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Endocannabinoids modulate stress-induced suppression of hippocampal cell proliferation and activation of defensive behaviours

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Abstract

The endocannabinoid system has been shown to regulate both the hypothalamic-pituitary-adrenal (HPA) axis and emotionality. The present experiment was designed to examine whether pharmacological modulation of the endocannabinoid system would affect the suppression of hippocampal cell proliferation and increase in defensive behaviours seen following exposure to predator odour (trimethylthiazoline; TMT) stress. Rats were administered either an endocannabinoid uptake inhibitor (AM404; 2 mg/kg) or a cannabinoid CB1 receptor antagonist (AM251; 5 mg/kg) 30 min prior to exposure to TMT. Exposure to TMT reduced cell proliferation in the dentate gyrus and increased the expression of defensive burying. Administration of AM404 significantly inhibited defensive burying, and attenuated the reduction in cell proliferation in response to TMT exposure. Administration of AM251 alone significantly increased cell proliferation; however, pretreatment with AM251 prevented neither the stress-induced suppression of cell proliferation nor the stress-induced increase in behavioural responses. These results support previous research demonstrating that augmentation of endocannabinoid signalling can suppress stress-responsive systems. They also suggest that endocannabinoids may play a complex role in the regulation of neurogenesis via cell proliferation in the hippocampus.

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... mice and in animals treated with URB597, an FAAH inhibitor [27]. On the other hand, the ECB uptake inhibitor, AM404, reversed the trimethylthiazoline (TMT)induced decrease of neurogenesis [104]. Finally, the genetic ablation of the enzyme responsible for 2-AG synthesis reduced cell proliferation, the number of doublecortin (a neuroblast marker) positive cells, and decreased the survival of newborn cells in the DG [31,105]. ...
... Also, repeated administration of the CB 1 antagonists/inverse agonists, SR141716A, and AM251, decreased neurogenesis in some studies [106]. Other groups, nevertheless, suggested that these drugs facilitate neurogenesis [30,104,107]. Interestingly, the effects of some of these cannabinergic drugs were preserved in CB 1 but not in TRPV 1 -deficient mice [107]. ...
... Some of these studies are not only based on associative results, but suggest causality, once the direct ablation of hippocampal neurogenesis by different methods prevented the therapeutic effects induced by distinct cannabinoids tested. Acute treatment with AM404, an ECB uptake inhibitor, reversed the trimethylthiazoline-induced decrease of hippocampal cell proliferation and pro-moted anxiolytic-like effect [104]. In the same sense, sub-chronic treatment with the CB 1 /CB 2 agonist HU210 induced anxiolytic-and antidepressant-like effects accompanied by an increase in neurogenesis [101]. ...
Chapter
Neurogenesis plays an indispensable role in the formation of the nervous system during development. The discovery that the adult brain still maintains neurogenic niches that allow the continued production of new cells after birth has changed the field of neuroscience. It has also opened a new venue of opportunities for the treatment of central nervous system disorders related to neuronal loss. This chapter has reviewed the studies showing that genetic or pharmacological manipulation of cannabinoid receptors (CB1 and CB2) or the enzymes responsible for endocannabinoid metabolism modify/regulate cell proliferation and neurogenesis during development and in the adult brain. A better characterization of the mechanisms involved in these effects could contribute to the development of new therapeutic alternatives to neurodegenerative and psychiatric disorders.
... De los resultados de los estudios preclínicos se puede generalizar que la exposición de animales a estresores agudos afecta principalmente la proliferación de las células progenitoras del GD del hipocampo, sin afectar en su mayoría la diferenciación y la sobrevivencia. [34][35][36][37][38][39] Entre los modelos más empleados en estas investigaciones están la exposición a olores de depredadores, [35][36][37][38] así como el modelo de restricción física y el choque eléctrico. [36][37][38][39] En cambio, los modelos de estrés crónico han mostrado que, además de afectar la etapa de proliferación celular, también altera la sobrevivencia celular y la diferenciación neuronal. ...
... De los resultados de los estudios preclínicos se puede generalizar que la exposición de animales a estresores agudos afecta principalmente la proliferación de las células progenitoras del GD del hipocampo, sin afectar en su mayoría la diferenciación y la sobrevivencia. [34][35][36][37][38][39] Entre los modelos más empleados en estas investigaciones están la exposición a olores de depredadores, [35][36][37][38] así como el modelo de restricción física y el choque eléctrico. [36][37][38][39] En cambio, los modelos de estrés crónico han mostrado que, además de afectar la etapa de proliferación celular, también altera la sobrevivencia celular y la diferenciación neuronal. ...
Article
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El hallazgo de la formación de nuevas neuronas en el giro dentado (GD) del hipocampo amplió el conocimiento acerca de la plasticidad del encéfalo. En este sentido, la neurogénesis es un proceso que involucra diferentes eventos celulares tales como: la división de las células madre, la proliferación de los neuroblastos, la migración y la sobrevivencia celular, así como la maduración dendrítica, la elongación axonal y la integración de las neuronas nuevas a los circuitos neuronales existentes. En conjunto, todas estas etapas causan cambios estructurales y funcionales en el cerebro. Por lo tanto, la formación de neuronas es un proceso regulado de manera fina por diferentes factores entre los que se incluyen: el nicho; algunos neurotransmisores como la serotonina, la dopamina, el glutamato y el GABA; factores de crecimiento como el factor de crecimiento de fibroblastos, el factor de crecimiento epidermal y el factor de crecimiento vascular endotelial (FGF, EGF y VEGF, por sus siglas en inglés); neurotrofinas como el factor neurotrópico derivado del cerebro y por la neurotrofina 3 (BDNF y NT3, por sus siglas en inglés).
... Cannabinoids also prevent the neuroplastic events triggered by stress. Exposure to predator odor decreased the proliferative rate of neural stem cells located in the dentate gyrus, an effect inhibited by the treatment with the endocannabinoid uptake inhibitor AM404, but not by the concomitant treatment with AM404 and the CB 1 antagonist AM251 (Hill et al., 2006). Campos et al. (2013) found that mice exposed to CUS for 14 days presented a reduced labeling for the proliferative marker 5-bromo-2'-deoxyuridine (BrdU) and doublecortin expression, a marker of immature neurons, in the dentate gyrus, supporting an anti-neurogenic action of stress. ...
... The inhibition of AEA uptake by AM404 attenuated predator scent-induced activation of defensive burying and suppression of cell proliferation in the hippocampus (Hill et al., 2006). However, the administration of AM404 into the ventral portions of the hippocampus produced opposite effects depending on previous stressful experience. ...
Article
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Exposure to stressful situations is one of the risk factors for the precipitation of several psychiatric disorders, including Major Depressive Disorder, Posttraumatic Stress Disorder, and Schizophrenia. The hippocampal formation is a forebrain structure highly associated with emotional, learning and memory processes; being particularly vulnerable to stress. Exposure to stressful stimuli leads to neuroplastic changes and imbalance between inhibitory/excitatory networks. These changes have been associated with an impaired hippocampal function. Endocannabinoids are one of the main systems controlling both excitatory and inhibitory neurotransmission, as well as neuroplasticity within the hippocampus. Cannabinoids receptors are highly expressed in the hippocampus, and several lines of evidence suggest that facilitation of cannabinoid signaling within this brain region prevents stress-induced behavioral changes. Also, chronic stress modulates hippocampal CB1 receptors expression and endocannabinoid levels. Moreover, cannabinoids participate in mechanisms related to synaptic plasticity and adult neurogenesis. Here, we discussed the main findings supporting the involvement of hippocampal cannabinoid neurotransmission in stress-induced behavioral and neuroplastic changes.
... Accordingly, inhibitors of AEA hydrolysis as well as CB 1 agonists increase the firing activity of serotonin neurons in the dorsal raphe and noradrenergic neurons in the locus coeruleus (Bambico et al., 2007;Gobbi et al., 2005;Oropeza et al., 2005). Lastly, given that factors that predispose to depression, such as stress, suppress neurogenesis (Drew and Hen, 2007;Perera et al., 2008), the antidepressant action of FAAH inhibitors might be due to the documented ability of these agents to increase hippocampal neurogenesis in adult rats (Goncalves et al., 2008;Hill et al., 2006;Marchalant et al., 2009). Overall, these experimental findings indicate that enhancement of AEA/CB 1 signaling via inhibition of FAAH activity may be an effective strategy for preventing/correcting chronic stress-induced depressive-like symptomatology (Fig. 2). ...
Article
Numerous studies have documented a link between psychological disorders and cardiac disease. Yet, no systematic attempts have been made to develop pharmacological approaches for mood and anxiety disorders that could also be beneficial for cardiac health. The endocannabinoid system has been implicated in the regulation of stress, emotional behavior and cardiovascular function. General preclinical findings indicate that the endocannabinoid anandamide modulates physiological and behavioral stress responses and may also protect the heart from arrhythmias. Moreover, recent experimental studies suggest that pharmacological enhancement of anandamide signaling via inhibition of its degrading enzyme fatty acid amide hydrolase (FAAH) exerts anxiolytic- and antidepressive-like effects and improves cardiac autonomic function and the electrical stability of the myocardium in rodent models that reproduce aspects of human psychological/cardiac comorbidity. Here we summarize and discuss such experimental findings, which might guide future preclinical studies towards a systematic evaluation of the therapeutic potential of pharmacological approaches that target FAAH activity for the treatment of the comorbidity between psychological disorders and cardiac disease.
... The SGZ gives rise to new granule cells in the dentate gyrus (DG) of the hippocampus. Rates of proliferation and survival of these new neurons can be modulated by a number of factors, including the richness of environment, exercise, learning, sleep, stress, and levels of glucocorticoids [3][4][5][6][7][8][9]. Many of these factors are under circadian control, suggesting that the circadian clock may influence proliferation and survival of neurons formed during adulthood [10]. ...
Article
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The subgranular zone of the hippocampal formation gives rise to new neurons that populate the dentate gyrus throughout life. Cells in the hippocampus exhibit rhythmic clock gene expression and the circadian clock is known to regulate the cycle of cell division in other areas of the body. These facts suggest that the circadian clock may regulate adult neurogenesis in the hippocampus as well. In the present study, neurogenesis in the hippocampal subgranular zone was examined in arrhythmic Bmal1 knockout (-KO) mice and their rhythmic heterozygous and wildtype littermates. Proliferation and survival of newly generated subgranular zone cells were examined using bromodeoxyuridine labelling, while pyknosis (a measure of cell death) and hippocampal volume were examined in cresyl violet stained sections. There was no significant difference in cellular proliferation between any of the groups, yet survival of proliferating cells, 6 weeks after the bromodeoxyuridine injection, was significantly greater in the BMAL1-KO animals. The number of pyknotic cells was significantly decreased in Bmal1-KO animals, yet hippocampal volume remained the same across genotypes. These findings suggest that while a functional circadian clock is not necessary for normal proliferation of neuronal precursor cells, the normal pruning of newly generated neurons in the hippocampus may require a functional circadian clock.
