to the CNS and in adults, but also almost all other organs and in children, e.g. epilepsy.
... Likewise, the behavioral responses to classical tests of fear and anxiety differ between the sexes (reviewed in Johnston and File, 1991), and are moderated by gonadal hormones (see reviews by Toufexis et al., 2006;Lebron-Milad and Milad, 2012). In support of interactions between the ECS and gonadal hormones, Hill et al. (2007) reported estradiol-dependent effects of CB1 receptor signaling on anxiety-like behaviors in the EPM and OFT; the anxiolytic effects of the indirect CB receptor agonist URB597 and the anxiogenic effects of the CB1 receptor antagonist AM251 were only present in ovariectomized (OVX) rats pre-treated with estradiol 48 h before behavioral testing. Thus, sex-differences in the ECS may help explain some of the sex-differences in behavioral fear. ...
... There are few studies into the effects of the CB1 receptor-selective agonist arachidonyl 2 0 -chlorethylamide (ACEA) on behavioral fear (Moreira et al., 2007;Casarotto et al., 2012;Fogac¸a et al., 2012;Reich et al., 2013;Kochenborger et al., 2014), and of those, none have investigated females. Here, we build upon our previous study in males (Simone et al., 2015) and the study of Hill et al. (2007) in OVX females, to investigate the effects of the highly selective CB1 receptor agonist ACEA and antagonist/inverse agonist AM251 on unconditioned and conditioned fear. Further, as the ECS is known to regulate hypothalamic-pituitary-adrenal (HPA) axis response to stressors (see reviews by Cota, 2008;Steiner and Wotjak, 2008;Riebe and Wotjak, 2011;Hill and Tasker, 2012), and as stress is known to influence anxiety and conditioned fear responses (see reviews by Akirav, 2013;De Bitencourt et al., 2013), we also investigated the effects of CB1 receptor agonism and antagonism on fear-induced corticosterone (stress hormone; measure of HPA output). ...
... To mimic the alternating high and low concentrations of estradiol in natural cycling females, we administered the same dose of estradiol either 6 or 48 h before behavioral testing. Based on the findings of Hill et al. (2007), we predicted that the effects of ACEA and AM251 observed in intact females would be attenuated in OVX rats, and that pretreatment with 17b-Estradiol before behavioral testing would restore the effects. ...
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There is growing interest in the development of cannabis-based therapies for the treatment of fear and anxiety disorders. There are a few studies, but none in females, of the effects of the highly selective CB1 receptor agonist, ACEA, on behavioural fear. In experiment 1 involving gonadally-intact females, ACEA (either 0.1 or 0.01 mg/kg) was without effect in the elevated plus maze (EPM), and the lower dose decreased anxiety in the open field test (OFT). AM251 increased anxiety in the EPM and decreased locomotor activity in the OFT. Twenty-four hours after fear conditioning, neither ACEA nor AM251 affected generalized fear or conditioned fear recall. AM251 and 0.1 mg / kg ACEA impaired, and 0.01 mg / kg ACEA enhanced, within-session fear extinction. AM251 increased plasma corticosterone concentrations after the fear extinction session, whereas ACEA was without effect. Based on evidence that estradiol may moderate the effects of CB1 receptor signalling in females, experiment 2 involved ovariectomized (OVX) rats provided with 10 μg 17β-Estradiol and compared with OVX rats without hormone replacement (oil vehicle). Irrespective of hormone treatment, AM251 increased anxiety in the EPM, whereas ACEA (0.01 mg/kg) was without effect. Neither hormone nor drug altered anxiety in the OFT, but estradiol increased and AM251 decreased distance travelled. After fear conditioning, AM251 decreased generalized fear. Neither hormone nor drug had any effect on recall or extinction of conditioned fear, however, ACEA and AM251 increased fear-induced plasma corticosterone concentrations. Further, when results with intact rats were compared with those from OVX rats, gonadal status did not moderate the effects of either AM251 or ACEA, although OVX displayed greater anxiety and fear than did intact rats. Thus, the effects of CB1 receptor antagonism and agonism in adult female rats do not depend on ovarian estradiol. Copyright © 2015. Published by Elsevier Ltd.
... In general, estrogen decreases FAAH activity and it has been shown that estrogen has anxiolytic and antidepressant effects that are dependent on the eCB system (Waleh et al., 2002;Hill et al., 2007). Similarly, inhibition of the FAAH enzyme reduces anxiety on several rodent models (Hill et al., 2007;Gorzalka and Dang, 2011;Craft et al., 2013). ...
... In general, estrogen decreases FAAH activity and it has been shown that estrogen has anxiolytic and antidepressant effects that are dependent on the eCB system (Waleh et al., 2002;Hill et al., 2007). Similarly, inhibition of the FAAH enzyme reduces anxiety on several rodent models (Hill et al., 2007;Gorzalka and Dang, 2011;Craft et al., 2013). As the effects of estrogen involve the eCB system, it has been suggested that estrogen may modulate emotional behavior in the female rats through a FAAH-related mechanism (Hill et al., 2007). ...
... Similarly, inhibition of the FAAH enzyme reduces anxiety on several rodent models (Hill et al., 2007;Gorzalka and Dang, 2011;Craft et al., 2013). As the effects of estrogen involve the eCB system, it has been suggested that estrogen may modulate emotional behavior in the female rats through a FAAH-related mechanism (Hill et al., 2007). ...
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Women are more vulnerable to stress-related mental disorders than men and the naturally occurring fluctuation in estrogen that occur across the estrus cycle can dramatically influence the pathophysiology observed following traumatic events. It has been demonstrated that the endocannabinoid (eCB) system could represent a therapeutic target for the treatment of post-traumatic stress disorder (PTSD) in males. The current study aimed to examine the effects of exposure to a traumatic event and acute enhancement of eCB signaling on hippocampal-dependent learning and plasticity in male and female rats. Males and females were exposed to the single prolonged stress (SPS) model of PTSD (restraint, forced swim, and sedation) followed by acute administration of the fatty acid amide hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg). Females were in diestrus during SPS exposure. SPS exposure impaired extinction and hippocampal plasticity tested a week later in males and females. Sex differences were observed in the effects of URB597 on hippocampal plasticity of SPS-exposed rats. Also, URB597 normalized the SPS-induced upregulation in CB1 receptor levels in the amygdala, prefrontal cortex (PFC), and hippocampus in males. In females, URB597 normalized the SPS-induced up regulation in CB1 receptors in the amygdala and PFC, but not hippocampus. Our findings support the eCB system as a therapeutic target for the treatment of disorders associated to inefficient fear coping in males and females. There are differences in the hippocampal response of males and females to the enhancement of eCB signaling after intense stress suggesting sex differences in treatment efficacy. This article is protected by copyright. All rights reserved.
... 12 In addition, cannabinoid treatments, including administration of anandamide, as well as antagonists of cannabinoid degradative enzymes, improve postovariectomy complications and reduce anxiety. [13][14][15] Further, administration of cannabinoids typically results in vasorelaxation, 16 suggesting that cannabinoid-based therapies may be particularly salient for treating vasomotor symptoms of menopause. In particular, estrogen deficiency results in downregulation of systems involved in hemodynamic regulation and is associated with vasomotor symptoms; 2 weeks of treatment with anandamide has been shown to reverse this downregulation in ovariectomized rats. ...
... Preclinical research suggests that estrogen may modulate anxiety through the endocannabinoid system and administration of cannabinoid-based therapies reduces anxiety in ovariectomized animals. 13,14 Further, use of MC to address symptoms of anxiety and mood have been reported in several human observational studies of MC examining a broad variety of medical conditions (but not specifically menopause-related symptoms). [18][19][20][21][22][23] Taken together, these findings suggest that mood and anxiety symptoms may be especially problematic during menopause, particularly perimenopause, and may be a salient target for future clinical trials of cannabinoid-based therapies. ...
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Objective: Expanding access to legal cannabis has dovetailed with increased interest in medical cannabis (MC) use; however, there is a paucity of research examining MC use to alleviate menopause-related symptoms. This survey study assessed patterns of MC use in perimenopausal and postmenopausal individuals. Methods: Participants (perimenopausal, n = 131; postmenopausal, n = 127) completed assessments of menopause-related symptomatology and cannabis use, including modes of use, type of use, and menopause-related symptoms addressed by MC use. Results: Most participants reported current cannabis use (86.1%) and endorsed using MC for menopause-related symptoms (78.7%). The most common modes of use were smoking (84.3%) and edibles (78.3%), and the top menopause-related symptoms for MC use were sleep disturbance (67.4%) and mood/anxiety (46.1%). Relative to postmenopausal participants, perimenopausal participants reported significantly worse menopause-related symptomatology on the vasomotor and psychosocial subscales of the Menopause-Specific Quality of Life Questionnaire (Ps ≤ 0.04), including greater burden of anxiety (P = 0.01) and hot flash (P = 0.04) symptoms. In addition, perimenopausal participants reported higher incidence of depression (P = 0.03) and anxiety diagnoses (P < 0.01), as well as increased use of MC to treat menopause-related mood/anxiety symptoms relative to postmenopausal participants (P = 0.01). Conclusions: Results suggest that many individuals are currently using MC as an adjunctive treatment for menopause-related symptoms, particularly sleep disturbance and mood/anxiety. Future research should examine the impact of different MC use characteristics (e.g., cannabinoid profiles) on the efficacy of MC use for menopause-related symptoms. Increased severity and prevalence of mood and anxiety symptoms in perimenopausal participants suggest promising targets for clinical trials of cannabinoid-based therapies.
... Enriched with glucocorticoid (GC) receptors, the hippocampus is vital in processing information about stressful events to allow for adaptation 86,92 . The amygdala, which is important in regulating anxiety and affective responses, 93 also contains CRH-expressing neurons which express GC receptors 94 . In addition, studies show a properly functioning basolateral amygdala (BLA) with GC receptors is needed to facilitate memory ...
... While not fully understood it is postulated that E2 may have an inhibiting effect on dopamine receptors which are centrally located in motor function regions (mesostriatal and mesolimbic systems) of the brain90 . In the present study, E2 effects in conditions of no stress is consistent with the literature[91][92][93][94] . Further, under conditions of chronic stress, E2 improved startle reflex, PPI, anxiety and latency to target in the Barnes maze. ...
... Indeed, there is evidence for an interaction between gonadal hormones and FAAH activity. There is an estrogen response element in the FAAH gene that inhibits FAAH transcription upon translocation of the estrogen receptor to the nucleus (Hill et al., 2007;Waleh et al., 2002). It has been suggested that the anxiolytic effects of estrogen are due, at least in part, to an elevation of AEA and, thus, CB 1 receptor signalling. ...
... It has been suggested that the anxiolytic effects of estrogen are due, at least in part, to an elevation of AEA and, thus, CB 1 receptor signalling. Data to support this hypothesis include findings that a CB 1 antagonist reversed the anxiolytic effect of estradiol in rats (Hill et al., 2007). With regard to the present findings, estrogen levels would be expected to be lower in older females, which would result in disinhibition of FAAH expression and, thus is consistent with the hypothesis that the anxiolytic effects of estrogen are mediated by AEA. ...
