scholarly journals Endocannabinoid-Epigenetic Cross-Talk: A Bridge toward Stress Coping

2020 ◽  
Vol 21 (17) ◽  
pp. 6252 ◽  
Author(s):  
Francesco Rusconi ◽  
Tiziana Rubino ◽  
Elena Battaglioli
Keyword(s):  
Stress Responses ◽  
Glutamate Release ◽  
Disease Onset ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Protective Role ◽  
Cb1 Receptor ◽  
Traumatic Experiences ◽  
Stress Coping ◽  
As Stress

There is no argument with regard to the physical and psychological stress-related nature of neuropsychiatric disorders. Yet, the mechanisms that facilitate disease onset starting from molecular stress responses are elusive. Environmental stress challenges individuals’ equilibrium, enhancing homeostatic request in the attempt to steer down arousal-instrumental molecular pathways that underlie hypervigilance and anxiety. A relevant homeostatic pathway is the endocannabinoid system (ECS). In this review, we summarize recent discoveries unambiguously listing ECS as a stress coping mechanism. As stress evokes huge excitatory responses in emotional-relevant limbic areas, the ECS limits glutamate release via 2-arachydonilglycerol (2-AG) stress-induced synthesis and retrograde cannabinoid 1 (CB1)-receptor activation at the synapse. However, ECS shows intrinsic vulnerability as 2-AG overstimulation by chronic stress rapidly leads to CB1-receptor desensitization. In this review, we emphasize the protective role of 2-AG in stress-response termination and stress resiliency. Interestingly, we discuss ECS regulation with a further nuclear homeostatic system whose nature is exquisitely epigenetic, orchestrated by Lysine Specific Demethylase 1. We here emphasize a remarkable example of stress-coping network where transcriptional homeostasis subserves synaptic and behavioral adaptation, aiming at reducing psychiatric effects of traumatic experiences.

scholarly journals The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6178
Author(s):  
Saoirse Elizabeth O’Sullivan ◽  
Andrew S. Yates ◽  
Richard K. Porter
Keyword(s):  
Body Weight ◽  
Cannabinoid Receptor ◽  
Clinical Stage ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Obesity And Diabetes ◽  
Satiety Hormone ◽  
Cb1 Antagonists ◽  
Therapeutic Utility

The cannabinoid 1 (CB1) receptor regulates appetite and body weight; however, unwanted central side effects of both agonists (in wasting disorders) or antagonists (in obesity and diabetes) have limited their therapeutic utility. At the peripheral level, CB1 receptor activation impacts the energy balance of mammals in a number of different ways: inhibiting satiety and emesis, increasing food intake, altering adipokine and satiety hormone levels, altering taste sensation, decreasing lipolysis (fat break down), and increasing lipogenesis (fat generation). The CB1 receptor also plays an important role in the gut–brain axis control of appetite and satiety. The combined effect of peripheral CB1 activation is to promote appetite, energy storage, and energy preservation (and the opposite is true for CB1 antagonists). Therefore, the next generation of CB1 receptor medicines (agonists and antagonists, and indirect modulators of the endocannabinoid system) have been peripherally restricted to mitigate these issues, and some of these are already in clinical stage development. These compounds also have demonstrated potential in other conditions such as alcoholic steatohepatitis and diabetic nephropathy (peripherally restricted CB1 antagonists) and pain conditions (peripherally restricted CB1 agonists and FAAH inhibitors). This review will discuss the mechanisms by which peripheral CB1 receptors regulate body weight, and the therapeutic utility of peripherally restricted drugs in the management of body weight and beyond.

Medial prefrontal cortex endocannabinoid system modulates baroreflex activity through CB1 receptors

2012 ◽  
Vol 302 (7) ◽  
pp. R876-R885 ◽  
Author(s):  
Nilson C. Ferreira-Junior ◽  
Alessandra G. Fedoce ◽  
Fernando H. F. Alves ◽  
Fernando M. A. Corrêa ◽  
Leonardo B. M. Resstel
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Fatty Acid Amide Hydrolase ◽  
Glutamate Release ◽  
Acid Amide ◽  
Endocannabinoid System ◽  
Receptor Activation ◽  
Glutamatergic Neurotransmission ◽  
Glutamatergic Synapses ◽  
Amide Hydrolase