... During adulthood, acute and chronic stressors can activate the HPA axis, resulting in elevated glucocorticoid levels and reduced neurogenic activity (Gould et al., 1997(Gould et al., , 1998Lagace et al., 2010). In rodents, paradigms of acute psychological stress such as exposure to the odor of natural predators, have been associated with decreased cell proliferation and differentiation of the immature neurons in the DG of hippocampus (Tanapat et al., 2001;Mirescu et al., 2004;Hill et al., 2006;Kambo and Galea, 2006). Similar results have been demonstrated in mice exposed to social defeat or following foot-or tail-electric shock (Duman, 2002;Malberg and Duman, 2003;Yap et al., 2006;Fornal et al., 2007;Lagace et al., 2010). ...
Article
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Neural stem cells (NSCs), the progenitors of the nervous system, control distinct, position-specific functions and are critically involved in the maintenance of homeostasis in the brain. The responses of these cells to various stressful stimuli are shaped by genetic, epigenetic, and environmental factors via mechanisms that are age and developmental stage-dependent and still remain, to a great extent, elusive. Increasing evidence advocates for the beneficial impact of the stress response in various settings, complementing the extensive number of studies on the detrimental effects of stress, particularly in the developing brain. In this review, we discuss suggested mechanisms mediating both the beneficial and detrimental effects of stressors on NSC activity across the lifespan. We focus on the specific effects of secreted factors and we propose NSCs as a “sensor,” capable of distinguishing among the different stressors and adapting its functions accordingly. All the above suggest the intriguing hypothesis that NSCs are an important part of the adaptive response to stressors via direct and indirect, specific mechanisms.
... These data are supported by evidence that repeated administration of CBD to wild-type mice increases hippocampal NPC proliferation via CB1 receptors, which may underlie the anxiolytic effect of CBD in chronically stressed animals (Campos et al., 2013). The CB1 receptor inverse agonist AM251 is often used to oppose the effects of endocannabinoids at the receptor and acute administration of this drug increases cell proliferation in the SGZ 24 h post-treatment (Hill et al., 2006; Wolf et al., 2010). However, this increase reverts to a decrease from 48 h onwards (Wolf et al., 2010 ), again suggesting a complex temporal role for cannabinoid signalling in NSC fate. ...
Article
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The processes underpinning post-developmental neurogenesis in the mammalian brain continue to be defined. Such processes involve the proliferation of neural stem cells (NSCs) and neural progenitor cells (NPCs), neuronal migration, differentiation and integration into a network of functional synapses within the brain. Both intrinsic (cell signalling cascades) and extrinsic (neurotrophins, neurotransmitters, cytokines, hormones) signalling molecules are intimately associated with adult neurogenesis and largely dictate the proliferative activity and differentiation capacity of neural cells. Cannabinoids are a unique class of chemical compounds incorporating plant-derived cannabinoids (the active components of Cannabis sativa), the endogenous cannabinoids and synthetic cannabinoid ligands, and these compounds are becoming increasingly recognized for their roles in neural developmental processes. Indeed, cannabinoids have clear modulatory roles in adult neurogenesis, likely through activation of both CB1 and CB2 receptors. In recent years a large body of literature has deciphered the signalling networks involved in cannabinoid-mediated regulation of neurogenesis. This timely review summarises the evidence that the cannabinoid system is intricately associated with neuronal differentiation and maturation of NPCs, and highlights intrinsic/extrinsic signalling mechanisms that are cannabinoid targets. Overall these findings identify the central role of the cannabinoid system in adult neurogenesis in the hippocampus and the lateral ventricles, and hence provide insight into the processes underlying post-developmental neurogenesis in the mammalian brain. This article is protected by copyright. All rights reserved.
... Moreover, inhibition of endocannabinoid reuptake exhibits antianxiety and antidepressant properties and suggest that this system may act as a buffer in the stress response. Recent evidence, both in vitro and in vivo studies, have indicated that activation of CB1 (cannabinoid type 1) receptors facilitates cell proliferation and neurogenesis in the hippocampus, furthermore, can suppress the neuroendocrine response to stress [21]. Recently shown that chronic Δ9-Tetrahydrocannabinol (THC) administration in females, adolescent rats induces subtle but lasting alterations in the emotional circuit ending in depressive-like behavior at adulthood, for example, increased immobility in the forced swim test, decreased sucrose preference, suggestive of anhedonia, and a deficit in spatial working memory. ...
... In addition to synaptic plasticity, there is also evidence that eCB signaling is important for the regulation of neurogenesis, another form of neuroplasticity. For example, administration of AM404 can reverse acute stress-induced suppression of cell proliferation in the dentate gyrus (Hill et al, 2006). Consistent with this, administration of the phytocannabinoid cannabidiol is capable of reversing chronic stress-induced reductions in neurogenesis and this appears to be driven by a cannabidiol-mediated inhibition of FAAH activity and consequential elevation in AEA levels (Campos et al, 2013). ...
Article
Stress affects a constellation of physiological systems in the body and evokes a rapid shift in many neurobehavioral processes. A growing body of work indicates that the endocannabinoid (eCB) system is an integral regulator of the stress response. In the current review, we discuss the evidence to date that demonstrates stress-induced regulation of eCB signaling and the consequential role changes in eCB signaling have with respect to many of the effects of stress. Across a wide array of stress paradigms, studies have generally shown that stress evokes bidirectional changes in the two eCB molecules, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG), with stress exposure reducing AEA levels and increasing 2-AG levels. Additionally, in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of cannabinoid type 1 (CB1) receptors. With respect to the functional role of changes in eCB signaling during stress, studies have demonstrated that the decline in AEA appears to contribute to the manifestation of the stress response, including activation of the hypothalamic–pituitary–adrenal (HPA) axis and increases in anxiety behavior, while the increased 2-AG signaling contributes to termination and adaptation of the HPA axis, as well as potentially contributing to changes in pain perception, memory and synaptic plasticity. More so, translational studies have shown that eCB signaling in humans regulates many of the same domains and appears to be a critical component of stress regulation, and impairments in this system may be involved in the vulnerability to stress-related psychiatric conditions, such as depression and posttraumatic stress disorder. Collectively, these data create a compelling argument that eCB signaling is an important regulatory system in the brain that largely functions to buffer against many of the effects of stress and that dynamic changes in this system contribute to different aspects of the stress response.
... Furthermore, both pharmacological and genetic inhibition of FAAH prevents chronic restraint stress-induced anxiety in the elevated plus-maze [39], as well as CUS-induced anhedonia [91]. Possible mechanisms of action of eCB augmentation in the mitigation of stress-induced behavioral dysregulation include modulation of hippocampal neurogenesis [92,93] and amygdala dendritic hypertrophy [39]. ...
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.
... The mechanism could be related to AEA synthesis since the effect of CBD was opposed by high FAAH activity. Importantly, activation of ECS reverses the effects of chronic stress to reduce hippocampal neurogenesis [260]. ...
Article
The purpose of this review is to examine human and preclinical data that are relevant to the following hypotheses. The first hypothesis is that deficient CB1R-mediated signaling results in symptoms that mimic those seen in depression. The second hypothesis is that activation of CB1R-mediated signaling results in behavioral, endocrine and other effects that are similar to those produced by currently used antidepressants. The third hypothesis is that conventional antidepressant therapies act through enhanced CB1R mediated signaling. Together the available data indicate that activators of CB1R signaling, particularly inhibitors of fatty acid amide hydrolase, should be considered for clinical trials for the treatment of depression.
... In addition to injections of exogenous agonists, the participation of ECs in the modulation of neurogenesis has also been investigated. Chronic treatment with URB597 (10 days) increased cell proliferation, while the ECs uptake inhibitor, AM404, reversed the trimethylthiazoline(TMT)induced decrease of neurogenesis and inhibited defensive burying [94,97]. ...
Article
Full-text available
Similar to clinically used antidepressants, cannabinoids can also regulate anxiety and depressive symptoms. Although the mechanisms of these effects are not completely understood, recent evidence suggests that changes in endocannabinoid system could be involved in some actions of antidepressants. Chronic antidepressant treatment modifies the expression of CB1 receptors and endocannabinoid (EC) content in brain regions related to mood and anxiety control. Moreover, both antidepressant and cannabinoids activate mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase(PI3-K)/Akt or PKB signaling, intracellular pathways that regulate cell proliferation and neural cell survival. Facilitation of hippocampal neurogenesis is proposed as a common effect of chronic antidepressant treatment. Genetic or pharmacological manipulations of cannabinoid receptors (CB1 and CB2) or enzymes responsible for endocannabinoid-metabolism have also been shown to control proliferation and neurogenesis in the hippocampus. In the present paper we reviewed the studies that have investigated the potential contribution of cannabinoids and neurogenesisto antidepressant effects. Considering the widespread brain distribution of the EC system, a better understanding of this possible interaction could contribute to the development of therapeutic alternatives to mood and anxiety disorders.
... ID: sakthivelm Time: 13:35 I Path: N:/3b2/HIPO/Vol00000/130134/APPFile/JW-HIPO130134 CB 1 R signaling decrease both cell proliferation and neurogenesis in the adult male mouse hippocampus (Jin et al., 2004; Lee et al., 2009; Wolf et al., 2010 ). Lastly, suppression of hippocampal anandamide (N-arachidonoylethanolamine) signaling is implicated in the ability of acute stress to suppress cell proliferation in the hippocampus of adult male rats (Hill et al., 2006b ). Comparing the existing adult literature with our findings , it appears adult CB 1 R activation increases neurogenesis in the hippocampus, while adolescent CB 1 R activation decreases adult neurogenesis in the male hippocampus. ...