Article
Public opinion surrounding the recreational use and therapeutic potential of cannabis is shifting. This review describes new work examining the behavioural and neural effects of cannabis and the endocannabinoid system, highlighting key regions within corticolimbic brain circuits. First, we consider the role of human genetic factors and cannabis strain chemotypic differences in contributing to interindividual variation in the response to cannabinoids, such as THC, and review studies demonstrating that THC-induced impairments in decision-making processes are mediated by actions at prefrontal CB1 receptors. We further describe evidence that signalling through prefrontal or ventral hippocampal CB1 receptors modulates mesolimbic dopamine activity, aberrations of which may contribute to emotional processing deficits in schizophrenia. Lastly, we review studies suggesting that endocannabinoid tone in the amygdala is a critical regulator of anxiety, and report new data showing that FAAH activity is integral to this response. Together, these findings underscore the importance of cannabinoid signalling in the regulation of cognitive and affective behaviours, and encourage further research given their social, political, and therapeutic implications.
... Ovariectomy prevents the estrogen-induced down-regulation of FAAH expression, and both progesterone and estrogen reduce basal levels of FAAH (Maccarrone et al., 2000). The impact of estrogen-mediated regulation of FAAH activity at behavioral and neurochemical level is still under investigation (Hill et al., 2007). ...
... Numerous studies show sex differences in functions in which the endocannabinoid system is involved, which span from regulation of motivated behaviors, like sex activity (Gorzalka et al., 2010;López, 2010;Androvicova et al., 2017) and food intake (Farhang et al., 2009), to locomotor and exploratory activity (Craft and Leitl, 2008;Craft et al., 2017), nociception (Tseng and Craft, 2001;Craft et al., 2017), working memory (Crane et al., 2013), anxiety (Viveros et al., 2011;Bowers and Ressler, 2016) and vulnerability to develop addictive disorders (Fattore et al., 2014;Marusich et al., 2014;Becker, 2016). Endocannabinoids are also directly involved in the anxiolytic effects of estrogen; in turn, estrogen may elicit changes in emotional behavior through an endocannabinoid mechanism (Hill et al., 2007). ...
Article
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Cannabis is the most commonly used illicit drug worldwide. Although its use is associated with multiple adverse health effects, including the risk of developing addiction, recreational and medical cannabis use is being increasing legalized. In addition, use of synthetic cannabinoid drugs is gaining considerable popularity and is associated with mass poisonings and occasional deaths. Delineating factors involved in cannabis use and addiction therefore becomes increasingly important. Similarly to other drugs of abuse, the prevalence of cannabis use and addiction differs remarkably between males and females, suggesting that sex plays a role in regulating cannabinoid sensitivity. Although it remains unclear how sex may affect the initiation and maintenance of cannabis use in humans, animal studies strongly suggest that endogenous sex hormones modulate cannabinoid sensitivity. In addition, synthetic anabolic-androgenic steroids alter substance use and further support the importance of sex steroids in controlling drug sensitivity. The recent discovery that pregnenolone, the precursor of all steroid hormones, controls cannabinoid receptor activation corroborates the link between steroid hormones and the endocannabinoid system. This article reviews the literature regarding the influence of endogenous and synthetic steroid hormones on the endocannabinoid system and cannabinoid action.
... For example, testosterone exhibited anxiolytic effect through androgen receptor, 50) and estrogen decreased the anxiety level in females. 51) Previous researches also proved that estradiol eliminated difference in OAT% between proestrous and diestrous rats. 52) In addition, estradiol administration elicited anxiolytic and antidepressant-like effects on ovariectomized rats, 51) or enhanced the oxytocin-induced anxiolytic effect in mice. ...
... 51) Previous researches also proved that estradiol eliminated difference in OAT% between proestrous and diestrous rats. 52) In addition, estradiol administration elicited anxiolytic and antidepressant-like effects on ovariectomized rats, 51) or enhanced the oxytocin-induced anxiolytic effect in mice. 53) The effect of estrogen action on anxiety might associated with the estrous cycle stage. ...
Article
Cedrol has been reported to be effective in reducing anxiety of male mice. The limited application of females in animal models of anxiety makes it difficult to systematically investigate new drug substitutes with potential anxiolytic activity. In the present study, we investigated the behavioral response of female ICR mice to cedrol after intraperitoneal (i.p.) administration using the elevated plus maze (EPM) and the light-dark box (LDB) test, followed by determination of neurochemical changes in brain. The data suggested that cedrol at dose of 1200-1600 mg∙kg⁻¹ exhibited anxiolytic activity on the female mice, as reflected by greater percentage of entries into the open arms and time spent in the open arms in the EPM, and greater transitions between chambers and percentage of time spent in the light chamber in the LDB. Cedrol increased the level of 5-hydroxytryptamine (5-HT), decreased the level of dopamine (DA), reduced the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT and increased the ratio of 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA, compared with the control group, indicative of an anxiolytic-like effect on female mice via the 5-HTnergic or DAnergic pathways.
... For instance, URB597 is a potent inhibitor of fatty acid amide hydrolase (FAAH, which catalyzes the intracellular hydrolysis of anandamide), but does not bind cannabinoid receptors and does not induce the well known effects of CB1 cannabinoid receptor agonists, such as catalepsy, hypothermia, or hyperphagia (Kathuria et al., 2003). However, it exerts analgesic-, anxiolytic-, and antidepressant-like effects in rodents (Gobbi et al., 2005;Hill et al., 2007;Kathuria et al., 2003;Naidu et al., 2007;Rademacher and Hillard, 2007;Realini et al., 2011). Furthermore, we have previously shown that URB597, administered either systemically (Trezza and Vanderschuren, 2008) or into limbic brain regions such as the nucleus accumbens and amygdala (Trezza et al., 2012b), enhances social play behavior in rats. ...
... The anandamide hydrolysis inhibitor URB597 (National Institute of Mental Health's Chemical Synthesis and Drug Supply Program, Bethesda, MD) was dissolved in 5% Tween 80/5% polyethylene glycol/saline and administered intraperitoneally (i.p.) 2 h before testing. Drug dose and pre-treatment intervals were based on literature (Hill et al., 2007;Kathuria et al., 2003;Naidu et al., 2007;Trezza et al., 2012b;Trezza and Vanderschuren, 2008) and on pilot experiments. Solutions were freshly prepared on the day of the experiment and were administered in a volume of 2 ml/kg in adolescent rats and 1 ml/kg in adult rats. ...
Article
Genetic and environmental factors play an important role in the cannabinoid modulation of motivation and emotion. Therefore, the aim of the present study was to test whether anandamide modulation of social behavior is strain- and context-dependent. We tested the effects of the anandamide hydrolysis inhibitor URB597 on social behavior and 50-kHz ultrasonic vocalizations (USVs) in adolescent and adult Wistar and Sprague–Dawley rats tested in different emotionally arousing conditions (familiarity/unfamiliarity to the test cage, low/high light). Under all experimental conditions, adolescent and adult Sprague–Dawley rats displayed higher levels of social behavior and emitted more 50-kHz USVs than Wistar rats. URB597 enhanced social play behavior in adolescent Wistar rats under all experimental conditions. However, URB597 only increased social interaction in adult Wistar rats under unfamiliar/high light conditions. URB597 did not affect adolescent social play behavior and adult social interaction in Sprague–Dawley rats under any experimental condition. Moreover, URB597 increased the USVs emitted during social interaction by adolescent Wistar and adult Sprague–Dawley rats tested under familiar/high light and unfamiliar/high light, respectively. These results show that anandamide has distinct roles in adolescent and adult social behaviors. Anandamide modulation of adolescent social play behavior is strain- but not context-dependent. Conversely, anandamide modulation of adult social behavior and USV emission depends upon both strain and experimental context. Furthermore, these results confirm that profound behavioral differences exist between Wistar and Sprague–Dawley rats, which may explain the sometimes contradictory effects of cannabinoid drugs on emotionality in different strains of rodents.
... Most pertinent to the aim of this chapter, is that the estradiol modulation of endocannabinoid tone, and its consequent suppression of inhibition, is sex-specific, occurring in female but not in male rats [140]. Estradiol may also elicit changes in emotional behaviour through an endocannabinoid mechanism, which appears more evident in females than in males [141]. ...
... Sex-dependent differences in the perception of the rewarding effects of cannabinoids can also be explained by the presence, and action in the brain, of estrogens. Indeed, estrogen has powerful anxiolytic effects in rats that involve endocannabinoids [141] and, therefore, it may minimize the aversive effects of cannabinoids, unmasking euphorigenic effects. The estrogenic modulation of the reinforcing effects of cannabinoids mirrors that consistently observed with stimulant drugs [279]. ...
Article
In humans as in animals, males and females are dissimilar in their genetic and hormonally driven behaviour; they process information differently, perceive experiences and emotions in different ways, and display diverse attitudes. In the human population, gender differences in the frequency and patterns of cannabis use have been identified in clinical studies and in anecdotal observations, although the nature of these differences is still poorly explored. The motivations for smoking cannabis are also different between sexes, especially in adolescents. A number of potential factors which could provide a neurobiological basis for gender-based differences in cannabinoid addiction have been identified, among which are organizational and activational effects of gonadal hormones, socio-cultural factors, different stress responsiveness and impulse-control ability as well as different cannabinoid pharmacodynamic and pharmacokinetic in males and females. In this chapter we will review both clinical and laboratory-based research evidence revealing important sex-related differences in cannabinoid-induced effects on reward and motivation.
... There are some notable differences between males and females in CB1R-binding site density, including greater binding in the BLA of female rats [111] and across limbic regions in human female subjects [107]. Despite these differences, FAAH inhibitors retain anxiolytic-and antidepressant-like effects in ovariectomized female rats [112]. Interestingly, however, anxiolytic-and antidepressant-like effects produced by estradiol administration are attenuated by CB1R blockade [112], whereas estradiol administration increases AEA levels [113] or AEA signaling [114], possibly via downregulation of FAAH driven by an estrogen response element on the FAAH gene that suppresses FAAH transcription when bound by estrogen [115]. ...
... Despite these differences, FAAH inhibitors retain anxiolytic-and antidepressant-like effects in ovariectomized female rats [112]. Interestingly, however, anxiolytic-and antidepressant-like effects produced by estradiol administration are attenuated by CB1R blockade [112], whereas estradiol administration increases AEA levels [113] or AEA signaling [114], possibly via downregulation of FAAH driven by an estrogen response element on the FAAH gene that suppresses FAAH transcription when bound by estrogen [115]. These observations suggest that FAAH-AEA signaling may be one important mechanism linking gonadal hormone status and account, at least in part, for sex differences in anxiety. ...
Article
A long-standing literature linking endocannabinoids (ECBs) to stress, fear, and anxiety has led to growing interest in developing novel anxiolytics targeting the ECB system. Following rapid on-demand biosynthesis and degradation upon neuronal activation, the ECB N-arachidonoylethanolamide (anandamide, AEA) is actively degraded by the serine hydrolase enzyme, fatty acid amide hydrolase (FAAH). Exposure to stress rapidly mobilizes FAAH to deplete the signaling pool of AEA and increase neuronal excitability in a key anxiety-mediating region - the basolateral amygdala (BLA). Gene deletion or pharmacological inhibition of FAAH prevents stress-induced reductions in AEA and associated increases in BLA dendritic hypertrophy and anxiety-like behavior. Additionally, inhibition of FAAH facilitates long-term fear extinction and rescues deficient fear extinction in rodent models by enhancing AEA-CB1 (cannabinoid type 1) receptor signaling and synaptic plasticity in the BLA. These preclinical findings propose restoring deficient BLA AEA levels by pharmacologically inhibiting FAAH as a mechanism to therapeutically mitigate the effects of traumatic stress.