Neural reflex mechanisms, such as the baroreflex, are involved in the regulation of cardiovascular system activity. Previous results from our group (Resstel LB, Correa FM. Medial prefrontal cortex NMDA receptors and nitric oxide modulate the parasympathetic component of the baroreflex. Eur J Neurosci 23: 481–488, 2006) have shown that glutamatergic synapses in the ventral portion of the medial prefrontal cortex (vMPFC) modulate baroreflex activity. Moreover, glutamatergic neurotransmission in the vMPFC can be modulated by the endocannabinoids system (eCBs), particularly the endocannabinoid anandamide, through presynaptic CB1 receptor activation. Therefore, in the present study, we investigated eCBs receptors that are present in the vMPFC, and more specifically whether CB1 receptors modulate baroreflex activity. We found that bilateral microinjection of the CB1 receptor antagonist AM251 (100 or 300 pmol/200 nl) into the vMPFC increased baroreflex activity in unanesthetized rats. Moreover, bilateral microinjection of either the anandamide transporter inhibitor AM404 (100 pmol/200 nl) or the inhibitor of the enzyme fatty acid amide hydrolase that degrades anandamide, URB597 (100 pmol/200 nl), into the MPFC decreased baroreflex activity. Finally, pretreatment of the vMPFC with an ineffective dose of AM251 (10 pmol/200 nl) was able to block baroreflex effects of both AM404 and URB597. Taken together, our results support the view that the eCBs in the vMPFC is involved in the modulation of baroreflex activity through the activation of CB1 receptors, which modulate local glutamate release.

scholarly journals Loss of mGluR5 in D1 Receptor-Expressing Neurons Improves Stress Coping

2021 ◽  
Vol 22 (15) ◽  
pp. 7826
Author(s):  
Luca Zangrandi ◽  
Claudia Schmuckermair ◽  
Hussein Ghareh ◽  
Federico Castaldi ◽  
Regine Heilbronn ◽  
...  
Keyword(s):  
Stress Responses ◽  
Metabotropic Glutamate Receptor ◽  
Forced Swim Test ◽  
Functional Integration ◽  
D1 Receptor ◽  
Conditional Knockout ◽  
Stress Coping ◽  
Metabotropic Glutamate ◽  
Internal States

The metabotropic glutamate receptor type 5 (mGluR5) has been proposed to play a crucial role in the selection and regulation of cognitive, affective, and emotional behaviors. However, the mechanisms by which these receptors mediate these effects remain largely unexplored. Here, we studied the role of mGluR5 located in D1 receptor-expressing (D1) neurons in the manifestation of different behavioral expressions. Mice with conditional knockout (cKO) of mGluR5 in D1 neurons (mGluR5D1 cKO) and littermate controls displayed similar phenotypical profiles in relation to memory expression, anxiety, and social behaviors. However, mGluR5D1 cKO mice presented different coping mechanisms in response to acute escapable or inescapable stress. mGluR5D1 cKO mice adopted an enhanced active stress coping strategy upon exposure to escapable stress in the two-way active avoidance (TWA) task and a greater passive strategy upon exposure to inescapable stress in the forced swim test (FST). In summary, this work provides evidence for a functional integration of the dopaminergic and glutamatergic system to mediate control over internal states upon stress exposure and directly implicates D1 neurons and mGluR5 as crucial mediators of behavioral stress responses.

Cocaine-induced increases in motivation require 2-arachidonoylglycerol mobilization and CB1 receptor activation in the ventral tegmental area

2021 ◽  
pp. 108625
Author(s):  
Sheila A. Engi ◽  
Erin J. Beebe ◽  
Victoria M. Ayvazian ◽  
Fabio C. Cruz ◽  
Joseph F. Cheer ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Receptor Activation ◽  
Cb1 Receptor ◽  
Ventral Tegmental

scholarly journals Early Consumption of Cannabinoids: From Adult Neurogenesis to Behavior

2021 ◽  
Vol 22 (14) ◽  
pp. 7450
Author(s):  
Citlalli Netzahualcoyotzi ◽  
Luis Miguel Rodríguez-Serrano ◽  
María Elena Chávez-Hernández ◽  
Mario Humberto Buenrostro-Jáuregui
Keyword(s):  
Young Adulthood ◽  
Adult Neurogenesis ◽  
Critical Period ◽  
Consumption Rate ◽  
Behavioral Outcomes ◽  
Endocannabinoid System ◽  
Illegal Drug ◽  
Adult Brain ◽  
As Stress

The endocannabinoid system (ECS) is a crucial modulatory system in which interest has been increasing, particularly regarding the regulation of behavior and neuroplasticity. The adolescent–young adulthood phase of development comprises a critical period in the maturation of the nervous system and the ECS. Neurogenesis occurs in discrete regions of the adult brain, and this process is linked to the modulation of some behaviors. Since marijuana (cannabis) is the most consumed illegal drug globally and the highest consumption rate is observed during adolescence, it is of particular importance to understand the effects of ECS modulation in these early stages of adulthood. Thus, in this article, we sought to summarize recent evidence demonstrating the role of the ECS and exogenous cannabinoid consumption in the adolescent–young adulthood period; elucidate the effects of exogenous cannabinoid consumption on adult neurogenesis; and describe some essential and adaptive behaviors, such as stress, anxiety, learning, and memory. The data summarized in this work highlight the relevance of maintaining balance in the endocannabinoid modulatory system in the early and adult stages of life. Any ECS disturbance may induce significant modifications in the genesis of new neurons and may consequently modify behavioral outcomes.