Article
Cannabinoid exposure during adolescence has adverse effects on neuroplasticity, emotional behaviour, cognition and reward sensitivity in adult rats. We investigated whether escalating doses of cannabinoid receptor 1 (CB1 R) agonist, HU-210, in adolescence would affect adult hippocampal neurogenesis and behavioural processes putatively modulated by hippocampal neurogenesis, in adult male and female Sprague-Dawley rats. Escalating doses of HU-210 (25, 50, and 100 µg/kg), or vehicle were administered from postnatal day (PND) 35 to 46. Animals were left undisturbed until PND 70, when they were treated with 5-bromo-2-deoxyuridine (BrdU; 200 mg/kg) and perfused 21 days later to examine density of BrdU-ir and BrdU/NeuN cells in the dentate gyrus. In another cohort, hypothalamic-pituitary-adrenal (HPA) axis reactivity to an acute restraint stress (30 min; PND 75) and behavioural sensitization to d-amphetamine sulfate (1-2 mg/kg; PND 105-134) were assessed in adulthood. Adolescent HU-210 administration suppressed the density of BrdU-ir cells in the dentate gyrus in adult male, but not adult female rats. Adolescent HU-210 administration also induced significantly higher peak corticosterone levels and reminiscent of the changes in neurogenesis, this effect was more pronounced in adult males than females. However, adolescent cannabinoid treatment resulted in significantly higher stereotypy scores in adult female, but not male, rats. Thus, adolescent CB1 R activation suppressed hippocampal neurogenesis and increased stress responsivity in adult males, but not females, and enhanced amphetamine sensitization in adult female, but not male, rats. Taken together, increased CB1 R activation during adolescence results in sex-dependent, long-term, changes to hippocampal structure and function; an effect that may shed light on differing vulnerabilities to developing disorders following adolescent cannabinoid exposure, based on sex. © 2013 Wiley Periodicals, Inc.
... One such threat-exposure to predators-is known to decrease brain cell proliferation in the laboratory [9,10]. However, this effect has not been examined in the wild, where animals may experience predator threats differently because they can execute a broader range of behaviours to evade predators than they can in captivity. ...
Article
Full-text available
Compared to laboratory environments, complex natural environments promote brain cell proliferation and neurogenesis. Predators are one important feature of many natural environments, and, in the laboratory, predatory stimuli tend to inhibit brain cell proliferation. Often, laboratory predator stimuli also elevate plasma glucocorticoids, which can then reduce brain cell proliferation. However, it is unknown how natural predators affect cell proliferation or whether glucocorticoids mediate the neurogenic response to natural predators. We examined brain cell proliferation in six populations of the electric fish, Brachyhypopomus occidentalis, exposed to three forms of predator stimuli: a) natural variation in the density of predatory catfish, b) tail injury, presumably from predation attempts, and c) the acute stress of capture. Populations with higher predation pressure had lower density of proliferating (PCNA+) cells, and fish with injured tails had lower proliferating cell density than those with intact tails. However, plasma cortisol did not vary at the populationlevel according to predation pressure or at the individual level according to tail injury. Capture stress significantly increased cortisol, but only marginally decreased cell proliferation. Thus, it appears that the presence of natural predators inhibits brain cell proliferation, but not via mechanisms that depend on changes in basal cortisol levels. This study is the first demonstration of predator-induced alteration of brain cell proliferation in a free-living vertebrate.
... An emerging paradigm from cannabinoid research is that the eCB system constitutes an allostatic signalling system that contributes to cellular plasticity responses in adaptation to stress-induced alterations (Patel and Hillard, 2008). Indeed, stress induces an inhibitory effect on neurogenesis that can be partially reverted by engaging the eCB system (Hill et al., 2006 ;present report). The role of adult neurogenesis in the regulation of cognition and mood is the object of intense study since the initial discovery of the adult hippocampal neurogenic niche (David et al., 2010 ;Deng et al., 2010). ...
Article
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Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation. These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.
... AM-404 is able to act both on CB1 and TRPV1, but usually TRPV1 activation leads to a worse response to stress. The cell proliferation reduction in hippocampus is due to the stress condition, but AM-404 failed to induce proliferation when administered in a normal-state condition [126]. ...
Article
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The concept of neurons as irreplaceable cells does not hold true today. Experiments and evidence of neurogenesis, also, in the adult brain give hope that some compounds or drugs can enhance this process, helping to reverse the outcomes of diseases or traumas that once were thought to be everlasting. Cannabinoids, both from natural and artificial origins, already proved to have several beneficial effects (e.g., anti-inflammatory, anti-oxidants and analgesic action), but also capacity to increase neuronal population, by replacing the cells that were lost and/or regenerate a damaged nerve cell. Neurogenesis is a process which is not highly represented in literature as neuroprotection, though it is as important as prevention of nervous system damage, because it can represent a possible solution when neuronal death is already present, such as in neurodegenerative diseases. The aim of this review is to resume the experimental evidence of phyto- and synthetic cannabinoids effects on neurogenesis, both in vitro and in vivo, in order to elucidate if they possess also neurogenetic and neurorepairing properties.
... This effect is mediated through the activations of CB 1 and CB 2 receptors (Jin et al., 2004;Hill et al., 2010). The effects of the endogenous cannabinoid system can be bidirectional; i.e., the endogenous cannabinoid system can promote cell proliferation during development or after brain insult (Aguado et al., 2005(Aguado et al., , 2007 or reduce cell proliferation when overstimulated by the administration of cannabinoids (Rueda et al., 2002;Hill et al., 2006). The contribution of the endogenous cannabinoid system to cocaine-induced alterations in neurogenesis is not known. ...
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Addiction to major drugs of abuse such as cocaine has been recently linked to alterations on adult neurogenesis in the hippocampus. The endogenous cannabinoid system modulated this proliferative response since pharmacological activation/blockade of cannabinoid CB1 and CB2 receptors by modulating not only neurogenesis but also cell death in the brain. In the present study, we evaluated whether the endogenous cannabinoid system affects cocaine-induced alterations in cell proliferation . To this end we examined if pharmacological blockade of either CB1 (Rimonabant, 3 mg/kg) or CB2 receptors (AM630, 3 mg/kg) affects cell proliferation (labeled with BrdU), found in the subventricular zone (SVZ) of the lateral ventricles and the dentate subgranular zone (SGZ). In addition, we measured cell apoptosis (monitored by the expression of cleaved caspase-3) and glial activation ( by analizing the expression of GFAP and Iba-1) in the striatum and hippocampus, during acute or repeated (4 days) cocaine administration (20 mg/kg). Results showed that acute cocaine decreased the number of BrdU+ cells in SVZ and SGZ. In contrast, repeated cocaine reduced the number of BrdU+ cells in SVZ only. Both acute and repeated cocaine increased the number of cleaved caspase-3+, GFAP+ and Iba1+ cells in the hippocampus, an effect counteracted by AM630 or Rimonabant that increased the number of BrdU+, GFAP+ and Iba1+ cells in the hippocampus. These results indicate that changes on neurogenic, apoptotic and gliosis processes, which were produced as a consequence of repeated cocaine administration, were normalized by the pharmacological blockade of CB1 and CB2. The restoring effects of cannabinoid receptor blockade on hippocampal cell proliferation were associated with a prevention of the induction of conditioned locomotion, but not of cocaine-induced sensitization.
... However, chronic injections of AM251 increased neurogenesis in stressed animals. Other studies had also found that AM251 or SR141716A, another CB 1 antagonist/inverse agonist, facilitates neurogenesis, respectively, after 30 min (Hill et al., 2006) and 4 h or 3 days of administration (Jin et al., 2004;Rueda et al., 2002). The pro-neurogenic effect of SR141716A was absent in animals knockout to TRPV 1 , but not CB 1 receptors, suggesting that it could be indirectly mediated by the facilitation of eCBs action on TRPV 1 receptors (Jin et al., 2004). ...
Article
Repeated injections of cannabidiol (CBD), the major non-psychotomimetic compound present in the Cannabis sativa plant, attenuate the anxiogenic effects induced by Chronic Unpredictable Stress (CUS). The specific mechanisms remain to be fully understood but seem to involve adult hippocampal neurogenesis and recruitment of endocannabinoids. Here we investigated for the first time if the behavioral and pro-neurogenic effects of CBD administered concomitant the CUS procedure (14 days) are mediated by CB1, CB2or 5HT1Areceptors, as well as CBD effects on dendritic remodeling and on intracellular/synaptic signaling (fatty acid amide hydrolase - FAAH, Akt, GSK3β and the synaptic proteins Synapsin Ia/b, mGluR1 and PSD95). After 14 days, CBD injections (30 mg/kg) induced anxiolytic responses in stressed animals in the elevated plus-maze and novelty suppressed feeding tests, that were blocked by pre-treatment with a CB1(AM251, 0.3 mg/kg) or CB2(AM630, 0.3 mg/kg), but not by a 5HT1A(WAY100635, 0.05 mg/kg) receptor antagonist. Golgi staining and immunofluorescence revealed that these effects were associated with an increase in hippocampal neurogenesis and spine density in the dentate gyrus of the hippocampus. AM251 and AM630 abolished the effects of CBD on spines density. However, AM630 was more effective in attenuating the pro-neurogenic effects of CBD. CBD decreased FAAH and increased p-GSK3β expression in stressed animals, which was also attenuated by AM630. These results indicate that CBD prevents the behavioral effects caused by CUS probably due to a facilitation of endocannabinoid neurotransmission and consequent CB1/CB2receptors activation, which could recruit intracellular/synaptic proteins involved in neurogenesis and dendritic remodeling.
... CB1R is also involved in developmental processes such as proliferation, survival, and differentiation of neural progenitor cells derived from embryonic and adult rodent brain (Wilson and Nicoll, 2002). Though these studies demonstrate the importance of CB1R in adult brain neurogenesis, controversy exists regarding whether activation or inhibition of CB1R induces neuronal differentiation of brain progenitor cells (Rueda et al., 2002;Hill et al., 2006;Aguado et al., 2007). The contrasting, but not necessarily conflicting, results can be attributed to various factors such as chronic versus acute administration of cannabinoid drugs or thymidine analogs, endogenous versus synthetic cannabinoid compounds, and the patho-physiological context under which these compounds are administered (Rueda et al., 2002;Galve-Roperh et al., 2006. ...
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In contrast to the adult brain, the adult spinal cord is a non-neurogenic environment. Understanding how to manipulate the spinal cord environment to promote the formation of new neurons is an attractive therapeutic strategy for spinal cord injury and disease. The cannabinoid 1 receptor (CB1R) has been implicated as a modulator of neural progenitor cell proliferation and fate specification in the brain; however, no evidence exists for modulation of adult spinal cord progenitor cells. Using adult rat spinal cord primary cultures, we demonstrated that CB1R antagonism with AM251 significantly decreased the number of Nestin(+) cells, and increased the number of βIII tubulin(+) and DCX(+) cells, indicative of neuronal differentiation. AM251’s effect was blocked by co-application of the CB1R agonists, WIN 55,212-2 or ACEA. Consistent with our hypothesis, the chronic absence of CB1R via the use of knock-out (CB1-/-) mice resulted in significantly higher levels of DCX(+) cells compared to wild type (CB1+/+) cultures, indicative of enhanced neuronal differentiation in CB1-/- spinal cords. Moreover, AM251 promoted neuronal differentiation in CB1+/+, but not in CB1-/- cultures. Since CB1R modulates synaptic transmission, and synaptic transmission has been shown to influence progenitor cell fate, we evaluated whether AM251-induced neuronal differentiation was affected by chronic inactivity. Interestingly, either the presence of the voltage-dependent sodium channel blocker tetrodotoxin (TTX), or the removal of mature neurons, inhibited the AM251-induced increase in DCX (+) cells. In summary, antagonism or absence of CB1R promotes neuronal differentiation in adult spinal cord cultures, and this action appears to require TTX-sensitive neuronal activity.