... The treatment with 17β estradiol also modulated Nacyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD) and FAAH expression and activity, suggesting that the hormone could have a neuroprotective effect by reducing endogenous cannabinoids levels and their ability to induce CB1 receptormediated response [93]. FAAH modulation by estrogens was corroborated in studies of Hill and co-workers (2007) [94] who analyzed the mechanisms by which estrogens elicit anxiolytic and antidepressant-like effects. They investigated the ability of estrogens to modulate the ECS in ovariectomized rats. ...
... They investigated the ability of estrogens to modulate the ECS in ovariectomized rats. Results showed that both the pharmacological inhibition of CB1 receptor and the administration of the FAAH inhibitor URB597 were able to reverse the significant increase in open arm entries in the elevated plus-maze (EPM) test and time spent in the center quadrant of the open field test (OFT) following 17β estradiol treatment [94]. These findings demonstrated that estrogen may produce changes in emotional behavior by modulating ECS activity mainly through FAAH inhibition. ...
Article
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The endocannabinoid system (ECS) is a lipid cell signaling system involved in the physiology and homeostasis of the brain and peripheral tissues. Synaptic plasticity, neuroendocrine functions, reproduction, and immune response among others all require the activity of functional ECS, with the onset of disease in case of ECS impairment. Estrogens, classically considered as female steroid hormones, regulate growth, differentiation, and many other functions in a broad range of target tissues and both sexes through the activation of nuclear and membrane estrogen receptors (ERs), which leads to genomic and non-genomic cell responses. Since ECS function overlaps or integrates with many other cell signaling systems, this review aims at updating the knowledge about the possible crosstalk between ECS and estrogen system (ES) at both central and peripheral level, with focuses on the central nervous system, reproduction, and cancer.
... The first class of eCB degradation inhibitors targeted FAAH [30]. Blocking FAAHmediated AEA degradation decreases anxiety in the elevated plus-maze [19,[30][31][32][33][34][35], and the light-dark box test [36]; importantly, several studies indicate these effects are enhanced under conditions of high environmental aversiveness [34,37] or following exposure to stress [38,39]. FAAH inhibition also decreases anxiety in the rat pup ultrasonic vocalization test [26], light-dark exploration assay [25] and marble-burying assay [40]. ...
... Although a significant discrepancy exists between the antidepressant-like effects of the genetic and pharmacological CB1 receptor blockades, generally more consistent findings have been published with regard to the antidepressant-like effects of FAAH inhibition. Both acute pharmacological and lifelong genetic deletion of FAAH produce antidepressant-like effects in the forced swim test and tail suspension test [33,34,70,71,75,76]. Some studies have found that these effects are more robust under highly aversive testing conditions [34]. ...
Article
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Accumulating evidence over the past decade has highlighted an important role of the endocannabinoid (eCB) system in the regulation of stress and emotional behavior across divergent species, from rodents to humans. The general findings from this work indicate that the eCB system plays an important role in gating and buffering the stress response, dampening anxiety and regulating mood. Work in rodents has allowed researchers to determine the neural mechanisms mediating this relationship while work in human populations has demonstrated the possible importance of this system in stress-related psychiatric diseases, such as post-traumatic stress disorder, generalized anxiety and major depression. These stress-protective effects of eCB signaling appear to be primarily mediated by their actions within corticolimbic structures, particularly the amygdala and the prefrontal cortex. The aim of this review is to provide an up-to-date discussion of the current level of knowledge in this field, as well as address the current gaps in knowledge and specific areas of research that require attention.
... injection of 10 μg -oestradiol 3-benzoate (Sigma-Aldrich, Italy) dissolved in peanut oil. The oestradiol treatment protocol was based on an established protocol showing that it elicits a wide range of behavioural effects in rodents [66][67][68][69]. ...
... Surprisingly, ovariectomy and oestradiol replacement did not have a significant effect on the social interaction test, and they did not affect the length of time spent interacting with the partner or the number of social contacts. In light of the evidence that in rats ovariectomy elicits a reliable increase in anxiety and depression-like behaviours in tests of emotionality, and that oestrogen administration produces anxiolytic and antidepressant-like effects [107,67], these results were unforeseen to us. ...
Article
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Sex-dependent differences are frequently observed in the biological and behavioural effects of substances of abuse, including cannabis. We recently demonstrated a modulating effect of sex and oestrous cycle on cannabinoid-taking and seeking behaviours. Here, we investigated the influence of sex and oestrogen in the regulation of cannabinoid CB1 receptor density and function, measured by [3H]CP55940 and CP55940-stimulated [35S]GTP?S binding autoradiography, respectively, in the prefrontal cortex (Cg1 and Cg3), caudate-putamen, nucleus accumbens, amygdala and hippocampus of male and cycling female rats, as well as ovariectomised (OVX) rats and OVX rats primed with oestradiol (10 μg/rat) (OVX+E). CB1 receptor density was significantly lower in the prefrontal cortex and amygdala of cycling females than in males and in OVX females, a difference that appeared to be oestradiol-dependent, because it was no more evident in the OVX+E group. CP55940-stimulated [35S]GTPαS binding was significantly higher in the Cg3 of OVX rats relative to cycling and OVX+E rats. No difference was observed in CB1 receptor density or function in any of the other brain areas analysed. Finally, sex and oestradiol were also found to affect motor activity, social behaviour and sensorimotor gating in rats tested in locomotor activity boxes, social interaction and prepulse inhibition tasks, respectively. Our findings provide biochemical evidence for sex- and hormone-dependent differences in the density and function of CB1 receptors in selected brain regions, and in behaviours associated with greater vulnerability to drug addiction, revealing a more vulnerable behavioural phenotype in female than in male rats.
... Under stress exposure conditions (Figure 1), the protein FAAH is mobilized to degrade the AEA, therefore increasing the neuronal excitability in the amygdala, a key anxiety-mediating region of the brain [5]. In opposition, the inhibition of FAAH decreases anxiety-like behavior [41] and may produce an antidepressant effect mediated by CB1 receptor stimulation [42]. Previously, the rs324420 A allele was associated with a lower expression of FAAH levels [41]; in the population of the Iberian and African peninsula, it has a percentage of 16% and 37%, respectively [43]. ...
... Additionally, rs324420 might play different roles depending on sport requirements, which needs to be further explored. Furthermore, although significant sex differences among our athletes were not observed for rs324420 genotype frequencies as previously described, it has been shown that estrogens modify emotional behavior through the dysregulation of the FAAH enzyme, thus causing an increase in the signaling of the endocannabinoid system, consequently decreasing anxiety in women [42]. Therefore, further studies would be needed to confirm this hypothesis in female athletes. ...
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Genetic factors are among the major contributors to athletic performance. Although more than 150 genetic variants have been correlated with elite athlete status, genetic foundations of competition-facilitating behavior influencing elite performances are still scarce. This is the first study designed to examine the distribution of genetic determinants in the athletic performance of elite rink-hockey players. A total of 116 of the world’s top best rink-hockey players (28.2 ± 8.7 years old; more than 50% are cumulatively from the best four world teams and the best five Portuguese teams), who participated at the elite level in the National Rink-Hockey Championship in Portugal, were evaluated in anthropometric indicators/measurements, training conditions, sport experience and sport injuries history. Seven genetic polymorphisms were analyzed. Polymorphism genotyping was performed using the TaqMan® Allelic Discrimination Methodology. Rink-hockey players demonstrated significantly different characteristics according to sex, namely anthropometrics, training habits, sports injuries and genetic variants, such as Vitamin D Receptor (VDR) rs731236 (p < 0.05). The Fatty Acid Amide Hydrolase (FAAH) rs324420 A allele was significantly associated with improved athletic performance (AA/AC vs. CC, OR = 2.80; 95% Cl, 1.23–6.35; p = 0.014; p = 0.008 after Bootstrap) and confirmed as an independent predictor among elite rink-hockey players (adjusted OR = 2.88; 95% Cl, 1.06–7.80; p = 0.038). Our results open an interesting link from FAAH-related biology to athletic performance.
... Preclinical work demonstrates that pharmacological inhibition of FAAH (e.g. URB-597 and PF-3845; Hill et al. 2007;Kathuria et al. 2003) and AEA transport (AM-404; Bortolato et al. 2006) has anxiolytic properties in several tests of anxiety, including: the elevated zero maze, elevated plus maze, defensive withdrawal and social isolation-induced ultrasonic vocalization tests. Moreover, transgenic mice with a FAAH deficiency exhibit increased central AEA levels and a less anxious phenotype in the elevated plus maze and light-dark box relative to wild-type controls, which is prevented by systemic injection of a CB 1 R antagonist, Rimonabant (Moreira et al. 2008). ...
Article
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 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 endocannabinoid signaling changes dynamically and coincides with different sensitive periods of fear learning, suggesting that endocannabinoid signaling underlies age-specific fear learning responses. Moreover, perturbations to these normative fluctuations in corticolimbic endocannabinoid 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 endocannabinoid system and discuss clinical and rodent models demonstrating endocannabinoid 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 endocannabinoid system in the central nervous system, and models of pharmacological augmentation of endocannabinoid signaling during development in the context of fear learning and anxiety.
... Since CB1 receptors, FAAH and MAGL are not equally distributed in the brain; the indirect stimulation of CB1 receptors by endocannabinoid breakdown blockers could modulate the endocannabinoid signaling in selected brain areas which control mood [160]. The FAAH inhibitor URB597 has shown CB1 receptor-mediated antidepressantlike effects by enhancing AEA signaling in several experimental models such as FST [132,133,161,162], TST [163], CMS paradigm [97,164], adolescent Δ9-THC exposure [146] and tail-pinch test [165]. Another FAAH inhibitor, oleamide, elicited antidepressant-like effects through a CB1 receptor-mediated mechanism [136,166]. ...
Chapter
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The endogenous cannabinoid system (ECS) works as pro-homeostatic and pleiotropic signaling system activated in a time-and tissue-specific way during physiological conditions, which include cognitive, emotional and motivational processes. It is composed of two G protein-coupled receptors (the cannabinoid receptors types 1 and 2 [CB1 and CB2] for marijuana's psychoactive ingredient Δ9-tetrahydrocannabinol [Δ9-THC]), their endogenous small lipid ligands (anan-damide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabi-noids), and the proteins for endocannabinoid biosynthesis and deactivation. Data from preclinical and clinical studies have reported that a hypofunction of the endo-cannabinoid signaling could induce a depressive-like phenotype; consequently, enhancement of endocannabinoid signaling could be a novel therapeutic avenue for the treatment of depression. To this aim there have been proposed cannabinoid receptor agonists or synthetic molecules that inhibit endocannabinoid degradation. The latter ones do not induce the psychotropic side effects by direct CB1 receptor activation, but rather elicit antidepressant-like effects by enhancing the monoami-nergic neurotransmission, promoting hippocampal neurogenesis and normalizing the hyperactivity of hypothalamic-pituitary-adrenal axis, similarly as the standard antidepressants. The dysfunction of elements belonging to the ECS and the possible therapeutic use of endocannabinoid deactivation inhibitors and phytocannabinoids in depression is discussed in this chapter.
... The FST was performed according to the method described by Porsolt et al. [27]. Each rat was introduced for 15 min into sepa- rate transparent cylindrical containers (diameter 30 cm and height 45 cm) that were filled with water to 30 cm so that rats could only touch the bottom with the tip of the tail [28]. Fresh water was introduced prior to each test and water temperature was maintained at 25 ± 2 °C They were removed 15 min later, dried and placed in their home cage. ...
