Cannabinoid Receptor Activation Prevents the Effects of Chronic Mild Stress on Emotional Learning and LTP in a Rat Model of Depression

Segev, Amir; Rubin, Adva S; Abush, Hila; Richter‐Levin, Gal; Akirav, Irit

doi:10.1038/npp.2013.292

Cited by 78 publications

(61 citation statements)

References 92 publications

(144 reference statements)

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“…Animal studies show that cannabinoid agonists promote antidepressant-and anxiolytic-like responses (Bortolato et al 2007;McLaughlin et al 2007;GanonElazar and Akirav 2012;Abush and Akirav 2013;Segev et al 2013).…”

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confidence: 99%

Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood

2016

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Early life stress (ES) significantly increases predisposition to psychopathologies. Cannabinoids may cause cognitive deficits and exacerbate the effects of ES. Nevertheless, the endocannabinoid system has been suggested as a therapeutic target for the treatment of stress-and anxiety-related disorders. Here we examined whether cannabinoids administered during "late adolescence" (extensive cannabis use in humans at the ages 18 -25) could reverse the long-term adverse effects of ES on neurocognitive function in adulthood. Male and female rats were exposed to ES during post-natal days (P) 7-14, injected with the cannabinoid CB1/2 receptor agonist WIN55,212-2 (WIN; 1.2 mg/kg, i.p.) for 2 wk during late adolescence (P45 -60) and tested in adulthood (P90) for working memory, anxiety, and alterations in CB1 receptors (CB1r), and glucocorticoid receptors (GRs) in the stress circuit [hippocampus, prefrontal cortex (PFC), and basolateral amygdala (BLA)]. ES males and females exhibited impaired performance in short-term memory in adulthood in the spatial location and social recognition tasks; males were also impaired in the novel object recognition task. WIN administered during late adolescence prevented these stress-induced impairments and reduced anxiety levels. WIN normalized the ES-induced up-regulation in PFC-GRs and CA1 -CB1r in females. In males, WIN normalized the ES-induced up-regulation in PFC-GR and down-regulation in BLA-CB1r. There is a crucial role of the endocannabinoid system in the effects of early life stress on behavior at adulthood. Differences in recognition memory and in the expression of GRs and CB1r in the fear circuit suggest sex differences in the mechanism underlying coping with stress.

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confidence: 99%

Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood

2016

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“…CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depressionlike symptoms, such as coping with stress behavior, weight gain, and sucrose consumption [35]. Exposure to CMS produces downregulation of the cannabinoid 1 (CB1) receptor in the hippocampus of male rats.…”

Section: Literaturementioning

confidence: 99%

“…Liu et al [34] demonstrated that a rat model of CUS induced a cognitive impairment in spatial memory and the Morris water maze test and a hippocampal LTP impairment accompanied by microglial activation and attenuated phosphorylation of glutamate receptor 1 (GluR1 or GluA1). Blockade of microglial activation by chronic treatment with minocycline before CUS prevented CUS-induced impairments of both spatial memory and LTP induction as well as increased phosphorylation of GluR1.CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depressionlike symptoms, such as coping with stress behavior, weight gain, and sucrose consumption [35]. Exposure to CMS produces downregulation of the cannabinoid 1 (CB1) receptor in the hippocampus of male rats.…”

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confidence: 95%

Studies on stress-induced modulation of long term potentiation in rodent hippocampus: what can we learn about pathogenesis of depression?