... In particular, while an exercise of moderate intensity was confirmed to increase the plasma levels of AEA in human volunteers, surprisingly no changes in plasma ECs were observed following a very-high-and very-low-intensity exercise [21][22][23]. Of note, the increased ECS activity induced by exercise was positively correlated with the beneficial antidepressant effects of exercise at central as well as peripheral levels including sense of well-being, anxiety reduction, postexercise calm, and reduced pain sensation [20,[23][24][25][26]. Interestingly, Hill et al. found that augmentation of exercise-induced increase of endocannabinoid tone suppresses stress-associated behaviors and promotes hippocampal cell proliferation, in a manner dependent on stimulation of CB1 stimulation [27,28]. In addition, Heyman et al. provided evidence in humans that following acute exercise AEA and BDNF, a key neurotrophic factor regulating the brain development and cognitive functions [19], were positively correlated at the end of exercise and after the 15-min recovery. ...
... In particular, while an exercise of moderate intensity was confirmed to increase the plasma levels of AEA in human volunteers, surprisingly no changes in plasma ECs were observed following a very-high-and very-low-intensity exercise [21][22][23]. Of note, the increased ECS activity induced by exercise was positively correlated with the beneficial antidepressant effects of exercise at central as well as peripheral levels including sense of well-being, anxiety reduction, postexercise calm, and reduced pain sensation [20,[23][24][25][26]. Interestingly, Hill et al. found that augmentation of exercise-induced increase of endocannabinoid tone suppresses stress-associated behaviors and promotes hippocampal cell proliferation, in a manner dependent on stimulation of CB1 stimulation [27,28]. In addition, Heyman et al. provided evidence in humans that following acute exercise AEA and BDNF, a key neurotrophic factor regulating the brain development and cognitive functions [19], were positively correlated at the end of exercise and after the 15-min recovery. ...
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The scientific community uses the term endocannabinoid system (ECS) to refer to a large group of molecules that in our body control the production and function of the two major cannabinoid lipid mediators, namely, anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Following their discovery, an impressive number of studies have shown that both AEA and 2-AG play a key role in a large plethora of functions in living organisms. Consequently, functional impairment or dysregula-tion of AEA and 2-AG activity leads to a variety of disorders affecting the nervous system as well as peripheral organs and tissues. For this reason, cannabinoids and/ or cannabinoid synthetic drugs currently represent an important area of research for their potential therapeutic use to treat many human diseases having or not a genetic component. Despite these evidences, the role of the endocannabinoid system and hence potential changes in its activity in inherited muscular dystrophies remains largely unknown. Only recently, the role of endocannabinoid CB1 receptors was identified in Duchenne's muscular dystrophy (DMD). In this chapter, I summarize the chemical properties and functional role of the endocannabinoids as well as plant-derived cannabinoids during skeletal muscle formation and repair under physiological conditions as well as DMD.
... Endocannabinoids can also inhibit neuronal proliferation and adult neurogenesis via the CB1 dependent ERK pathway (Rueda et al., 2002). In contrast, an endocannabinoid uptake inhibitor attenuates the stress mediated decrease in hippocampal cell proliferation (Hill et al., 2006), suggesting promotion of neurogenesis by endogenous endocannabinoids. ...
Article
Marijuana is one of the most commonly used illicit drugs worldwide. In addition, use of synthetic cannabinoids is increasing, especially among adolescents and young adults. Although human studies have shown that the use of marijuana during pregnancy leads to adverse behavioral effects, such as deficiencies in attention and executive function in affected offspring, the rate of marijuana use among pregnant women is steadily increasing. Various aspects of human behavior including emotion, learning, and memory are dependent on complex interactions between multiple neurotransmitter systems that are especially vulnerable to alterations during the developmental period. Thus, exploration of neurotransmitter changes in response to prenatal cannabinoid exposure is crucial to develop an understanding of how homeostatic imbalance and various long-term neurobehavioral deficits manifest following the abuse of marijuana or other synthetic cannabinoids during pregnancy. Current literature confirms that vast alterations to neurotransmitter systems are present following prenatal cannabinoid exposure, and many of these alterations within the brain are region specific, time-dependent, and sexually dimorphic. In this review, we aim to provide a summary of observed changes to various neurotransmitter systems following cannabinoid exposure during pregnancy and to draw possible correlations to reported behavioral alterations in affected offspring.
... Alterations in the metabolic enzymes of eCBs due to stress or any other insults could alter eCB tone leading to adaptive changes in CB1 receptor signaling. In animal studies, exposure to stress is shown to reduce eCB levels and upregulate mRNA of CB1 receptor [26,27]. Notably, we found significantly lower AEA levels in hippocampus of WKY rats compared to WIS rats. ...
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While the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors. The role of the endocannabinoid (eCB) system in depressive behavior was examined in Wistar Kyoto (WKY) rat strain, a genetic model of depression. Our findings revealed selective abnormalities in the eCB system in the brains of WKY rats compared to Wistar (WIS) rats. Immunoblot analysis indicated significantly higher levels of fatty acid amide hydrolase (FAAH) in frontal cortex and hippocampus of WKY rats with no alteration in the level of N-arachidonyl phosphatidyl ethanolamine specific phospholipase-D (NAPE-PLD). Significantly higher levels of CB1 receptor-mediated G-protein coupling and lower levels of anandamide (AEA) were found in frontal cortex and hippocampus of WKY rats. While the levels of brain derived neurotropic factor (BDNF) were significantly lower in frontal cortex and hippocampus of WKY rats compared to WIS rats, pharmacological inhibition of FAAH elevated BDNF levels in WKY rats. Inhibition of FAAH enzyme also significantly increased sucrose consumption and decreased immobility in the forced swim test in WKY rats. These findings suggest a critical role for the eCB system and BDNF in the genetic predisposition to depressive-like behavior in WKY rats and point to the potential therapeutic utility of eCB enhancing agents in depressive disorder.
... In fact, some reports demonstrated that DG cell proliferation and survival was significantly impaired when using CB 1 R and CB 2 R knockout mice models Palazuelos et al., 2006) and that CB 1 R or CB 2 R activation per se promoted an increase in cell proliferation in the DG (Jiang et al., 2005;Palazuelos et al., 2012) or rescued the deleterious effect on NSPC proliferation promoted by ethanol (Rivera et al., 2015). However, other studies showed that CB 1 R antagonism resulted in an enhanced DG cell proliferation (Hill et al., 2006;Wolf et al., 2010). Our data is in accordance with Aguado et al. (2005) that observed that WIN55,212-2 treatment promoted an increase on DG cell proliferation and advances a step in the field by revealing a tight interaction between CB 1 R and CB 2 R in the regulation of this process. ...
Article
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Neurogenesis in the adult mammalian brain occurs mainly in two neurogenic niches, the subventricular zone (SVZ) and the subgranular zone (SGZ) of the dentate gyrus (DG). Cannabinoid type 1 and 2 receptors (CB1R and CB2R) have been shown to differently modulate neurogenesis. However, low attention has been given to the interaction between CB1R and CB2R in modulating postnatal neurogenesis (proliferation, neuronal differentiation and maturation). We focused on a putative crosstalk between CB1R and CB2R to modulate neurogenesis and cultured SVZ and DG stem/progenitor cells from early postnatal (P1-3) Sprague-Dawley rats. Data showed that the non-selective cannabinoid receptor agonist WIN55,212-2 promotes DG cell proliferation (measured by BrdU staining), an effect blocked by either CB1R or CB2R selective antagonists. Experiments with selective agonists showed that facilitation of DG cell proliferation requires co-activation of both CB1R and CB2R. Cell proliferation in the SVZ was not affected by the non-selective receptor agonist, but it was enhanced by CB1R selective activation. However, either CB1R or CB2R selective antagonists abolished the effect of the CB1R agonist in SVZ cell proliferation. Neuronal differentiation (measured by immunocytochemistry against neuronal markers of different stages and calcium imaging) was facilitated by WIN55,212-2 at both SVZ and DG. This effect was mimicked by either CB1R or CB2R selective agonists and blocked by either CB1R or CB2R selective antagonists, cross-antagonism being evident. In summary, our findings indicate a tight interaction between CB1R and CB2R to modulate neurogenesis in the two major neurogenic niches, thus contributing to further unraveling the mechanisms behind the action of endocannabinoids in the brain.
... Neural progenitor cells express the elements of the cannabinoid system, and thus actively use endocannabinoids as signalling molecules [214]. Activation of cannabinoid receptors by agonists [215,216] or by elevation of endocannabinoid levels [215,217,218] promotes cell proliferation, neurogenesis and neuronal diversification [219]. It was shown that CB1 receptor activity is necessary for the upregulation of neurogenesis and proliferation after excitotoxic stress [220]. ...
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The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.
... Acute stress also produces behavioural effects, including reduced exploration, defensive postures, and anhedonia. These behavioural manifestations of stress are also dampened by the ECS [7][8][9]. On the other hand, data demonstrating that the ECS plays a role in dampening immobility responses in the forced swim assay (interpreted as a measure of despair in response to a stressful situation) is not consistent. Some investigators find that CB1 activation reduces immobility [10,11] while others report that CB1 receptor inhibition reduces immobility [12]. ...
... In an exploratory attempt, we thus performed assessments of stereotypic and basal home-cage behaviors (Latham and Würbel, 2006;Pawlowicz et al., 2010;Richter et al., 2008;Bult et al., 1993;Bult et al., 1992;Carter et al., 2000). As it was shown that endocannabinoids (i) mediate some of the beneficial effects of acute exercise (Fuss et al., 2015), (ii) seem to be crucial for the motivation to perform wheel running in the long-term (Dubreucq et al., 2013;Fuss and Gass, 2010;Fuss et al., 2015;Raichlen et al., 2012;Sparling et al., 2003) and (iii) may play a role in the regulation of hippocampal neurogenesis (Hill et al., 2006), we also measured plasma endocannabinoids in an exploratory design. ...