Article
The effects of aqueous and ethanolic extracts of Crocus sativus L. stigma and their constituents safranal and crocin were studied for the antidepressant activity using forced swimming test in mice. The extracts and constituents were injected intraperitoneally to mice. The aqueous and ethanolic extracts of stigma (0.2-0.8 g/kg) decreased immobility time in comparison to normal saline. Safranal (0.15-0.5 ml kg) and crocin (50-600 mg/kg) also reduced immobility time. Swimming time was increased by fluoxetine and both extracts. Safranal increased swimming time. Climbing time was increased by imipramine and both extracts. Safranal with a higher dose (0.5 mg/kg) and crocin at doses 50 and 600 increased climbing time. In the open field activity test, the ethanolic extract and safranal increased stereotypic activities. On the basis of these results, the antidepressant effect of C. sativus stigma extracts may be mediated via safranal and crocin. Crocin may act via the uptake inhibition of dopamine and norepinephrine, and safranal via serotonin.
... Gender disparities in CB 1 receptor regulation were observed at this step in the stress response such that chronic stress reliably produced a downregulation of CB 1 receptors in male animals (Hill et al., 2008a, Hill et al., 2005, Reich et al., 2009) and a robust upregulation of CB 1 receptors in female animals (Reich et al., 2009) which was associated with impaired CB 1 receptor-mediated eCB signaling (Suarez et al., 2009). Whereas there is evidence for developmental influence of sex hormones on eCB function (Hill et al., 2007), the observed CB 1 receptor changes were found in both intact and gonadectomized animals and are therefore not a result of circulating sex hormones or glucocorticoids (Reich et al., 2009). ...
Article
Posttraumatic stress disorder (PTSD) is a prevalent, chronic, and disabling anxiety disorder that may develop following exposure to a traumatic event. Despite the public health significance of PTSD, relatively little is known about the etiology or pathophysiology of this disorder, and pharmacotherapy development to date has been largely opportunistic instead of mechanism-based. Recently, an accumulating body of evidence has implicated the endocannabinoid system in the etiology of PTSD, and targets within this system are believed to be suitable for treatment development. Herein, we describe evidence from translational studies arguing for the relevance of the endocannabinoid system in the etiology of PTSD. We also show mechanisms relevant for treatment development. There is convincing evidence from multiple studies for reduced endocannabinoid availability in PTSD. Brain imaging studies show molecular adaptations with elevated cannabinoid type 1 (CB1) receptor availability in PTSD which is linked to abnormal threat processing and anxious arousal symptoms. Of particular relevance is evidence showing reduced levels of the endocannabinoid anandamide and compensatory increase of CB1 receptor availability in PTSD, and an association between increased CB1 receptor availability in the amygdala and abnormal threat processing, as well as increased severity of hyperarousal, but not dysphoric symptomatology, in trauma survivors. Given that hyperarousal symptoms are the key drivers of more disabling aspects of PTSD such as emotional numbing or suicidality, novel, mechanism-based pharmacotherapies that target this particular symptom cluster in patients with PTSD may have utility in mitigating the chronicity and morbidity of the disorder. Copyright © 2014 Elsevier Ltd. All rights reserved.
... Además, en estudios recientes se ha descrito una importante influencia de los esteroides sexuales sobre el sistema endocannabinoide. En animales adultos, los estrógenos son capaces de modular la liberación de agonistas endocannabinoides, bien aumentando su liberación (Hill et al., 2007), bien inhibiéndola (Amantea et al., 2007). Es posible que estas relaciones se establezcan desde períodos tempranos del desarrollo, lo que contribuiría a explicar la diferente susceptibilidad a los tratamientos farmacológicos en machos y hembras observadas a largo plazo (capítulo 1), y a corto plazo (capítulo 3). ...
... For example, CB1 receptor expression and density appear to be under the control of sex steroids in both males and females in some cerebral areas (47,48). More recently, it has been reported that endocannabinoids and gonadal hormones may reciprocally regulate each other, and interestingly, estrogen can recruit endocannabinoids to modulate emotionality (49,50). This is particularly important when considering that ovarian hormones may actively contribute to the remodeling event in the female brain during puberty and adolescence, as recently suggested by Juraska et al. (51). ...
Article
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The goal of this review is to summarize current evidence for sex differences in the response to cannabinoid compounds, focusing mainly on a specific age of exposure, i.e., adolescence. Preclinical as well as clinical studies are examined. Among the different possible underlying mechanisms, the consistent dimorphism in the endocannabinoid system and delta9-tetrahydrocannabinol metabolism may play a part. All the collected data point to the need of including females in basic research as well as of analyzing results for sex differences in epidemiological studies.
... Selective pharmacological inhibition of FAAH in rodents contributed to elucidate the role of AEA in socioemotional processes. Thus, FAAH inhibition results in CB1mediated and context-dependent anxiolytic-and antidepressant-like effects in rats and mice (Gobbi et al., 2005;Hill et al., 2007;Kathuria et al., 2003;Naidu et al., 2007;Rademacher and Hillard, 2007;Realini et al., 2011), and increased sociability in adolescent (Trezza et al., 2012b;Vanderschuren, 2008a, 2008b) and adult rats Realini et al., 2011). ...
Article
To date, our understanding of the relative contribution and potential overlapping roles of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG) in the regulation of brain function and behavior is still limited. To address this issue, we investigated the effects of systemic administration of JZL195, that simultaneously increases AEA and 2-AG signaling by inhibiting their hydrolysis, in the regulation of socio-emotional behavior in adolescent and adult rats. JZL195, administered at the dose of 0.01mg/kg, increased social play behavior, that is the most characteristic social activity displayed by adolescent rats, and increased social interaction in adult animals. At both ages, these behavioral effects were antagonized by the CB1 cannabinoid receptor antagonist SR141716A and were associated with increased brain levels of 2-AG, but not AEA. Conversely, at the dose of 1mg/kg, JZL195 decreased general social exploration in adolescent rats without affecting social play behavior, and induced anxiogenic-like effects in the elevated plus-maze test both in adolescent and adult animals. These effects, mediated by activation of CB1 cannabinoid receptors, were paralleled by simultaneous increase in AEA and 2-AG levels in adolescent rats, and by an increase of only 2-AG levels in adult animals. These findings provide the first evidence for a role of 2-AG in social behavior, highlight the different contributions of AEA and 2-AG in the modulation of emotionality at different developmental ages and suggest that pharmacological inhibition of AEA and 2-AG hydrolysis is a useful approach to investigate the role of these endocannabinoids in neurobehavioral processes. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
... A possible explanation for these gender differences could be an interaction between estrogen and the endocannabinoid system. Estrogen regulates the fatty acid, amide hydrolase (FAAH), which is the enzyme that degrades AEA (Deutsch and Chin, 1993;Hill et al., 2007). Downregulation of FAAH by estrogen increases AEA signaling. ...
Article
The present study investigated the role of the endocannabinoid system on sexual motivation in the female rat. In Experiment 1, gonadally intact female rats were first tested for partner preference after a vehicle injection. Approximately 2weeks later, all rats were tested again after an injection of the endocannabinoid antagonist, SR141716 (SR; also known as Rimonabant; 1.0mg/kg). During the first 10min of each partner preference test, subjects could spend time near either a male or female stimulus animal that was placed behind a wire mesh (No-Contact). During the second 10min of each partner preference test, subjects had unrestricted access to both stimulus animals (Contact). When the female subjects were treated with SR, they made fewer visits to either stimulus animal during the no-contact phase of the partner preference test compared to when they were treated with vehicle. In Experiment 2, ovariectomized (OVX) subjects primed with estrogen were administered SR or vehicle and tested for partner preference (Experiment 2A). Approximately 2weeks later, the subjects from the control group were tested again after an injection of SR (Experiment 2B). In contrast to Experiment 1, treatment with SR reduced the number of visits specifically to the male stimulus during the contact phase of the test in Experiment 2. Experiment 3 tested the effects of SR on general locomotion and found no effect of SR on line crossings in an open field. Finally, in Experiment 4, OVX estrogen- and progesterone-primed subjects were administered the endocannabinoid agonist anandamide (AEA: 1.0mg/kg) or vehicle and tested for partner preference. AEA-treated subjects made more visits to the male stimulus than vehicle-treated subjects during the contact phase of the test. The results of the present study suggest that the endocannabinoid system may contribute to sexual motivation in female rats by specifically altering approach behavior.
... The FST was performed according to the method described by Porsolt et al. [27]. Each rat was introduced for 15 min into sepa-rate transparent cylindrical containers (diameter 30 cm and height 45 cm) that were filled with water to 30 cm so that rats could only touch the bottom with the tip of the tail [28]. Fresh water was introduced prior to each test and water temperature was maintained at 25 ± 2 °C They were removed 15 min later, dried and placed in their home cage. ...
Article
Crocus sativus L., commonly known as saffron, is a perennial stemless herb in Iridaceae family. It has been used in traditional medicine as well as in modern pharmacological studies for variety of conditions including depression. Recent studies have suggested brain-derived neurotrophic factor (BDNF), VGF Neuropeptide, Cyclic-AMP Response Element Binding Protein (CREB) and phospho-CREB (p-CREB) may play roles in depression. In this research the molecular mechanism of antidepressant effect of aqueous extract of saffron and its effect on the levels of BDNF, VGF, CREB and p-CREB in rat hippocampus, were investigated. The aqueous extract of saffron (40, 80 and 160 mg/kg/day) and imipramine 10 mg/kg/day were injected intraperitoneally (i.p.) for 21 days to rats. The FST (forced swimming test) was performed on the days 1st and 21st. The protein expression and transcript levels of BDNF, VGF CREB and phospho-CREB in rat hippocampus, were evaluated using western blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The results of FST showed that saffron reduced the immobility time. The protein levels of BDNF, CREB and p-CREB were significantly increased in saffron treated rats. VGF protein expression was also increased, but not significantly. The transcript levels of BDNF significantly increased. No significant changes in CREB and VGF transcript levels were observed. It was concluded that aqueous extract of saffron has antidepressant effects and the mechanism of its antidepressant effect may be due to increasing the levels of BDNF, VGF, CREB and P-CREB in rat hippocampus.
... High doses of estrogen can have an anxiolytic effect. Hill et al. proposed that the anxiolytic effect is mediated by alterations in FAAH [97]. It may be that eCBs regulate the onset of puberty. ...
Article
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The endocannabinoid system (ECS) is an evolutionarily conserved master system deeply involved in the central and local control of reproductive functions in both sexes. The tone of these lipid mediators-deeply modulated by the activity of biosynthetic and hydrolyzing machineries-regulates reproductive functions from gonadotropin discharge and steroid biosynthesis to the formation of high quality gametes and successful pregnancy. This review provides an overview on ECS and reproduction and focuses on the insights in the regulation of endocannabinoid production by steroids, in the regulation of male reproductive activity, and in placentation and parturition. Taken all together, evidences emerge that the activity of the ECS is crucial for procreation and may represent a target for the therapeutic exploitation of infertility.
... The cannabinoid system also appears to modulate prefrontal dendritic complexity and cognitive flexibility disparately in males and females [19]. In rats, an anxiolytic effect of estradiol may be mediated by fatty acid amide hydrolase (FAAH), an endocannabinoid degradative enzyme [20]. ...