Calmidazolium selectively inhibits exocytotic glutamate release evoked by P2X7 receptor activation

2012 ◽  
Vol 60 (8) ◽  
pp. 768-772 ◽  
Author(s):  
Chiara Cervetto ◽  
Maria Chiara Mazzotta ◽  
Daniela Frattaroli ◽  
Susanna Alloisio ◽  
Mario Nobile ◽  
...  
Keyword(s):  
P2x7 Receptor ◽  
Glutamate Release ◽  
Receptor Activation ◽  
P2x7 Receptor Activation

Presynaptic Modulation of Synaptic Transmission by Pregnenolone Sulfate as Studied by Optical Recordings

2005 ◽  
Vol 94 (6) ◽  
pp. 4131-4144 ◽  
Author(s):  
Ling Chen ◽  
Masahiro Sokabe
Keyword(s):  
Synaptic Transmission ◽  
Glutamate Release ◽  
Hippocampal Slices ◽  
Receptor Activation ◽  
Optical Recording ◽  
Perforant Path ◽  
Dependent Manner ◽  
Pregnenolone Sulfate ◽  
Voltage Sensitive Dyes ◽  
Dose Dependent

The effects of pregnenolone sulfate (PREGS), a putative neurosteroid, on the transmission of perforant path–granule cell synapses were investigated with an optical recording technique in rat hippocampal slices stained with voltage-sensitive dyes. Application of PREGS to the bath solution resulted in an acute augmentation of EPSP in a dose-dependent manner. The PREGS effect was dependent on the extracellular Ca2+ concentration ([Ca2+]o), but independent of NMDA receptor activation. PREGS caused a decrease in paired-pulse facilitation, which implies that PREGS positively modulates presynaptic neurotransmitter releases. Firmer support for this mechanism was that PREGS augmented the synaptically induced glial depolarization (SIGD) that reflects the activity of electrogenic glutamate transporters in glial cells during the uptake of released glutamate. The selective α7nAChR antagonist α-BGT or MLA prevented the SIGD increase by PREGS. Furthermore DMXB, a selective α7nAChR agonist, mimicked the PREGS effect on SIGD and antagonized the effect of PREGS. The presynaptic effect of PREGS was partially attenuated by the L-type Ca2+ channel (VGCC) blocker nifedipine. Based on these findings, we proposed a novel mechanism underlying the facilitated synaptic transmission by PREGS: this neurosteroid sensitizes presynaptic α7nAChR that is followed by an activation of L-type VGCC to increase the presynaptic glutamate release.

Glutamate Neurotransmission Is Not Required for, But May Modulate, Hypoxic Sensitivity of Pre-Bötzinger Complex In Vivo

2005 ◽  
Vol 93 (3) ◽  
pp. 1278-1284 ◽  
Author(s):  
Irene C. Solomon
Keyword(s):  
Phrenic Nerve ◽  
Excitatory Amino Acid ◽  
Glutamate Release ◽  
Receptor Activation ◽  
Motor Output ◽  
Induced Response ◽  
Homocysteic Acid ◽  
Bötzinger Complex ◽  
Nerve Discharge

Focal hypoxia in the pre-Bötzinger complex (pre-BötC) in vivo elicits excitation of inspiratory motor output by modifying the patterning and timing of phrenic bursts. Hypoxia, however, has been reported to enhance glutamate release in some regions of the brain, including the medullary ventral respiratory column; thus the pre-BötC–mediated hypoxic respiratory excitation may result from, or be influenced by, hypoxia-induced activation of ionotropic glutamate [i.e., excitatory amino acid (EAA)] receptors. To test this possibility, the effects of focal pre-BötC hypoxia [induced by sodium cyanide (NaCN)] were examined before and after blockade of ionotropic EAA receptors [using kynurenic acid (KYN)] in this region in chloralose-anesthetized, vagotomized, mechanically ventilated cats. Before blockade of ionotropic EAA receptors, unilateral microinjection of NaCN (1 mM; 10–20 nl) into the pre-BötC produced either phasic or tonic excitation of phrenic nerve discharge. Unilateral microinjection of KYN (50–100 mM; 40 nl) decreased the amplitude and frequency of basal phrenic nerve discharge; however, subsequent microinjection of NaCN, but not dl-homocysteic acid (DLH, a glutamate analog), still produced excitation of phrenic motor output. Under these conditions, the NaCN-induced excitation included frequency modulation (FM) of phasic phrenic bursts, and in many cases, augmented and/or fractionated phrenic bursts. These findings show that the hypoxia-sensing function of the in vivo pre-BötC, which produces excitation of phrenic nerve discharge, is not dependent on activation of ionotropic glutamate receptors, but ionotropic glutamate receptor activation may modify the expression of the focal hypoxia-induced response. Thus these findings provide additional support to the concept of intrinsic hypoxic sensitivity of the pre-BötC.

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