Gulyaeva¹

2016

Transl Brain Rhythmicity

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Long-term potentiation (LTP) reflecting continuous changes in synaptic efficacy is regarded as a cellular model of learning and memory. In this mini-review the data relating to hippocampal LTP alterations in rodent models of depression are analyzed to learn whether disturbances in LTP may be reliable markers of synaptic plasticity impairments underlying depressive and anxiety states. LTP disturbances result from synaptic reorganizations induced by multiple inter-related and mutually dependent events: hypothalamic-pituitary-adrenal axis disfunction; malfunction of neurotransmitter systems; failure to maintain the balance of neurotrophic systems; neuroinflammatory processes; disturbance in neurogenesis. Stable deficits in hippocampal LTP reflect the synapse-related basic mechanisms for cognitive and emotional behavioral deficits characterisic for depression/anxiety, and altered LTP is indicative of the development of stress-induced psychopathology.Correspondence to: Natalia V.Gulyaeva, Institute of Higher Nervous Activity and Neurophysiology RAS, 5a Butlerov Street, Moscow, 117485, Russia, E-mail: nata_gul@pisem.net Key words: depression, anxiety, synaptic plasticity, long term potentiation (LTP), stress LiteratureChronic stress is considered to be a major risk factor in the development of mood diseases. In order to study mechanisms involved in the etiology of human affective disorders, there is an abundant use of various animal models based on different stress paradigms. Depressive disorders are the most common psychiatric pathology, and a great number of people who experience depression also experience anxiety. Sometimes, anxiety is more expressed than depression, while in many cases neither is clearly predominant. In rodent stress-based models anxiety and depression symptoms often are demonstrated in parallel.Activity-dependent changes in synaptic strength are widely accepted as key mechanisms for information storage in the brain [1]. Long-term potentiation (LTP) is an electrophysiological phenomenon, an hours-lasting increase of postsynaptic potentials after tetanization. It is believed to reflect long-term changes in synaptic efficacy in distributed networks, associated with constant changes in the behavioral phenomena, which are often interpreted as the retention of information [2]. Thus, hippocampal LTP is regarded as a cellular model of learning and memory. Cognitive impairments and LTP impairments are increasingly recognized as events accompanying and reflecting experimental depression, anxiety and other experimental stress-related chronic psychological disorders, therefore, disturbances in LTP may be reliable markers of synaptic plasticity impairments underlying depressive and anxiety states. The dentate gyrus (DG) of the hippocampus is supposed to play a critical role in defining the impact of stress on hippocampal functioning. The DG is a dynamic structure susceptible to stress, its variable and complex stress response being reflected in changes of LTP and local circuit activity associated wit...

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“…We found that the CB1/2 receptor agonist WIN55,212-2 (WIN) prevented the effects of stress on learning and plasticity, as well as the behavioral and neuroendocrine outcomes of stress (Abush and Akirav, 2013;Ganon-Elazar and Akirav, 2009, 2013. Specifically, systemic administration of WIN or the GR antagonist RU-38486 (RU) prevented the impairment in extinction and NAc plasticity induced by exposure to chronic mild stress (Segev et al, 2014), and intra-BLA WIN or RU administered before stress exposure prevented the stress-induced enhancement of memory consolidation for reduction in reward magnitude .…”

Section: Introductionmentioning

confidence: 99%

“…Stress and glucocorticoids can trigger eCB synthesis and CB1 receptors signaling to constrain HPA axis activity under acute conditions (Hill et al, 2011;Rademacher et al, 2008;Steiner and Wotjak, 2008). Blocking BLA GRs prevented the effects of stress on a variety of memory tasks (Maroun and Akirav, 2007;Roozendaal et al, 2002;Segev et al, 2012Segev et al, , 2014.…”

Section: Introductionmentioning

confidence: 99%

Cannabinoids and Glucocorticoids in the Basolateral Amygdala Modulate Hippocampal–Accumbens Plasticity After Stress

Segev

Akirav

2015

Neuropsychopharmacol

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Acute stress results in release of glucocorticoids, which are potent modulators of learning and plasticity. This process is presumably mediated by the basolateral amygdala (BLA) where cannabinoids CB1 receptors have a key role in regulating the hypothalamic-pituitaryadrenal (HPA) axis. Growing attention has been focused on nucleus accumbens (NAc) plasticity, which regulates mood and motivation. The NAc integrates affective and context-dependent input from the BLA and ventral subiculum (vSub), respectively. As our previous data suggest that the CB1/2 receptor agonist WIN55,212-2 (WIN) and glucocorticoid receptor (GR) antagonist RU-38486 (RU) can prevent the effects of stress on emotional memory, we examined whether intra-BLA WIN and RU can reverse the effects of acute stress on NAc plasticity. Bilateral, ipsilateral, and contralateral BLA administration of RU or WIN reversed the stress-induced impairment in vSub-NAc long-term potentiation (LTP) and the decrease in cAMP response element-binding protein (CREB) activity in the NAc. BLA CB1 receptors were found to mediate the preventing effects of WIN on plasticity, but not the preventing effects of RU, after stress. Inactivating the ipsilateral BLA, but not the contralateral BLA, impaired LTP. The possible mechanisms underlying the effects of BLA on NAc plasticity are discussed; the data suggest that BLA-induced changes in the NAc may be mediated through neural pathways in the brain's stress circuit rather than peripheral pathways. The results suggest that glucocorticoid and cannabinoid systems in the BLA can restore normal function of the NAc and hence may have a central role in the treatment of a variety of stress-related disorders.

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Cannabinoid Receptor Activation Prevents the Effects of Chronic Mild Stress on Emotional Learning and LTP in a Rat Model of Depression

Cited by 78 publications

References 92 publications

Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood

Cannabinoids reverse the effects of early stress on neurocognitive performance in adulthood

Studies on stress-induced modulation of long term potentiation in rodent hippocampus: what can we learn about pathogenesis of depression?

Cannabinoids and Glucocorticoids in the Basolateral Amygdala Modulate Hippocampal–Accumbens Plasticity After Stress

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