... Exposure to stress mobilizes FAAH to lower AEA level and increase neuronal excitability in amygdala, a key anxiety-mediating region of the brain (Gunduz-Cinar et al., 2013a). On the other hand, inhibition of FAAH prevents anxiety-like behavior and may have antidepressant effect mediated by CB1 receptor stimulation (Hill et al., 2007). We speculated that elite athletes could benefit from FAAH P129T (C385A, rs324420) polymorphism, given the recent reports of its impact on brain's emotion centers activity (Gunduz-Cinar et al., 2013b). ...
Article
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The aim of the study was to assess whether selected genetic variants are associated with elite athlete performance in a group of 413 elite athletes and 451 sedentary controls. Polymorphisms in ACE, ACTN3, AGT, NRF-2, PGC1A, PPARG, and TFAM implicated in physical performance traits were analyzed. Additionally, polymorphisms in CHRNB3 and FAAH coding for proteins modulating activity of brain's emotion centers were included. The results of univariate analyses indicated that the elite athletic performance is associated with four polymorphisms: ACE (rs4341, P = 0.0095), NRF-2 (rs12594956, P = 0.011), TFAM (rs2306604, P = 0.049), and FAAH (rs324420, P = 0.0041). The multivariate analysis adjusted for age and gender confirmed this association. The higher number of ACE D alleles (P = 0.0021) and the presence of NRF-2 rs12594956 A allele (P = 0.0067) are positive predictors, whereas TFAM rs2306604 GG genotype (P = 0.031) and FAAH rs324420 AA genotype (P = 0.0084) negatively affect the elite athletic performance. The CHRNB3 variant (rs4950, G allele) is significantly more frequent in the endurance athletes compared with the power ones (P = 0.025). Multivariate analysis demonstrated that the presence of rs4950 G allele contributes to endurance performance (P = 0.0047). Our results suggest that genetic inheritance of psychological traits should be taken into consideration while trying to decipher a genetic profile of top athletic performance.
... Consistent with the loss-of-function studies described above, pharmacological and genetic augmentation of eCB signaling via inhibition or deletion of 2-AG and AEA degradation decreases anxiety-like behaviors in a variety of preclinical models. For example, pharmacological inhibition of FAAH decreases unconditioned anxiety-like behaviors behavior in rats and mice in an array of behavioral tests including the light-dark box, the elevated-plus maze, the open-field test, and the novelty-induced suppression of feeding task (Duan et al, 2016;Hill et al, 2007;Kathuria et al, 2003;Kinsey et al, 2011;Moise et al, 2008;Morena et al, 2016a;Naidu et al, 2007;Patel and Hillard, 2006;Scherma et al, 2008). Moreover, genetic deletion of FAAH decreases anxiety-like behaviors via a CB1-dependent mechanism (Kathuria et al, 2003;Moreira et al, 2008). ...
Article
Exposure to stress is an undeniable, but in most cases surmountable, part of life. However, in certain individuals, exposure to severe or cumulative stressors can lead to an array of pathological conditions including posttraumatic stress disorder (PTSD), characterized by debilitating trauma-related intrusive thoughts, avoidance behaviors, hyperarousal, as well as depressed mood and anxiety. In the context of the rapidly changing political and legal landscape surrounding use of cannabis products in the United States, there has been a surge of public and research interest in the role of cannabinoids in the regulation of stress-related biological processes and in their potential therapeutic application for stress-related psychopathology. Here we review the current state of knowledge regarding the effects of cannabis and cannabinoids in PTSD and the preclinical and clinical literature on the effects of cannabinoids and endogenous cannabinoid signaling systems in the regulation of biological processes related to the pathogenesis of PTSD. Potential therapeutic implications of the reviewed literature are also discussed. Lastly, we propose that a state of endocannabinoid deficiency could represent a stress-susceptibility endophenotype predisposing to the development of trauma-related psychopathology and provide biologically plausible support for the self-medication hypotheses used to explain high rates of cannabis use in patients with trauma-related disorders.
... In the present experiments, adolescent CB1 receptor antago- nism/inverse agonism had no effect on anxiety in the EPM in male or female rats tested 24 h after repeated drug exposure. Although this result contrasts reports of increased anxiety after CB1 receptor antagonism in adult males (Haller et al., 2002; Navarro et al., 1997;Simone et al., 2015a) and females ( Hill et al., 2007;Simone et al., 2015b), those studies measured behaviour 30e60 min after administration, whereas we measured behaviour 24 h after the final exposure to the drug. Our findings are consistent with the report of no effect of an acute administration of 0.25 mg/kg AM251 on anxiety in an open field test in adolescent male rats ( Pandolfo et al., 2007) and with the report that adult male rats treated repeatedly with 5 mg/kg AM251 during adolescence did not differ from controls in the EPM when tested in a drug-free state in adulthood ( ). ...
Article
There is a paucity of research regarding the role of endogenous cannabinoid signalling in adolescence on brain and behaviour development. We previously demonstrated effects of repeated CB1 receptor antagonism in adolescence on socioemotional behaviours and neural protein expression 24-48 h after the last drug administration in female rats, with no effect in males. Here we investigate whether greater effects would be manifested after a lengthier delay. In Experiment 1, male and female rats were administered either 1 mg / kg of the CB1 receptor-selective antagonist AM251, vehicle (VEH), or did not receive injections (NoINJ) daily on postnatal days (PND) 30-44 either alone (no adolescent confinement stress; noACS), or in tandem with 1 h ACS. On PND 70, adolescent AM251 exposure reduced anxiety in an elevated plus maze in males, irrespective of ACS, with no effects in females. On PND 73, there were no group differences in either sex in plasma corticosterone concentrations before or after 30 min of restraint stress, although injection stress resulted in higher baseline concentrations in males. Brains were collected on PND 74, with negligible effects of either AM251 or ACS on protein markers of synaptic plasticity and of the endocannabinoid system in the hippocampus and medial prefrontal cortex. In Experiment 2, rats from both sexes were treated with vehicle or AM251 on PND 30-44 and were tested for contextual fear conditioning and extinction in adulthood. AM251 females had greater fear recall than VEH females 24 h after conditioning, with no group differences in within- or between-session fear extinction. There were no group differences in long-term extinction memory, although AM251 females froze more during a reconditioning trial compared with VEH females. There were no group differences on any of the fear conditioning measures in males. Together, these findings indicate a modest, sex-specific role of CB1 receptor signalling in adolescence on anxiety-like behaviour in males and conditioned fear behaviour in females.
... Transcriptional repression of FAAH through ER binding traditional estrogen response elements results in elevated AEA tone. Presumably it is through this mechanism that estradiol elevates AEA to elicit anxiolytic effects in female rats, which are blocked with a CB1R antagonist (Hill et al., 2007). Moreover, this nuclear action of estradiol converges with membrane actions at the same functional endpoint to increase AEA (Huang and Woolley, 2012;Tabatadze et al., 2015). ...
Article
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Compared with men, women show enhanced responses to drugs of abuse, and consequently are thought to be more vulnerable to addiction. The ovarian hormone estradiol has emerged as a key facilitator in the heightened development of addiction in females. These actions of estradiol appear mediated by estrogen receptor (ER) activation of metabotropic glutamate receptor type 5 (mGluR5). However, the downstream effectors of this ER/mGluR5 signaling pathway are unknown. Here we investigate whether cannabinoid 1 receptor (CB1R) activation is a part of the mechanism whereby estradiol influences behavioral and synaptic correlates of addiction. Following repeated cocaine administration, estradiol-treated ovariectomized rats exhibited both sensitized locomotor responses and decreases in the dendritic spine density of nucleus accumbens core medium-spiny neurons in comparison to oil-treated controls. Both effects of estradiol were blocked by AM251, a CB1R inverse agonist. These results indicate that part of the signaling mechanism through which estradiol impacts behavioral and synaptic correlates of addiction in female rats requires activation of CB1Rs.
... Female rats also show ECB fluctuations across the estrous cycle, and it has been suggested that ovarian hormones modulate the ECB system, and vice versa (see Gorzalka and Dang, 2012 for a review). For example, estradiol (E2) decreases anxiety in ovariectomized (OVX) rats, but this E2-induced reduction in anxiety-like behavior is prevented by administration of a CB1R antagonist (Hill et al., 2007). Female wild-type mice also drink more alcohol than male wildtype mice but this sex difference is abolished by CB1R deletion (Hungund et al., 2003), implying that ECBs are moderating this sex difference. ...
Article
Chronic intermittent alcohol (CIA) exposure produces altered motivational states characterized by anxiety and escalated alcohol consumption during withdrawal. The endocannabinoid (ECB) system contributes to these symptoms, and sex differences in alcohol dependence, as well as bidirectional interactions between ECBs and gonadal hormones have been documented. Thus, we evaluated sex differences in alcohol consumption, anxiety-like behavior, and ECB mRNA expression in the nucleus accumbens (NAc) of alcohol-dependent rats during acute withdrawal. Male rats exposed to six weeks of CIA showed escalated alcohol consumption during acute withdrawal and reductions in NAc NAPEPLD, DAGLα, and MAGL mRNA. Intact alcohol-dependent female rats also escalated their consumption, but notably, this effect was also present in non-dependent females. No differences in NAc ECB mRNA were observed between CIA- and air-exposed females during acute withdrawal. However, when these data were analyzed according to estrous stage, significant differences in NAPEPLD and MAGL mRNA expression emerged in the NAc of air-exposed control rats, which were absent in alcohol-dependent females. We subsequently measured alcohol consumption and NAc ECB mRNA in ovariectomized (OVX) females with or without estradiol (E2) replacement during withdrawal. Neither E2 nor CIA altered alcohol consumption in OVX females. However, E2 reduced both DAGLα and MAGL mRNA, suggesting that E2 may influence the biosynthesis and degradation of 2-arachidonoylglycerol (2-AG) in the NAc. Collectively, these studies indicate sexual dimorphism in alcohol consumption in non-dependent rats and suggest that E2-mediated alterations in NAc ECB mRNA expression during withdrawal may be a mechanism by which sex differences in alcohol dependence emerge.
... There are also no published investigations on 2-AG degrading enzyme monoacylglycerol acid lipase, while there is a single study on FAAH which shows that E2's anxiolytic effects are contingent on CB1R functionality in rats. 54 Further related to receptor and ligand abundances, the metrics of receptor reorganization, including (1) the levels of activation required to initiate these events, (2) rate, and (3) overall efficiency of receptor downregulation or upregulation in vivo are not well defined. These details would improve understanding between the cannabinoid receptor and endocannabinoid data presented in Tables 1 and 2. Finally, our literature search yielded no data on the role of CB2R. ...
Chapter
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Neurological crosstalk between the endocannabinoid and estrogen systems has been a growing topic of discussion over the last decade. Although the main estrogenic ligand, estradiol (E2), influences endocannabinoid signaling in both male and female animals, the latter experiences significant and rhythmic fluctuations in E2 as well as other sex hormones. This is referred to as the menstrual cycle in women and the estrus cycle in rodents such as mice and rats. Consisting of 4 distinct hormone-driven phases, the rodent estrus cycle modulates both endocannabinoid and exogenous cannabinoid signaling resulting in unique behavioral outcomes based on the cycle phase. For example, cannabinoid receptor agonist-induced antinociception is greatest during proestrus and estrus, when circulating and brain levels of E2 are high, as compared to metestrus and diestrus when E2 concentrations are low. Pain processing occurs throughout the cerebral cortex and amygdala of the forebrain; periaqueductal grey of the midbrain; and medulla and spine of the hindbrain. As a result, past molecular investigations on these endocannabinoid-estrogen system interactions have focused on these specific brain regions. Here, we will bridge regional molecular trends with neurophysiological evidence of how plasma membrane estrogen receptor (ER) activation by E2 leads to postsynaptic endocannabinoid synthesis, retrograde signaling, and alterations in inhibitory neurotransmission. These signaling pathways depend on ER heterodimers, current knowledge of which will also be detailed in this review. Overall, the aim of this review article is to systematically summarize how the cannabinoid receptors and endocannabinoids change in expression and function in specific brain regions throughout the estrus cycle.