Article
Beneficial effects of voluntary wheel running on hippocampal neurogenesis, morphology and hippocampal-dependent behavior have widely been studied in rodents, but also serious side effects and similarities to stereotypy have been reported. Some mouse strains run excessively when equipped with running wheels, complicating the comparability to human exercise regimes. Here, we investigated how exercise restriction to 6 h/day affects hippocampal morphology and metabolism, stereotypic and basal behaviors, as well as the endocannabinoid system in wheel running C57BL/6 mice; the strain most commonly used for behavioral analyses and psychiatric disease models. Restricted and unrestricted wheel running had similar effects on immature hippocampal neuron numbers, thermoregulatory nest building and basal home-cage behaviors. Surprisingly, hippocampal gray matter volume, assessed with magnetic resonance (MR) imaging at 9.4 Tesla, was only increased in unrestricted but not in restricted runners. Moreover, unrestricted runners showed less stereotypic behavior than restricted runners did. However, after blockage of running wheels for 24 h stereotypic behavior also increased in unrestricted runners, arguing against a long-term effect of wheel running on stereotypic behavior. Stereotypic behaviors correlated with frontal glutamate and glucose levels assessed by 1H–MR spectroscopy. While acute running increased plasma levels of the endocannabinoid anandamide in former studies in mice and humans, we found an inverse correlation of anandamide with the daily running distance after long-term running. In conclusion, although there are some diverging effects of restricted and unrestricted running on brain and behavior, restricted running does not per se seem to be a better animal model for aerobic exercise in mice.
... In the DH, several neurotransmitter systems are related to the modulation of defensive behaviors, such as GABAergic (Rezayat et al., 2005;Zhang et al., 2014), glutamatergic (Fabri et al., 2014;Kamprath et al., 2009) and endocannabinoid (eCB) systems (Hill et al., 2006). The eCB system is composed by cannabinoid receptors type 1 (CB1) and type 2 (CB2); by endogenous ligands, the endocannabinoids (eCBs), such as N-Arachidonoylethanolamine (Anandamide) and 2-arachidonoylglycerol; and synthesis and degradation enzymes (Iannotti et al., 2016;Lu and Mackie, 2016). ...
Article
The cannabinoid receptor type 1 (CB1) is highly expressed in the dorsal portion of hippocampus - a brain region that has been involved in the control of conditioned emotional response (CER) in the contextual fear conditioning (CFC) model. These responses are characterized by increased freezing behavior and autonomic parameters. Moreover, CB1 receptors activation negatively modulate the release of several neurotransmitters, including glutamate and GABA, which also have been related to modulation of CER. Therefore, our aim was to investigate the involvement of CB1 receptors in the dorsal hippocampus on CER expression. Independent groups of male Wistar rats submitted to the contextual fear conditioning received bilateral intra-hippocampal injections (500 nL/side) of the following drugs or vehicle before re-exposure to the aversive context: AM251 (CB1 antagonist; 0.1, 0.3 and 1nmol); AP7 (NMDA antagonist; 1nmol)+AM251 (0.3nmol); NPLA (0.01nmol; nNOS inhibitor)+AM251 (0.3nmol); Bicuculline (1.3pmol; GABAA antagonist)+AM251 (0.1 and 1nmol). In the present paper, AM251 (0.3nmol) increased CER, while this response was prevented by both AP7 and NPLA pretreatment. After pretreatment with Bicuculline, the lower and higher ineffective doses of AM251 were able to increase the CER, supporting the balance between GABAergic and glutamatergic mechanisms controlling this response. Our results suggest that increased CER evoked by CB1 blockade in the dorsal hippocampus depends on NMDA receptor activation and NO formation. Moreover, a fine-tune control promoted by GABAergic and glutamatergic mechanisms in this brain area modulate the CER after CB1 blockade.
Chapter
The last twenty years have been characterized by a huge progress in the field of cannabinoids. Metabotropic (CB1 and CB2) and ionotropic (TRPV1) receptors for cannabinoids were discovered and their endogenous ligands (endocannabinoids) were isolated. Cannabinoid research has evolved from studying the effects of exogenous cannabinoid substances to unraveling the functional role of the endocannabinoid system. Potent and selective cannabinoid agonists and antagonists, as well as endocannabinoid inhibitors, have been and are synthesized and characterized for their therapeutic potential. Since cannabis preparations have historically been abused for their psychotropic and mood-altering properties, many research efforts focused on endocannabinoids, regulation of affect, and mood disorders. Interesting but also apparently discordant results and hypothesis have thus emanated. In this chapter we will first review the link between cannabinoids and affective disorders as evidenced by clinical studies on cannabis users or abusers, as well as by genetic, postmortem, and biomarker studies in relevant populations. We will critically discuss the current neurobiological hypotheses of affective disorders and the functional role of the endocannabinoid system in the regulation and dysregulation of neuronal networks mediating emotional responses. We will finally examine the potential value of endocannabinoid targets in the search for novel and improved medications, in particular preclinical behavioral results with CB1 receptor antagonists, and with indirect cannabinoid agonists/endocannabinoid catabolism inhibitors, as well as recent findings from clinical studies with Rimonabant.
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Stress is known to inhibit neuronal growth in the hippocampus. In addition to reducing the size and complexity of the dendritic tree, stress and elevated glucocorticoid levels are known to inhibit adult neurogenesis. Despite the negative effects of stress hormones on progenitor cell proliferation in the hippocampus, some experiences which produce robust increases in glucocorticoid levels actually promote neuronal growth. These experiences, including running, mating, enriched environment living, and intracranial self-stimulation, all share in common a strong hedonic component. Taken together, the findings suggest that rewarding experiences buffer progenitor cells in the dentate gyrus from the negative effects of elevated stress hormones. This chapter considers the evidence that stress and glucocorticoids inhibit neuronal growth along with the paradoxical findings of enhanced neuronal growth under rewarding conditions with a view toward understanding the underlying biological mechanisms.
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Until recently, it was possible to state with some confidence that there was no evidence of cannabis-related brain damage in humans. There was some support from the animal literature, but few human studies had been conducted where the findings could not be explained by methodological or other confounding factors. Recent evidence for gross morphological, connectivity and microstructural changes has now emerged that warrants further consideration. If cannabis were found to alter the structural integrity of the brain, then this may assist us to understand the mechanisms by which cannabis triggers psychotic symptoms or overt psychosis in vulnerable individuals. Evidence from animal studies Cannabinoids, either endogenous or exogenous, possess both neuroprotective and neurotoxic properties (Sarne and Mechoulam, 2005; Kano et al., 2009). Cannabinoid-receptor activation induces morphological changes to neurons, such as inhibition of new synapse formation (Kano et al., 2009), and at crucial neurodevelopmental stages (prenatal and adolescent), exposure to cannabinoids impacts on neural cell survival and maturation (Chapters 6, 7) (Downer and Campbell, 2010). The role of different cannabinoids in controlling neural-cell survival or death is a complex issue that is influenced by the dose, duration of exposure and route of administration, but also the neural-cell type and its stage of differentiation (Downer and Campbell, 2010). Contradictory hypotheses circulate regarding the doses of Δ9-tetrahydrocannabinol (THC) that may be neurotoxic or neuroprotective. Some suggest that single high doses of THC are neuroprotective within a limited timeframe, but that low doses are neurotoxic and, with chronic exposure, induce neuronal death (Sarne and Keren, 2004; Tselnicker et al, 2007; Sarne and Mechoulam, 2005). However, large doses of THC applied directly to cultured hippocampal neurons, and both high and low doses to cultured cortical neurons, have been shown to cause cell death or significant neurotoxic changes (eg. shrinkage of cell bodies and DNA-strand breaks) characteristic of neuronal apoptosis (Chan et al., 1998; Campbell, 2001; Downer et al., 2001). Indeed, even a single administration of an ultra-low dose of THC (0.001–0.002 mg/kg) has been shown to result in long-term cognitive impairment (in spatial learning, strategy and working memory) in mice. These defecits persisted for at least 5 months post-injection and were associated with activation of extracellular-regulated kinase (ERK) in the cerebellum and hippocampus (Tselnicker et al., 2007; Amal et al., 2010). The authors suggested that low THC concentration is the main determinant of long-lasting neuronal effects following chronic exposure to cannabinoids, due to their slow clearance and accumulation (Amal et al., 2010).
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Stress and glucocorticoid stress hormones inhibit neurogenesis, whereas antidepressants increase neurogenesis and block stress-induced decrease in neurogenesis. Our previous studies have shown that leptin, an adipocyte-derived hormone with antidepressant-like properties, promotes baseline neurogenesis in the adult hippocampus. This study aimed to determine whether leptin is able to restore suppression of neurogenesis in a rat chronic unpredictable stress (CUS) model of depression. Chronic treatment with leptin reversed the CUS-induced reduction of hippocampal neurogenesis and depression-like behaviors. Leptin treatment elicited a delayed long-lasting antidepressant-like effect in the forced swim behavioral despair test, and this effect was blocked by ablation of neurogenesis with X-irradiation. The functional isoform of the leptin receptor, LepRb, and the glucocorticoid receptor (GR) were colocalized in hippocampal neural stem/progenitor cells in vivo and in vitro. Leptin treatment reversed the GR agonist dexamethasone (DEX)-induced reduction of proliferation of cultured neural stem/progenitor cells from adult hippocampus. Further mechanistic analysis revealed that leptin and DEX converged on glycogen synthase kinase-3β (GSK-3β) and β-catenin. While DEX decreased Ser9 phosphorylation and increased Tyr216 phosphorylation of GSK-3β, leptin increased Ser9 phosphorylation and attenuated the effects of DEX at both Ser9 and Tyr216 phosphorylation sites of GSK-3β. Moreover, leptin increased total level and nuclear translocation of β-catenin, a primary substrate of GSK-3β and a key regulator in controlling hippocampal neural progenitor cell proliferation, and reversed the inhibitory effects of DEX on β-catenin. Taken together, our results suggest that adult neurogenesis is involved in the delayed long-lasting antidepressant-like behavioral effects of leptin, and leptin treatment counteracts chronic stress and glucocorticoid-induced suppression of hippocampal neurogenesis via activating the GSK-3β/β-catenin signaling pathway.