... Subsequent studies with this FAAH inhibitor (URB597) showed that it also induced antidepressant properties (Gobbi et al., 2005;McLaughlin et al., 2012). To date, preclinical research has produced several results regarding the role of the ECS in affective disorders, such as depression (Bortolato et al., 2007;Gobbi et al., 2005;Griebel et al., 2005;Hill et al., 2007;Hill and Gorzalka, 2005a, b;Mangieri and Piomelli, 2007;Ortega et al., 2013;Witkin et al., 2005). ...
Chapter
Accumulating evidence has proven that both exogenous cannabinoids as well as imbalances in the endocannabinoid system are involved in the onset and development of mental disorders such as anxiety, depression, or schizophrenia. Extensive recent research in this topic has mainly focused on the molecular mechanisms by which cannabinoid agonists may contribute to the pathophysiology of these disorders. Initially, serotonin neurotransmitter garnered most attention due to its relationship to mood disorders and mental diseases, with little attention to specific receptors. To date, the focus has redirected toward the understanding of different serotonin receptors, through a demonstration of its versatile pharmacology and synergy with different modulators. Serotonin 2A receptors are a good example of this phenomenon, and the complex signaling that they trigger appears of high relevance in the context of mental disorders, especially in schizophrenia. This chapter will analyze most relevant attributes of serotonin 2A receptors and the endocannabinoid system, and will highlight the evidence toward the functional bidirectional interaction between these elements in the brain as well as the impact of the endocannabinoid system dysregulation on serotonin 2A receptors functionality.
... For instance, men are diagnosed with AUDs more often than women and report more severe symptoms of alcohol withdrawal (Deshmukh et al., 2003), while women report more alcohol-related medical and psychiatric problems, as well as fertility issues and menstrual cycle disruptions (Erol and Karpyak, 2015;Wilsnack et al., 1984). The ECB system and ovarian hormones also interact in a bidirectional manner (Gorzalka and Dang, 2012), and the ECB system has been implicated in the ability of ovarian hormones to modulate emotional behavior (Hill et al., 2007). Thus, sex differences observed in the symptoms of alcohol dependence may result, in part, from sex differences in the ECB system due to fluctuations in ovarian hormones. ...
Article
Alcohol dependence is associated with anxiety during withdrawal. The endocannabinoid (ECB) system participates in the neuroendocrine and behavioral response to stress and changes in corticolimbic ECB signaling may contribute to alcohol withdrawal-induced anxiety. Moreover, symptoms of alcohol withdrawal differ between sexes and sexual dimorphism in withdrawal-induced ECB recruitment may be a contributing factor. Herein, we exposed intact male and female rats and ovariectomized (OVX) female rats with or without estradiol (E2) replacement to 6 weeks of chronic intermittent alcohol vapor and measured anxiety-like behavior, ECB content, and ECB-related mRNA in the basolateral amygdala (BLA) and ventromedial prefrontal cortex (vmPFC). Acute alcohol withdrawal increased anxiety-like behavior, produced widespread disturbances in ECB-related mRNA, and reduced anandamide (AEA) content in the BLA and 2-arachidonoylglycerol (2-AG) content in the vmPFC of male, but not female rats. Similar to males, alcohol-exposed OVX females showed reductions in Napepld mRNA in the BLA, decreased AEA content in the BLA and vmPFC, and reductions in all ECB-related genes measured in the vmPFC. Importantly, E2 replacement prevented withdrawal-induced alterations in ECB content (but not mRNA) in OVX females, and although alcohol-exposed OVX females failed to exhibit more anxiety compared to their respective control, chronic alcohol exposure abolished the anxiolytic properties of E2 in OVX rats. These data indicate that ovarian sex hormones (but not E2 alone) protect against withdrawal-induced alterations in corticolimbic ECB signaling but do not impart resilience to withdrawal-induced anxiety. Thus, the mechanisms implicated in the manifestation of alcohol withdrawal-induced anxiety are most likely sex-specific.
... However, exposure to the specific FAAH inhibitor PF-04457845 also increased locomotor activity. This increase is in contrast to previous reports where acute exposure of adults to the FAAH inhibitor URB597 did not alter motor activity (Hill et al., 2007;Mazzola et al., 2009a, b) and repeated gestational/neonatal exposure to URB597 did not alter motor activity in the adult offspring (Wu et al., 2014). It is also in contrast to the previous report of decreased locomotor activity in adult animals exposed to URB597 during adolescence (Macri et al., 2012). ...
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The organophosphorus insecticide chlorpyrifos (CPF) is suspected to cause developmental neurotoxicity in children leading to long term effects. Developmental exposure of rat pups to CPF at low levels disrupts degradation of the brain endocannabinoids through the inhibition of fatty acid amide hydrolase (FAAH) and decreases the reactivity of juvenile rats in an emergence test. In this study, we further investigated the effects of developmental CPF exposure on behavior but also included exposure to PF-04457845, a specific inhibitor of FAAH, for comparison of behavior altered by FAAH inhibition with behavior altered by CPF. Ten day old rat pups were exposed orally either to 0.5, 0.75, or 1.0 mg/kg CPF or 0.02 mg/kg PF-04457845 daily for 7 days. In an open field (day 23), the high CPF and PF-04457845 groups exhibited increased motor activity but no differences in the time spent in the field's center. In an elevated plus maze (day 29), all treatment groups had increased open arm activity but ethological behaviors associated with anxiety were not altered. Behaviors in the maze associated with increased general activity and exploratory drive were increased. Social interactions (day 36) were measured and all treatment groups exhibited increased levels of play behavior. The similarities in behavior between PF-04457845 and CPF suggest that enhanced endocannabinoid signaling during the exposure period plays a role in the persistent alteration of behavior observed following developmental CPF exposure.
... Depressive episodes in women may also be partly associated with hormonal fluctuations especially during periods where estrogen levels undergo rapid change (Shors and Leuner, 2003). Estrogen can also recruit the endocannabinoid system to modulate mood and emotion (Gorzalka and Dang, 2012;Hill et al., 2007;Scorticati et al., 2004). The effects of sex hormones on biochemical and behavioral parameters were not tease out in the present study and the influence of sex hormones on the endocanabinoid system and behavioral outcome cannot be ruled out. ...
Article
Major depressive disorder (MDD) is common, often under-treated and a leading cause of disability and mortality worldwide. The causes of MDD remain unclear, including the role of the endocannabinoid system. Intriguingly, the prevalence of depression is significantly greater in women than men. In this study we examined the role of endocannabinoids in depressive behavior. The levels of endocannabinoids, N-arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG) were measured along with brain derived neurotrophic factor (BDNF) in postmortem ventral striata of female patients with MDD and non-psychiatric controls, and in Wistar Kyoto (WKY) rat, a selectively inbred strain of rat widely used for testing the depressive behavior. The effect of pharmacological elevation of endocannabinoids through inhibition of their catabolizing enzymes (fatty acid amide hydrolase [FAAH] and monoacyl glycerol lipase [MAGL]) on depressive-like phenotype was also assessed in WKY rat. The findings showed lower levels of endocannabinoids and BDNF in the ventral striata of MDD patients and WKY rats. A dual inhibitor of FAAH and MAGL, JZL195, elevated the endocannabinoids and BDNF levels in ventral striatum, and reduced the depressive-like phenotype in female WKY rats. Collectively, our study suggests a blunted ventral striatal endocannabinoid and BDNF signaling in depressive behavior and concludes that endocannabinoid enhancing agents may have an antidepressant effect.
... The FAAH gene contains an estrogen response element; translocation of the estrogen receptor caused a down-regulation of FAAH transcription (Waleh et al., 2002). This is consistent with the finding that a CNR1 receptor antagonist reversed the anxiolytic effect of estradiol in rats and that the FAAH inhibitor URB 597 produced an anxiolytic effect similar to that produced by estradiol (Hill et al., 2007). ...
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There are several findings indicating that endocannabinoid system (ECS) are important factors, acting in multiple ways in regulating reproductive function but changes of this system in the bovine endometrium have rarely been investigated; therefore, this study was designed to consider an association between endometrium ECS expression and different stages of the estrous cycles. MRNA expressions of the ECS were investigated during the late luteal phase and estrus using real-time PCR. Following estrous synchronization of sixteen Holstein dairy cows (34±1.3 kg/day of milk production), using two PGF2α injections given 14 days apart, in 30 and 44 days in milk (DIM), blood samples and ultrasonography (US) were performed every other day from the day of second PGF2α injection (44 DIM) until the start of the next estrous cycle (67±2 DIM) to verify CL development and ovulation. Based on blood and US results endometrial tissue collected on day 16 (late luteal phase) and 21 (estrus) of the synchronized estrous cycle (ovulation = d 0). Real-time PCR analysis of ECS mRNA expression revealed endocannabinoid receptor (CNR2), diacylglycerol lipase (DAGL), cyclooxygenase-2 (COX-2), fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGLL) had significant fold differences when comparing two different stages of the estrous cycle (late luteal phase vs. estrus). CNR2 and DAGL showed 2.01 and 2.57 fold increase, respectively (P = 0.04 and P = 0.02), in estrus cows. Among the analyzed genes FAAH (P = 0.01) and MGLL (P = 0.02) were significantly down-regulated in estrus cows, with a 5.01, and 2.44-fold difference in mRNA expression, respectively. Overall, this study highlights an association between the expression of the ECS in the bovine endometrium and stage of the estrous cycle.
... Interestingly, there was no consistent effect of sex on either basal or stress-induced changes in endocannabinoid signaling across these studies. Previous work has suggested that endocannabinoid levels, particularly that of AEA, may be sensitive to reproductive hormones such as estrogen (Hill et al., 2007;Maccarrone et al., 2002;Maia et al., 2017;Tabatadze et al., 2015). In the cohort of rats used for the restraint study, we found that females had globally higher AEA then males, regardless of stress condition; however, this was not seen in either of the other two cohorts. ...
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Research over the past few decades has established a role for the endocannabinoid system for contributing to the neural and endocrine responses to stress exposure. The two endocannabinoid ligands, anandamide (AEA) and 2-arachidonylyl glycerol (2-AG), both play roles in regulating the stress response and both exhibit dynamic changes in response to stress exposure. Most of this previous research, however, was conducted in male rodents. Given that, especially in rodents, the stress response is influenced by sex, an understanding of how these dynamic responses of endocannabinoids in response to stress is influenced by sex could provide insight into sex differences of the acute stress response. We exposed adult, Sprague Dawley rats to different commonly utilized acute stress modalities, specifically restraint, swim and foot shock stress. Thirty minutes following stress onset, we excised the amygdala, hippocampus and medial prefrontal cortex, corticolimbic brain regions involved in the stress response, to measure endocannabinoid levels. When AEA levels were altered in response to restraint and swim stress, they were reduced, whereas exposure to foot shock stress led to an increase in the amygdala. 2-AG levels, when they were altered by stress exposure were only increased, specifically in males in the amygdala following swim stress, and in the hippocampus and medial prefrontal cortex overall following foot shock stress. This increase in 2-AG levels following stress only in males was the only sex difference found in stress-induced changes in endocannabinoid levels. There were no consistent sex differences observed. Collectively, these data contribute to our further understanding of the interactions between stress and endocannabinoid function.
... Differences of ECS drive in males and females might thus manifest as different sensitivies to HPAA activity, or striatal dopamine release in response to stress (Dlugos et al., 2012), a transdiagnostic psychiatric risk factor (Agid et al., 2000). This theoretical link between sex dependent psychiatric vulnerabilities and the ECS is supported by observations of the intermediary role of the ECS in estradiol effects on addiction (Peterson et al., 2016) and anxiety behaviour (Hill et al., 2007) in female rats. Estradiol also seems to affect hippocampal inhibitory interneuron activity differently in males and females through an ECS dependent mechanism (Tabatadze et al., 2015). ...
Article
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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Depression is a common and potentially debilitating psychiatric disorder, and is twice as prevalent in women as in men. The traditional monoamine hypothesis of depression provides one perspective into the biological basis of depression, but it is unable to explain all facets of this disease. The reason for the sex difference is currently unclear. The endocannabinoid system, a major neuromodulatory system in the brain, interacts with multiple neurotransmitter and hormone systems, including the monoamine neurotransmitter norepinephrine. Increased endocannabinoid signaling appears to cause greater levels of noradrenergic activation in the locus coeruleus and in axons projecting into other parts of the brain. Dysfunctions in both the endocannabinoid system and the noradrenergic system have been linked to the physiology of depression, with the hypothalamic-pituitary-adrenal (HPA) axis stress response being a major area of interaction. Norepinephrine acts as a gatekeeper to the body's stress response, mobilizing the HPA axis to react to stressors. The endocannabinoid system is also a gatekeeper to this response, preventing maladaptive HPA hyperactivation and potentially protecting the noradrenergic system from entering into a burn-out state in the face of chronic stress. Sexual dimorphism in both systems, as well as in how cells of the locus coeruleus respond to stress, may contribute to some of the sex differences seen in depression. Disruptions to these systems may underlie some cases of depression, and provide potential targets for novel antidepressant treatments. © 2013 Springer Science+Business Media New York. All rights are reserved.
Article
The endocannabinoid system comprises the CB1 and CB2 receptors (the targets of the Cannabis sativa compound delta-9-tetrahydrocannabinol), the endogenous ligands (endocannabinoids) arachidonoyl ethanolamide (anandamide) and 2-arachidonoyl glycerol, their synthesizing machinery and membrane transport system, and the hydrolyzing enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively. The endocannabinoids may act on demand to confer protection against aversive stimuli, which suggests that increasing their brain levels may represent an approach for treatment of anxiety-related disorders. Thus, this article reviews the profile of endocannabinoid reuptake and hydrolysis inhibitors in experimental tests predictive of anxiolytic activity. The FAAH inhibitors and the blockers of anandamide transport, in contrast to direct CB1 receptor agonists, induce anxiolytic effects at doses that do not interfere with motor activity. MAGL inhibitors also reduce anxiety-like behavior, although they are more likely to impair motor activity. Regarding their mechanisms, increasing anandamide levels induce responses mediated by the CB1 receptor and occluded by the transient receptor potential vanilloid type-1 channels, whereas the effects of increasing 2-arachidonoyl glycerol depend on both CB1 and CB2 receptors. Their neuroanatomical targets include various structures related to anxiety and fear responses. Understanding the pharmacological properties of FAAH and MAGL inhibitors may contribute toward the development of new anxiolytic interventions based on the endocannabinoid system.
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The endocannabinoid system is an increasingly recognised pharmacological target for treating stress and anxiety disorders, including post-traumatic stress disorder (PTSD). Recent preclinical developments have implicated the endocannabinoid system in stress responses, emotional memories and fear extinction, all critical to PTSD aetiology. However, preclinical research in endocannabinoid biology has neglected the influential role of sex hormone differences on PTSD symptomology, which is particularly important given that PTSD is twice as common in women as in men. In this review, we compile and consider the evidence that the endocannabinoid system is influenced by ovarian hormones, with application to stress disorders such as PTSD. It is clear that therapeutic modulation of the endocannabinoid system needs to be approached with awareness of ovarian hormonal influences, and knowledge of these influences may enhance treatment outcomes for female PTSD populations.
Chapter
Sex-dependent differences have been consistently reported in the prevalence and frequency of use of Cannabis, with patterns of use, subjective effects, and progression to dependence being different in male and female smokers. As confirmed by animal studies, cannabinoids exert sex-dependent effects in many physiological and behavioral aspects, including food intake and energy balance (stronger in males) and emotional regulation (stronger in females). Following chronic THC exposure during adolescence, cannabinoid receptors undergo desensitization, which is greater in adolescent female animals than in male animals. Preclinical research is greatly contributing to elucidate the neurobiological bases for sex differences in cannabinoid effects, among which different cannabinoid pharmacodynamic and pharmacokinetic and gonadal hormones play crucial roles. The sexual dimorphism of the brain in cannabinoid subtype 1 receptor (CB1R) distribution and function massively contributes to the variety of differences reported in cannabinoid-induced effects between the two sexes. The distribution and activity of neuronal CB1Rs in the male and female brains and how they can be differently affected by stress and drugs of abuse have been investigated in many brain areas. In this chapter, we will first provide an overview on the brain sexual dimorphism and the sex-dependent effects of cannabinoids. Then we will review both clinical and laboratory-based research evidence revealing important sex-related differences in CB1 receptor level and function in different brain areas. Finally, the influence of gonadal hormones in determining such differences will be discussed.
Chapter
The stress response is an evolutionarily conserved mechanism to both allow an organism to cope with a threat and to restore homeostasis following exposure to a stressor. With respect to this response, preclinical research demonstrates that the endogenous cannabinoid (ECB) system constrains the hypothalamic-pituitary-adrenal axis and plays a major role in the habituation to stressors. Specifically, anandamide tonically constrains activation of stress responsive circuits in the brain under basal conditions; however, exposure to stress or glucocorticoids initiates a cascade of events whereby corticotropin-releasing hormone (CRH) rapidly reduces anandamide metabolism through CRHR1-mediated activation of fatty acid amide hydrolase (FAAH) in the basolateral amygdala (BLA), which ultimately facilitates activation of the neuroendocrine axis and emotional response to stress. On the other hand, 2-arachidonoylglycerol (2-AG) provides on-demand synaptic modulation and promotes short-term adaptation to stress via glucocorticoid receptor-dependent mobilization in the hypothalamus and extrahypothalamic inhibitory feedback centers such as the medial prefrontal cortex (mPFC) and hippocampus. Additionally, 2-AG is recruited in the BLA to facilitate habituation to chronic homotypic stress, thus facilitating long-term adaptation as well. Accordingly, impairments in ECB signaling within the hypothalamus, BLA, mPFC, and/or hippocampus may confer maladaptive neuroendocrine and behavioral responses to stress, thereby contributing to the emergence of stress-related disorders such as anxiety, depression, and substance abuse. Moreover, sexual dimorphism and genetic differences in the ECB system may contribute to individual differences in stress coping strategies, which can have profound ramifications. © Springer International Publishing AG 2017. All rights reserved.
Chapter
The medical properties of Cannabis sativa is known for centuries. Since the discovery and characterization of the endogenous cannabinoid system, several studies have evaluated how cannabinoid compounds and, particularly, how the modulation of the endocannabinoid (eCB) system influences a wide range of functions, from metabolic to mental disorders. Cannabinoids and eCB system often exert opposite effects on several functions, such as anxiety. Although the mechanisms are not completely understood, evidence points to different factors influencing those effects. In this chapter, the recent advances in research about the relationship between eCB system and anxiety disorders in humans, as well as in animal models, will be discussed. The recent data addressing modulation of the eCBs in specific brain areas, such as the medial prefrontal cortex, amygdaloid complex, bed nucleus of stria terminalis, hippocampus, and dorsal periaqueductal gray, will be summarized. Finally, data from animal models addressing the mechanisms through which the eCB system modulates anxiety-related behavior dependent on stressful situations, such as the involvement of different receptors, distinct eCBs, modulation of neurotransmitters release, HPA axis and immune system activation, and plastic mechanisms, will also be discussed.
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Background: Essential oil from Cananga odorata (ylang-ylang essential oil, YYO) is usually used in reducing blood pressure, improving cognitive functioning in aromatherapy in human. Few reports showed its effect on anxiety behaviors. Hypothesis/purpose: To investigate the anxiolytic effects of YYO exposure on anxiety animal models, determine the major active constituents and investigate the change of neurotransmitters after odor exposure. Study design and methods: ICR mice were subjected to three anxiety models including open field, elevated plus maze and light-dark box tests after acute and chronic YYO exposure. Main constituents of YYO were defined using GC/MS. These compounds were then tested on the male mice separately on three anxiety models. The monoamines neurotransmitters and their metabolites were analyzed after acute odor exposure and elevated plus maze test. Results: YYO exposure only showed significant anxiolytic effect on the male mice. It increased the time that mice visited open arms and light box area in elevated plus maze and light-dark box tests after acute and chronic YYO exposures. Three main constituents of YYO, benzyl benzoate, linalool and benzyl alcohol showed anxiolytic effect on the male mice individually. YYO exposure brought changes of neurotransmitters on the male mice more significantly than the female mice. It decreased the dopamine (DA) concentration in the striatum and increased the 5-hydroxytryptamine (5-HT) concentration in the hippocampus of the male mice. The major constituent benzyl benzoate changed neurotransmitters concentration in accordance with the YYO. Moreover, it decreased the ratio of 5-HIAA/5-HT in the hippocampus. Conclusion: Both acute and chronic YYO exposure showed anxiolytic effect on the male mice. YYO and its major constituent benzyl benzoate might act on the 5-HTnergic and DAnergic pathways.
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In the present study, we investigated the effects of acute pharmacological manipulation of the endocannabinoid (EC) system on the valence of cognitive judgement bias of rats in the ambiguous-cue interpretation (ACI) paradigm. To accomplish this goal, after initial behavioural training, different groups of rats received single, systemic injections of the irreversible anandamide (AEA) hydrolysis inhibitor URB597, the cannabinoid receptor type 1 (CB1) inverse agonist AM251, the cannabinoid receptor type 2 (CB2) inverse agonist AM630, the combination of URB597 and AM251, and a combination of URB597 and AM630 and were subsequently tested with the ACI paradigm. We report that URB597 at a dose of 1 mg/kg significantly biased animals towards positive interpretation of the ambiguous cue and that this effect was abolished by pre-treatment with AM251 (1 mg/kg) or AM630 (1 mg/kg). The CB1 and CB2 inverse agonists administered alone (1 mg/kg) had no statistically significant effects on the interpretation of the ambiguous cue by rats. Our findings suggest involvement of the endocannabinoid system in the mediation of optimistic judgement bias.
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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.