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Background: Chronic stress has been found to suppress adult neurogenesis, but it remains unclear whether it may affect the maturation process of adult-born neurons. Here, we examined the influence of chronic social defeat stress on the morphological and electrophysiological properties of adult-born dentate granule cells at different developmental stages. Methods: Adult C57BL/6 mice were subjected to 10 days of chronic social defeat stress followed by a social interaction test 24 hours after the last defeat. Defeated mice were segregated into susceptible and unsusceptible subpopulations based on a measure of social interaction test. Combining electrophysiology with retrovirus-mediated birth-dating and labeling, we examined the impact of chronic social defeat stress on temporal regulation of synaptic plasticity of adult-born dentate granule cells along their maturation. Results: Chronic social defeat stress decreases the survival and dendritic complexity of adult-born dentate granule cells. While chronic social defeat stress doesn’t alter the intrinsic electrophysiological properties and synaptic transmission of surviving adult-born dentate granule cells, it promotes the developmental switch in synaptic N-methyl-D-aspartate receptors from predominant GluN2B- to GluN2A-containing receptors, which transform the immature synapse of adult-born dentate granule cells from one that exhibits enhanced long-term potentiation to one that has normal levels of long-term potentiation. Furthermore, chronic social defeat stress increases the level of endogenous repressor element-1 silencing transcription factor mRNA in adult-born dentate granule cells, and knockdown of the repressor element-1 silencing transcription factor in adult-born dentate granule cells rescues chronic social defeat stress-induced morphological deficits and accelerated developmental switch in synaptic N-methyl-D-aspartate receptor subunit composition. Conclusions: These results uncover a previously unsuspected role of chronic social defeat stress in regulating adult neurogenesis and suggest that chronic social defeat stress can affect synaptic maturation process of adult-born dentate granule cells.
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/jbbs.2013.36051Neurogenesis in the adult brain has been a field of growing interest. There are two neurogenic niches in the mammalian adult brain: subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ), producing new neurons that use the rostral migratory stream (RMS) to reach olfactory bulb (OB). Cells in these two discrete regions retain the capacity to generate multiple lineages in vitro and in vivo. Thus far, the mechanisms involved in the regulation of these cells have not been well elucidated, once the underlying cellular signaling mechanism is not fully understood. The aim of this work is to collect the most recent papers published in this field to elucidate the signaling pathways involved in the adult “up” and “down” neurogenesis. The most cited pathways included directly or indirectly associations with neurotrophins and transcription factors. This work provides a schema showing the outline from “macro” to “micro” signaling for neurogenesis in the SGZ of the hippocampus. It also includes a session linking neurogenesis to the patho-physiology of mood disorders and stress-related cognitive dysfunctions. Further characterization of these molecular components could provide greater insight into the mechanisms involved in the regulation of neurogenesis in the adult brain.
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Endocannabinoid (eCB) signaling plays an important role in the stress response pathways of the mammalian brain, yet its role in the avian stress response has not been described. Understanding eCB signaling in avian species (such as the European starling, Sturnus vulgaris) allows a model system that exhibits natural attenuation of hypothalamic-pituitary-adrenal (HPA) responsiveness to stressors. Specifically, seasonally-breeding birds exhibit highest HPA activity during the breeding season and subsequently exhibit robust HPA down-regulation during molt. As eCB signaling in mammals has an overall inhibitory effect on HPA activity, we expected shifts in eCB signaling to regulate the seasonal HPA down-regulation during molt. However, our data did not support a role for eCB signaling in molt-related suppression of HPA activity. For example, injection of the cannabinoid receptor (CB1) antagonist, AM251 did not potentiate molt-suppressed HPA activity. Instead, our data suggest eCB regulation of HPA plasticity as birds transition from breeding to molt. In support of this hypothesis, birds in late breeding season demonstrated a more dynamic response at the level of avian amygdala eCB content in response to acute stress. The response and directionality of this effect match that seen in mammals. Overall, our data suggest eCB signaling may allow for dynamic range in HPA responsiveness (e.g., breeding) but the signaling pathway's role may be limited when the HPA response is restrained (e.g., molt). This first characterization of eCB signaling in the avian stress response also emphasizes that while the system functions similarly to other species, its exact role may be species-specific.
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The endocannabinoid (eCB) system is considered relevant in the pathophysiology of affective disorders, and a potential therapeutic target, as its hypoactivity is considered an important risk factor of depression. However, the biological mechanisms whereby the eCB system affects mood remain elusive. Through a systematic review, thirty-seven articles were obtained from the PubMed/Medline, Web of Science, Embase, PsychInfo, and CINAHL databases, investigating the role of the eCB system on the immune system and neurogenesis, as well as resulting behavioural effects in rodent models of affective disorders. Overall, activation of the eCB system appears to decrease depressive-like behaviour and to be anti-inflammatory, while promoting neuro- and synaptogenesis in various models. Activation of cannabinoid receptors (CBRs) is shown to be crucial in improving depressive-like and anxiety-like behaviour, although cannabidiol administration suggests a role of additional mechanisms. CB1R signalling, as well as fatty acid amide hydrolase (FAAH) inhibition, are associated with decreased pro-inflammatory cytokines. Moreover, activation of CBRs is required for neurogenesis, which is also upregulated by FAAH inhibitors. This review is the first to assess the association between the eCB system, immune system and neurogenesis, alongside behavioural outcomes, across rodent models of affective disorders. We confirm the therapeutic potential of eCB system activation in depression and anxiety, highlighting immunoregulation as an important mechanism whereby dysfunctional behaviour and neurogenesis can be improved.
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Recent years have produced rapid and enormous growth in our understanding of the mechanisms regulating adult neurogenesis. Emerging fields of research now aim at clarifying the relationships between neurogenesis and diseases. This paper deals with neurogenesis and stress-related disorders. After a brief overview of the stress response, we first provide a comprehensive analysis of the literature on the effects of stress on neurogenesis and the potential mechanisms underlying these effects. This analysis clearly indicates that, whatever the nature, intensity and duration of the stressor, stress decreases cell proliferation. Comparing different stress paradigms further indicates that these effects are transient when stress is performed during adulthood, while it has a much greater and longer lasting impact when applied during developmental periods. When uncontrolled or repeated, stressors are risk factors for physiological and psychiatric disorders such as depression, pathological aging, drug misuse, anxiety and post-traumatic stress disorder. Studies linking these pathologies and neurogenesis constitute an important field of research, but advances are hampered by the lack of adequate animal models. The challenge for future research will certainly be to develop these animal models in order to envision therapeutic strategies aimed at stimulating plasticity in the stressed brain and preventing the alteration of affective and cognitive function that may appear in some individuals.
Article
As outlined elsewhere in this book epidemiological, clinical and genetic approaches have linked cannabis to schizophrenia from aetiological, contributory and exacerbating perspectives. These studies implicate cannabis use as deleterious in schizophrenia either in increasing its incidence, precipitating illness onset or worsening its outcomes. This suggests that inhaled or ingested components of cannabis may interact directly with biological systems relevant to schizophrenia. Much work has focussed on the main psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), which appears to induce psychotic symptoms in both healthy controls and those with schizophrenia (D’Souza et al., 2005). However, there are at least 60 other bioactive components that could mediate the effects of cannabis in humans (Mechoulam and Hanus, 2000; and see Chapters 2 and 3). Hence, one explanation for the association of cannabis with schizophrenia is that the human endocannabinoid (eCB) system (ECS) may be disrupted in vulnerable individuals, predisposing them to the risk of developing, precipitating or exacerbating schizophrenia when exposed to cannabis. The human ECS is detailed elsewhere (see Chapter 3) and consists of a number of eCBs, their synthetic, degradative and transport pathways and the receptors to which they bind, principally the cannabinoid CB1 and CB2 receptors. The two major endocannabinoids are anandamide and 2-arachidonoyl glycerol (2-AG), with the latter predominating in the human central nervous system (CNS) (Piomelli, 2003). In addition to the CB1 and CB2 receptors, the endocannabinoids also activate other receptors in the CNS, including vanilloid (VR1), peroxisome proliferator-activated receptors, orphan G-protein coupled receptors (e.g. GPR55) and transmitter-gated ion channels (Pertwee, 2010). Although it is possible that any component of the ECS may be altered in individuals vulnerable to developing schizophrenia, methodological constraints have restricted investigation to a number of key elements.
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The present chapter summarizes information on the pathophysiology of mood disorders and mechanisms of action of antidepressants and mood stabilizers with focus on an endocannabinoid regulation of monoamines in depression and bipolar disorder. Leading role in neurochemistry and pathophysiology of mood disorders could be awarded to disturbed monoamine neurotransmission, dysfunction in energy metabolism of neurons, modulation of inflammatory and neuroendocrine pathways, and changes in activities of transcription factors, neurotrophic factors and other components involved in neuroplasticity. A role of endocannabinoid system in pathophysiology of mood disorders is supposed, but little known. In the light of new findings, there is potential for pharmacological regulation of endocannabinoid system in treatment of depressive and bipolar disorder. © 2013 Springer Science+Business Media New York. All rights are reserved.