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The psychoactive constituent of cannabis, Delta(9)-tetrahydrocannabinol, produces in humans subjective responses mediated by CB1 cannabinoid receptors, indicating that endogenous cannabinoids may contribute to the control of emotion. But the variable effects of Delta(9)-tetrahydrocannabinol obscure the interpretation of these results and limit the therapeutic potential of direct cannabinoid agonists. An alternative approach may be to develop drugs that amplify the effects of endogenous cannabinoids by preventing their inactivation. Here we describe a class of potent, selective and systemically active inhibitors of fatty acid amide hydrolase, the enzyme responsible for the degradation of the endogenous cannabinoid anandamide. Like clinically used anti-anxiety drugs, in rats the inhibitors exhibit benzodiazepine-like properties in the elevated zero-maze test and suppress isolation-induced vocalizations. These effects are accompanied by augmented brain levels of anandamide and are prevented by CB1 receptor blockade. Our results indicate that anandamide participates in the modulation of emotional states and point to fatty acid amide hydrolase inhibition as an innovative approach to anti-anxiety therapy.
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The present study evaluated the possible antidepressant-like action of the natural estrogen 17beta-estradiol (E(2), 2.5-10 microg/rat), the synthetic steroidal estrogen ethinyl-estradiol (EE(2), 1.25-10.0 microg/rat), and the nonsteroidal synthetic estrogen, diethyl-stilbestrol (DES, 0.25-1.0 mg/rat) in ovariectomized adult female Wistar rats using the forced swimming test (FST). The behavioral profile induced by the estrogens was compared with that induced by the antidepressants fluoxetine (FLX, 2.5-10 mg/kg) and desipramine (DMI, 2.5-10 mg/kg). In addition, the temporal course of the antidepressant-like action of the estrogenic compounds was analyzed. FLX and DMI induced an antidepressant-like effect characterized by a reduced immobility and increased swimming for FLX and decreased immobility and increased climbing for DMI. Both E(2) and EE(2) produced a decrease in immobility and an increase in swimming, suggesting an antidepressant-like action. DES did not affect the responses in this animal model of depression at any dose tested. The time course analysis of the actions of E(2) (10 microg/rat) and EE(2) (5 microg/rat) showed that both compounds induced an antidepressant-like effect observed 1 h after their injection lasting for 2-3 days.
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Uncertainties exist about prevalence and correlates of major depressive disorder (MDD). To present nationally representative data on prevalence and correlates of MDD by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria, and on study patterns and correlates of treatment and treatment adequacy from the recently completed National Comorbidity Survey Replication (NCS-R). Face-to-face household survey conducted from February 2001 to December 2002. The 48 contiguous United States. Household residents ages 18 years or older (N = 9090) who responded to the NCS-R survey. Prevalence and correlates of MDD using the World Health Organization's (WHO) Composite International Diagnostic Interview (CIDI), 12-month severity with the Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR), the Sheehan Disability Scale (SDS), and the WHO disability assessment scale (WHO-DAS). Clinical reinterviews used the Structured Clinical Interview for DSM-IV. The prevalence of CIDI MDD for lifetime was 16.2% (95% confidence interval [CI], 15.1-17.3) (32.6-35.1 million US adults) and for 12-month was 6.6% (95% CI, 5.9-7.3) (13.1-14.2 million US adults). Virtually all CIDI 12-month cases were independently classified as clinically significant using the QIDS-SR, with 10.4% mild, 38.6% moderate, 38.0% severe, and 12.9% very severe. Mean episode duration was 16 weeks (95% CI, 15.1-17.3). Role impairment as measured by SDS was substantial as indicated by 59.3% of 12-month cases with severe or very severe role impairment. Most lifetime (72.1%) and 12-month (78.5%) cases had comorbid CIDI/DSM-IV disorders, with MDD only rarely primary. Although 51.6% (95% CI, 46.1-57.2) of 12-month cases received health care treatment for MDD, treatment was adequate in only 41.9% (95% CI, 35.9-47.9) of these cases, resulting in 21.7% (95% CI, 18.1-25.2) of 12-month MDD being adequately treated. Sociodemographic correlates of treatment were far less numerous than those of prevalence. Major depressive disorder is a common disorder, widely distributed in the population, and usually associated with substantial symptom severity and role impairment. While the recent increase in treatment is encouraging, inadequate treatment is a serious concern. Emphasis on screening and expansion of treatment needs to be accompanied by a parallel emphasis on treatment quality improvement.
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The Women's Health Initiative trial of combined estrogen plus progestin was stopped early when overall health risks, including invasive breast cancer, exceeded benefits. Outstanding issues not previously addressed include characteristics of breast cancers observed among women using hormones and whether diagnosis may be influenced by hormone effects on mammography. To determine the relationship among estrogen plus progestin use, breast cancer characteristics, and mammography recommendations. Following a comprehensive breast cancer risk assessment, 16 608 postmenopausal women aged 50 to 79 years with an intact uterus were randomly assigned to receive combined conjugated equine estrogens (0.625 mg/d) plus medroxyprogesterone acetate (2.5 mg/d) or placebo from 1993 to 1998 at 40 clinical centers. Screening mammography and clinical breast examinations were performed at baseline and yearly thereafter. Breast cancer number and characteristics, and frequency of abnormal mammograms by estrogen plus progestin exposure. In intent-to-treat analyses, estrogen plus progestin increased total (245 vs 185 cases; hazard ratio [HR], 1.24; weighted P<.001) and invasive (199 vs 150 cases; HR, 1.24; weighted P =.003) breast cancers compared with placebo. The invasive breast cancers diagnosed in the estrogen plus progestin group were similar in histology and grade but were larger (mean [SD], 1.7 cm [1.1] vs 1.5 cm [0.9], respectively; P =.04) and were at more advanced stage (regional/metastatic 25.4% vs 16.0%, respectively; P =.04) compared with those diagnosed in the placebo group. After 1 year, the percentage of women with abnormal mammograms was substantially greater in the estrogen plus progestin group (716 [9.4%] of 7656) compared with placebo group (398 [5.4%] of 7310; P<.001), a pattern which continued for the study duration. Relatively short-term combined estrogen plus progestin use increases incident breast cancers, which are diagnosed at a more advanced stage compared with placebo use, and also substantially increases the percentage of women with abnormal mammograms. These results suggest estrogen plus progestin may stimulate breast cancer growth and hinder breast cancer diagnosis.
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Contrasting data were reported regarding the effects of cannabinoids on anxiety and social behaviour in both animals and humans. The cognitive effects of cannabinoids and their interactions with the HPA-axis raise the possibility that cannabinoid effects are context but not behaviour specific. To assess this hypothesis, we submitted CB1 receptor knock-out (CB1-KO) and wild-type (WT) mice to tests, which involved similar behaviours, but the behavioural context was different. The elevated plus-maze test was performed under less and more anxiogenic conditions, i.e. under low and high light, respectively. We also compared the social behaviour of the two genotypes in the resident/intruder and social interaction tests. Both tests represent a social challenge and induce similar behaviours, but involve different contexts. The behaviour of CB1-KO and WT mice was similar under low light, but CB1 gene disruption increased anxiety-like behaviour under the high light condition. CB1 gene disruption promoted aggressive behaviour in the home-cage, whereas it inhibited social behaviour in the unfamiliar cage. Thus, the anxiogenic-like effect was restricted to the more stressful unfamiliar environment. These data suggest that the effects of CB1 gene disruption were context and not behaviour specific. Novelty stress resulted in higher ACTH levels in CB1-KOs than in WTs, which suggests that context dependency occurred in conjunction with an altered HPA axis function. The present data at least partly explain contrasting effects of cannabinoids in different contexts as well as in different species and strains that show differential stress responses and coping strategies.
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Anandamide (0.01 to 10 microM) caused greater concentration-dependent reductions of the contractile-induced responses to noradrenaline in female than in male mesenteric vascular beds isolated from adult Sprague-Dawley rats. Greater relaxant responses in females were also induced by the vanilloid TRPV1 receptor agonist capsaicin (0.01 to 10 microM), whereas no sex differences were observed for the relaxations caused by either acetylcholine or sodium nitroprusside. The effect of anandamide in either sex was reduced by the vanilloid TRPV1 receptor antagonist capsazepine but not by the cannabinoid CB1 receptor antagonist N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-3-pyrazole-carboxamide (SR141716A). In males, the anandamide-induced relaxations were potentiated by in vitro exposure during 5 min to 0.5 microM 17beta-oestradiol and unmodified by the protein synthesis inhibitor cycloheximide. The vasorelaxant effects of anandamide in female rats were decreased by ovariectomy. This decrease was prevented by in vivo treatment with 17beta-oestradiol-3-benzoate (450 microg/kg i.m., once a week during 3 weeks) and counteracted by in vitro exposure to oestrogen. In vivo treatment with 17beta-oestradiol also potentiated anandamide-induced responses in males. In conclusion, this study shows an oestrogen-dependent sensitivity to the vanilloid TRPV1 receptor-mediated vasorelaxant effects of anandamide in the mesenteric vasculature of Sprague-Dawley rats, that could be mediated by both genomic and non-genomic mechanisms.
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BACKGROUND: The Women's Health Initiative (WHI) clinical trial of conjugated equine estrogens (CEEs), involving 10,739 postmenopausal women with hysterectomy, aged 50 to 79 years, was stopped early owing to lack of overall health benefit and increased risk of stroke. Because CEE is still prescribed for treatment of menopausal symptoms and prevention of osteoporosis, it is important to understand the overall impact of this therapy on health-related quality of life (HRQOL). METHODS: All participants completed 6 specific measures of quality of life at baseline and 1 year, and a subsample (n = 1189) also completed the questions 3 years after randomization. Changes in scores were analyzed for treatment effect. RESULTS: Randomization to CEE was associated with a statistically significant but small reduction in sleep disturbance at year 1 compared with baseline (mean benefit, 0.4 points on a 20-point scale) and a statistically significant but small negative effect on social functioning (mean effect, -1.3 points on a 100-point scale). There were no significant improvements due to CEE in the areas of general health, physical functioning, pain, vitality, role functioning, mental health, depressive symptoms, cognitive function, or sexual satisfaction at year 1. A subgroup examined 3 years after baseline had no significant benefits for any HRQOL outcomes. Among women aged 50 to 54 years with moderate to severe vasomotor symptoms at baseline, CEE did not improve any of the HRQOL variables at year 1. CONCLUSION: In this trial of postmenopausal women with prior hysterectomy, oral CEE did not have a clinically meaningful effect on HRQOL.
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Although anecdotal reports suggest that cannabis may be used to alleviate symptoms of depression, the psychotropic effects and abuse liability of this drug prevent its therapeutic application. The active constituent of cannabis, Delta(9)-tetrahydrocannabinol, acts by binding to brain CB, cannabinoid receptors, but an alternative approach might be to develop agents that amplify the actions of endogenous cannabinoids by blocking their deactivation. Here, we show that URB597, a selective inhibitor of the enzyme fatty-acid amide hydrolase, which catalyzes the intracellular hydrolysis of the endocannabinoid anandamide, exerts potent antidepressant-like effects in the mouse tail-suspension test and the rat forced-swim test. Moreover, URB597 increases firing activity of serotonergic neurons in the dorsal raphe nucleus and noradrenergic neurons in the nucleus locus ceruleus. These actions are prevented by the CB, antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB, agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of Delta(9)-tetrahydrocannabinol in rats. The findings support a role for anandamide in mood regulation and point to fatty-acid amide hydrolase as a previously uncharacterized target for antidepressant drugs.
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