Article
New neuron formation in the adult brain extends our knowledge and incorporates a novel dimension about brain plasticity. Adult neurogenesis is a complex process regulated by different factors within the niche, where adult neural stem cells reside, proliferate and differentiate. Neural stem cell together with astrocytes and endothelial cells form the principle components of this complex niche. Other molecular factors that regulate adult neurogenesis are the neuro-transmitters (GABA, glutamate, serotonin, dopamine); hormones (prolactin, growth hormone, estrogens and melatonin); growth factors (FGF, EGF, VEGF) and neurotrophins (BDNF, NT3). All of them regulate different aspects of the neurogenic process. Behavioral regulators that influence new neuron formation in the adult brain include physical activity, complex stimulatory environment best known as enrichment environment, and social interaction. Voluntary physical activity with free access to the running wheel increases the number of proliferating cells, while the complex stimulotory environment provided by enriched environment preferentially influences survival of newborn cells. In addition, social interaction has a positive influence on the new neuron formation in the dentate gyrus (DG). Although adult hippocampal neurogenesis is positively regulated by the aforementioned factors, there are different conditions with negative influence on this process. Some of these conditions are stress exposure and sleep deprivation. Both conditions are present in neuropsychiatric diseases such as depression, anxiety and schizophrenia. Thus, stress and sleep deprivation impair adult hippocampal neurogenesis. Alteration of the neurogenic process following stress occurs due to the high levels of glucocorticoid receptors within the hippocampus and because exposure to stress causes the increase in glucocorticoid levels. Preclinical studies have shown that exposure to different classes of stressors affect hippocompal neurogenesis. Prolonged exposure to stressors (chronic mild stress), predatory odor, foot shock, acute force swimming and psychosocial stress not only affect mature neuronal plasticity but also hippocampal neurogenesis. Although there is information about the effects of stress on adult neurogenesis, the mechanism by which stress causes inhibition of hippocampal neurogenesis remains unclear. Recent work showed that exposure to stress increases the pro-inflammatory cytokine interleukin-1 beta (IL-1 beta) in several brain areas. Also, administration of IL-1 beta exerts stress-like effects including down-regulation of hippocampal brain derived neurotrophic factor (BDNF). Additionally, inhibition of the receptor for IL-1 beta prevents stress-like effects. Moreover, the suppression of cell proliferation is mediated by direct actions of IL-1 beta) on IL-1RI receptors localized on precursor cells. These findings support that IL-1 beta is a critical mediator of the antineurbgenic effect caused by acute and chronic stress. However, IL-1 beta is not the unique mediator of stress that could be involved in the alteration of adult hippocampal neurogenesis. Recently it was reported that the decrease in cell proliferation concomitantly occurs with an increase of IL6 and TNF alpha levels. Preclinical studies have suggested that adult hippocbmpal neurogenesis is not a sole cause of depression or the sole mechanism of treatment efficacy, but it is likely an important contributor to this complex disorder. In order to revert the effects of stress on adult hippocampal neurogenesis, different therapies have been used, for example: electroconvulsive therapy (ECT), exercise, complex stimulatory environment and antidepressant drugs. Although the most rapid induction of neurogenesis is seen with ECT application, most studies have been done with antidepressant drugs. The effects of antidepressants are time-dependent as highest therapeutic effects ore observed within the time course of weeks. Different types of antidepressants (serotonin and norepinephrine reuptake inhibitors, monoamine oxidase inhibitors and atypical antidepressants) have been used to study their influence Ion the neurogenic process. Despite that serotonin reuptake inhibitors are the most prescribed treatments for major depression and that the therapeutic effects of antidepressants require chronic treatment, the mechanisms by which these drugs exert their effects on hippocampal neurogenesis are still unknown. Although serotonin reuptake inhibitors are very fast in increasing serotonin levels, the antidepressani action is delayed possibly because of the induction of structural or functional changes that possibly need longer time (2-4 weeks). In this regard, one of the actions of antidepressants is the regulation of adult hippocampal neuregenesis, a process that is consistent with the delayed onset of therapeutic effects of antidepressants. Fluoxetine is one of the antidepressants more used to study its influence on adult neurogenesis. Fluoxetine targets amplifying neural progenitors by increasing the rate of symmetric divisions without altering the division of stem-like cells in the DG. Considering previous classification based on the temporal protein markers expression, the neural progenitors targeted by fluoxetine correspond to type 2a, 2b and type 3. In addition, the increase in new neurons caused by fluoxetine is due to the expansion of neural progenitors. In addition to cell proliferation, the neurogenic process also involves a maturation step, Which is associated with the expression of doublecortin, a protein that binds to microtubules and that is expressed along the cytoplasm. of the cell. Further maturation of immature neurons such as. dendrite maturation, is controlled independently of the regulation of precursor cell proliferation. Thus, micro-regulatory events influence the course of adult hippocampal neurogenesis. Here, fluoxetine also affects dendrite maturation and functional integration of new neurons. Chronic fluoxetine treatment modifies dendrite morphology increasing dendrite arborisation and favors synaptic plasticity-of newborn granule cells. Also, chronic administration of fluoxetine causes behavioral improvement, an effect that was blocked when neurogenesis was ablated by X-ray irradiation. Other important factor that influences the effect of antidepressants on adult neurogenesis is the genetic background. Then antidepressants' induced behavioral improvement depending on the genetic background of the mouse strain used. Preclinical studies in mice have revealed different actions of antidepresants on-adult hippocampal neurogenesis. However, studies in humans, are scarce and deserve greater attention to discover the correlation between preclinical and Clinical studies. Recent work in human brains shows contradictory evidences about the regulation of neuronal development by antidepressants. These evidences are in the same line as recent published work in which it was demonstrated that the effects of ADs are age-dependent. Altogether, multiple evidences indicate that antidepressants affect several aspects of the neurogenic process. Therefore, chronic treatment is necessary for the antidepressant-dependent regulation of adult hippocampal neuregenesis. In addition, it has been shown that antidepressants act through different pathways involving both neurogenesis-dependent and neurogenesis-independent actions. Although there is an important increase in the adult hippocampal neurogenesis field, it is necessary to increase the number of studies performed in human beings to correlate the preclinical findings with clinical studies to address the role of adult neurogenesis in neuropsychiatric disorders.
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The effects of chronic stress on adult hippocampal neurogenesis as well as the effects of increased/decreased neurogenesis on vulnerability to stress, or on remission from the effects of exposure to chronic stress, have been well studied. Fewer data are available on the effects of neurogenesis on anxiety and/or vulnerability to the effects of acute stress, and conversely on the effects of acute stress on adult newborn neurons. Overall, they show that in most cases decreased neurogenesis did not alter normal anxiety behavior, even if some studies reported opposite results. On the other hand, acute stress decreased hippocampal cell proliferation and newborn neuron survival. Again, some also reported an absence of effects. Further studies are necessary to investigate the relationship of hippocampal adult neurogenesis and anxiety, particularly focusing on models of pathological anxiety such as posttraumatic stress disorder.
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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, Δ⁹-tetrahydrocannabinol, acts by binding to brain CB1 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 CB1 antagonist rimonabant, are accompanied by increased brain anandamide levels, and are maintained upon repeated URB597 administration. Unlike direct CB1 agonists, URB597 does not exert rewarding effects in the conditioned place preference test or produce generalization to the discriminative effects of Δ⁹-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. • depression • endocannabinoid • fatty-acid amide hydrolase • serotonin • URB597
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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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It is well documented that animals take risk of predation into account when making decisions about how to behave in particular situations, often trading-off risk against opportunities for mating or acquiring energy. Such an ability implies that animals have reliable information about the risk of predation at a given place and time. Chemosensory cues are an important source of such information. They reliably reveal the presence of predators (or their presence in the immediate past) and may also provide information on predator activity level and diet. In certain circumstances (eg, in the dark, for animals in hiding) they may be the only cues available. Although a vast literature exists on the responses of prey to predator chemosensory cues (or odours), these studies are widely scattered, from marine biology to biological control, and not well known or appreciated by behavioural ecologists. In this paper, we provide an exhaustive review of this literature, primarily in tabular form. We highlight some of the more representative examples in the text, and discuss some ecological and evolutionary aspects of the use of chemoscensory information for prey decision making. Curiously, only one example illustrates the ability of birds to detect predator odours and we have found no examples for terrestrial insects, suggesting a fruitful area for future study.
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This study was directed at exploring the structure-activity relationship for anandamide and certain of its analogues at the rat VR1 receptor in transfected cells and at investigating the relative extent to which anandamide interacts with CB1 and vanilloid receptors in the mouse vas deferens. pKi values for displacement of [3H]-resiniferatoxin from membranes of rVR1 transfected CHO cells were significantly less for anandamide (5.78) than for its structural analogues N-(4-hydroxyphenyl)-arachidonylamide (AM404; 6.18) and N-(3-methoxy-4-hydroxy)benzyl-arachidonylamide (arvanil; 6.77). pEC50 values for stimulating 45Ca2+ uptake into rVR1 transfected CHO cells were significantly less for anandamide (5.80) than for AM404 (6.32) or arvanil (9.29). Arvanil was also significantly more potent than capsaicin (pEC50=7.37), a compound with the same substituted benzyl polar head group as arvanil. In the mouse vas deferens, resiniferatoxin was 218 times more potent than capsaicin as an inhibitor of electrically-evoked contractions. Both drugs were antagonized to a similar extent by capsazepine (pKB=6.93 and 7.18 respectively) but were not antagonized by SR141716A (1 μM). Anandamide was less susceptible than capsaicin to antagonism by capsazepine (pKB=6.02) and less susceptible to antagonism by SR141716A (pKB=8.66) than methanandamide (pKB=9.56). WIN55212 was antagonized by SR141716A (pKB=9.02) but not by capsazepine (10 μM). In conclusion, anandamide and certain of its analogues have affinity and efficacy at the rat VR1 receptor. In the mouse vas deferens, which seems to express vanilloid and CB1 receptors, both receptor types appear to contribute to anandamide-induced inhibition of evoked contractions. British Journal of Pharmacology (2001) 132, 631–640; doi:10.1038/sj.bjp.0703850
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The possibility that the anandamide transport inhibitor N-(4-hydroxyphenyl)-5,8,11,14-eicosatetraenamide (AM404), structurally similar to the vanilloid receptor agonists anandamide and capsaicin, may also activate vanilloid receptors and cause vasodilation was examined. AM404 evoked concentration-dependent relaxations in segments of rat isolated hepatic artery contracted with phenylephrine. Relaxations were abolished in preparations pre-treated with capsaicin. The calcitonin-gene related peptide (CGRP) receptor antagonist CGRP-(8-37) also abolished relaxations. The vanilloid receptor antagonist capsazepine inhibited vasodilation by AM404 and blocked AM404-induced currents in patch-clamp experiments on Xenopus oocytes expressing the vanilloid subtype 1 receptor (VR1). In conclusion, AM404 activates native and cloned vanilloid receptors.
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The release of ACTH, corticosterone, and PRL was compared in capsaicin-pretreated rats, which lack afferent C-fibers, and their controls under somatosensory (cold, surgery) and central (restraint) forms of stress. Cold stress induced the release of ACTH and consequently that of corticosterone in the controls, but not in the capsaicin-pretreated rats. Intravenous injection of ACTH1-24 was equally effective in releasing corticosterone in both groups. Whereas PRL was not released in response to cold stress, restraint stress did induce the release of both ACTH and PRL, in the capsaicin-pretreated as well as in the control group. Pentobarbital anesthesia alone elicited PRL, but no ACTH release. ACTH release was evoked by surgery under pentobarbital anesthesia but was abolished by capsaicin pretreatment. PRL levels were not further increased by surgery. Nicotine in a small dose (5 micrograms intra-arterially) evoked stimulation of afferent C-fibers as observed on a depressor reflex. Intraperitoneal injection of nicotine (250 micrograms/kg) caused a marked rise in plasma ACTH both in the capsaicin-pretreated conscious rats and in their controls, probably resulting from central stimulation as this effect was shown to be inhibited during pentobarbital anesthesia. A moderate rise of PRL by nicotine was seen in conscious rats. The stimuli used, regarded as experimental models of stress, show essential differences in their ability to evoke the release of ACTH, corticosterone, and PRL. Those stimuli which cause the release of ACTH and corticosterone via afferent C-fiber stimulation do not release PRL, whereas emotional and cognitive stress causes the release of both ACTH and PRL.
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The dentate gyrus of the rat produces new granule neurons well into adulthood. In the adult, newly born granule neurons migrate from the hilus to the granule cell layer, receive synaptic input, extend axons into the mossy fiber pathway, and express a neuronal marker. No previous studies have identified factors that regulate neuronal birth in the adult dentate gyrus. In order to determine whether glucocorticoids control neurogenesis in the adult dentate gyrus, the effects of adrenal steroid manipulations on neuronal birth were assessed using [3H]thymidine autoradiography and immunohistochemistry for the neuronal marker neuron specific enolase. Acute treatment with corticosterone produced a significant decrease in the density of [3H]thymidine-labeled cells in the hilus of the dentate gyrus. In contrast, removal of endogenous adrenal steroids stimulated increased neuronal birth; adrenalectomy resulted in a significant increase in the number of neuron specific enolase-immunoreactive [3H]thymidine labeled cells in the granule cell layer compared to sham operation. Replacement of corticosterone to adrenalectomized rats after [3H]thymidine injection did not substantially alter the increase in neurogenesis observed following adrenalectomy, even though this replacement protects cells from adrenalectomy-induced cell death. These results indicate that the rate of neurogenesis in the dentate gyrus of the adult rat is dependent upon the levels of circulating adrenal steroids.
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A selective inhibitor of the carrier-mediated transport of endogenous cannabinoids, N-(4-hydroxyphenyl)-arachidonylethanolamide (AM404), has been recently synthesized and proposed as a useful tool for studying the physiological effects of endogenous cannabinoids and as a potential therapeutic agent in a variety of diseases. In the present study, we have examined the effects of this compound in two important brain processes in which a role for anandamide and other endogenous cannabinoids has been claimed: neuroendocrine regulation and extrapyramidal motor activity. A single and well-characterized dose of AM404, which presumably resulted in a significant elevation of the levels of endogenous cannabinoids, produced a marked decrease in plasma prolactin (PRL) levels, with no changes in luteinizing hormone (LH) levels. This decrease in PRL levels was accompanied by an increase in the activity of tyrosine hydroxylase (TH) in the medial basal hypothalamus. Both decreased PRL secretion and increased hypothalamic TH activity have been reported to occur after the administration of anandamide. Administration of AM404 also produced a marked motor inhibition in the open-field test, as also reported for anandamide, with a decrease in ambulatory and exploratory activities and an increase in the time spent in inactivity. This was accompanied by a decrease in the activity of TH in the substantia nigra, an effect also previously observed for anandamide.
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Predator odors may provide a species relevant aversive stimuli to study the central effects of stress in rats and may have several benefits over currently applied models. Here, we examined one such odor, TMT, isolated from the fox, a predator of the rat, on fear-induced behaviors, serum corticosterone, and central dopamine metabolism. Habituated rats were exposed to TMT, or a control odor, butyric acid, in an open field. For comparison, other rats were subjected to a model of conditioned fear - a traditional fear model. Several similarities between the two stresses were observed including increased serum corticosterone and increased dopamine metabolism in the medial prefrontal cortex. Differences were also observed. TMT, but not conditioned fear, activated dopamine metabolism in the amygdala, but not the nucleus accumbens core and shell. Rats exposed to conditioned fear, but not TMT odor, demonstrated altered behaviors associated with fear, including locomotion, grooming and immobility. Finally, rats reexposed to TMT after a 24-h delay did not demonstrate any of the changes observed with acute exposure to TMT. These data indicate acute exposure to a predator odor, TMT, can result in a unique pattern of biochemical activation that is similar, but not identical, to conditioned fear. The differences may indicate unique features of a central 'fear arousal' pathway that responds to innate, unlearned stressful stimuli, such as predator odors.
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To determine whether exposure to fox odor alters granule neuron production, we examined proliferating cells and their progeny in the dentate gyrus of adult male rats exposed to trimethyl thiazoline, a component of fox feces. Additionally, to determine whether this effect is adrenal hormone-mediated, we examined animals exposed to fox odor after bilateral adrenalectomy and replacement with low levels of the endogenous glucocorticoid corticosterone. Stereologic analyses of the number of 5-bromo-2'deoxyuridine (BrdU) -labeled cells revealed that exposure to fox odor but not other, nonthreatening, odors (mint or orange) rapidly decreased the number of proliferating cells in the dentate gyrus. This effect is dependent on a stress-induced rise in adrenal hormones; exposure to fox odor resulted in an increase in circulating corticosterone levels and prevention of this increase (by means of adrenalectomy plus low-dose corticosterone replacement) eliminated the suppression of cell proliferation. Examination at longer survival times revealed that the decrease in the number of new granule cells in fox odor-exposed animals was transient; a difference was still detectable at 1 week after BrdU labeling but not at 3 weeks. In both fox and sham odor-exposed animals, many new cells acquired morphologic and biochemical characteristics of mature granule neurons. The majority of these cells expressed a marker of immature granule neurons (TuJ1) by 1 week after BrdU labeling and markers of mature granule neurons (calbindin, NeuN) by 3 weeks after labeling. These findings suggest that stressful experiences rapidly diminish cell proliferation by increasing adrenal hormone levels, resulting in a transient decrease in the number of adult-generated immature granule neurons.
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The hypothalamus is a relatively small division of the vertebrate forebrain that plays especially important roles in neural mechanisms assuring homeostasis, defense, and reproduction. Previous studies from our laboratory have suggested a distinct circuit in the medial hypothalamic zone as critically involved in the organization of innate defensive behavior. Thus, after exposure to a natural predator known to elicit innate defensive responses, increased Fos levels in the medial zone of the hypothalamus have been found restricted to the anterior hypothalamic nucleus, dorsomedial part of the ventromedial nucleus, and dorsal premammillary nucleus (PMd). Previous anatomical studies have shown that these Fos-responsive cell groups in the medial hypothalamus are interconnected in a distinct neural system, in which the PMd appears to be a critical element for the expression of defensive responses elicited by the presence of a predator. The purpose of this review is to provide an overview of what is currently known about the functional and hodological organization of this hypothalamic circuit subserving defensive responses.
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Several laboratories have reported that exposure to predator odor can result in stress-like effects in rodents. While some laboratories have reported fear-like alterations in behavior, other laboratories, including our own, have failed to consistently observe fearful behaviors in rats exposed to the predator odor TMT. One potential contributing factor to this discrepancy is the handling of the rat and its test environment. In the current report, we examine biochemical, endocrinological, and behavioral effects of TMT in two distinct open fields: one small, familiar, and dimly lit, while the other was large, novel, and brightly lit. Only exposure to TMT in the large, novel open field resulted in fearful behavior; however, no increase in dopamine turnover was noted compared to no odor and control odor rats. As expected, the different open fields resulted in some biochemical and behavioral differences, including more horizontal locomotion and less grooming, higher serum corticosterone, and increased dopamine turnover in the ventral prefrontal cortex in the large open field. Finally, compared to the same open field controls, TMT exposure elevated rat serum corticosterone levels in both open fields and dopamine turnover in the dorsal and ventral medial prefrontal cortex and amygdala of rats only in the small, familiar open field. These results indicate that the TMT-induced biochemical activation of may occur without detectable fearful behaviors and may indicate a mechanism that prepares the animal for the expression of a fearful response if additional provocative stimuli are present.
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Defensive burying refers to the typical rodent behavior of displacing bedding material with vigorous treading-like movements of their forepaws and shoveling movements of their heads directed towards a variety of noxious stimuli that pose a near and immediate threat, such as a wall-mounted electrified shock-prod. Since its introduction 25 years ago by Pinel and Treit [J. Comp. Physiol. Psychol. 92 (1978) 708], defensive (shock-prod) burying has been the focus of a considerable amount of research effort delineating the methodology/ethology, psychopharmacology and neurobiology of this robust and species-specific active avoidance or coping response. The present review gives a summary of this research with special reference to the behavioral (face and construct) and pharmacological (predictive) validity of the shock-prod burying test as an animal model for human anxiety. Emphasis is also placed on some recent modifications of the paradigm that may increase its utility and reliability as to individual differences in expressed emotional coping responses and sensitivity to pharmacological treatments. Overall, the behavioral and physiological responses displayed in the shock-prod paradigm are expressions of normal and functionally adaptive coping patterns and the extremes of either active (i.e., burying) or passive (i.e., freezing) forms of responding in this test cannot simply be regarded as inappropriate, maladaptive or pathological. For this reason, the shock-prod paradigm is not an animal model for anxiety disorder or for any other psychiatric disease, but instead possesses a high degree of face and construct validity for normal and functionally adaptive human fear and anxious apprehension. However, the apparent good pharmacological validation (predictive validity) of this test reinforces the view that normal and pathological anxiety involves, at least partly, common neurobiological substrates. Therefore, this paradigm is not only suitable for screening potential anxiolytic properties of new drugs, but seems to be especially valuable for unraveling the neural circuitry and neurochemical mechanisms underlying the generation of active and passive coping responses as different expressions of anxiety.
Article
Males show suppressed cell proliferation in the hippocampus in response to acute stress but no studies to date have examined cell proliferation in response to acute stress in females. In the current study, we examined the effects of acute exposure to a predator odor stressor [trimethyl thiazoline (TMT); the main component of fox feces] or a control odor on cell proliferation and cell death in the dentate gyrus and on behavior in adult male and female [intact, ovariectomized (OVX) or OVX+estradiol benzoate (EB)] rats. Further, we examined whether TMT-induced changes in behavior were related to cellular changes. During TMT exposure, rats were injected with the cell synthesis marker bromodeoxyuridine and perfused 24 h later. Acute TMT exposure suppressed both cell proliferation and death in males but not in any group of females. Interestingly, in the OVX females we observed an increase in cell death that was eliminated by EB treatment. Consistent with prior studies, estradiol treatment increased cell proliferation regardless of odor condition. Regardless of sex or hormone treatment, TMT increased defensive behavior, suggesting that the behavioral response to TMT is dissociated from this cellular response. This is the first demonstration of a sex difference in cell proliferation and death in the adult dentate gyrus in response to stress.
Article
Lesions of the dorsal premammillary nucleus (PMd) have been reported to produce dramatic reductions in responsivity of rats to a live cat. Such lesions provide a means of analyzing the potentially differential neural systems involved in different defensive behaviors, and the relationship between these systems and concepts such as anxiety. Rats with bilateral electrolytic lesions of the PMd were run in an elevated plus maze (EPM), exposed first to cat odor and then to a live cat, and assessed for postshock freezing and locomotion. PMd lesions produced a dramatic reduction in freezing, avoidance, and stretch attend to the cat odor stimulus, and reduction in freezing, with greater activity, and enhanced stretch approach to cat exposure. However, PMd lesions had minimal effects in the EPM, and postshock freezing scores were unchanged. These results confirm earlier findings of reduced defensiveness of PMd-lesioned rats to a cat, extending the pattern of reduced defensiveness to cat odor stimuli as well, but also suggest that such lesions have few effects on nonolfactory threat stimuli.