Elsevier

European Journal of Pharmacology

Volume 834, 5 September 2018, Pages 230-239
European Journal of Pharmacology

Review
Endocannabinoid system, stress and HPA axis

https://doi.org/10.1016/j.ejphar.2018.07.039Get rights and content

Abstract

The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana's psychoactive ingredient ∆9-tetrahydrocannabinol (∆9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. In addition to its recreational actions, some of the earliest reports regarding the effects of Cannabis use on humans were related to endocrine system changes. Accordingly, the ∆9-THC and later on, the ECS signalling have long been known to regulate the hypothalamic-pituitary-adrenocortical (HPA) axis, which is the major neuroendocrine stress response system of mammals. However, how the ECS could modify the stress hormone secretion is not fully understood. Thus, the present article reviews current available knowledge on the role of the ECS signalling as important mediator of interaction between HPA axis activity and stressful conditions, which, in turn could be involved in the development of psychiatric disorders.

Introduction

Cannabis sativa is the most frequently abused recreational substance in the Western society, which popularity is due to its capacity to alter sensory perception, to increase sociability and to induce euphoria (Williamson and Evans, 2000). Although Cannabis sativa has been used by humans since ancient times, only in the last decades the identification of Δ-9-tetrahydrocannabinol (Δ9-THC) as the main psychoactive constituent of Cannabis sativa (Gaoni and Mechoulam, 1964) and later on, the cloning of specific cannabinoid receptors CB1 and CB2 (Matsuda et al., 1990) and the discovery of the endogenous cannabinoid system (ECS) in the brain has stimulated a tremendous amount of studies which have suggested that its dysregulation (both in terms of endogenous ligands and cannabinoid receptors) is associated with several pathological conditions such as pain (Luongo et al., 2014, Luongo et al., 2017), metabolic (Silvestri and Di Marzo, 2013), neurodegenerative (Mazzola et al., 2003, Micale et al., 2007, Micale et al., 2010) and stress-related disorders (Terzian et al., 2011, Kucerova et al., 2014, Navarria et al., 2014, Llorente-Berzal et al., 2015, Micale et al., 2009, Micale et al., 2015, Micale et al., 2017, Androvicova et al., 2017). In addition to the recreational actions of Cannabis sativa, many anecdotal reports from patients attest its acute antidepressant, anxiolytic, and stress-relieving effects (Iversen, 2003). Furthermore, cannabis users enhance consumption during times of increased stress and social anxiety triggers craving for cannabis in some users (Buckner et al., 2016). Multiple lines of evidence suggest that Δ9-THC is the constituent of Cannabis sativa primarily responsible of the psychoactive and physiological effects, however we cannot exclude other chemicals in the plant, which also shown beneficial effects, but whose mechanisms are not fully clarified (Izzo et al., 2009). Although the effects of exogenous cannabinoids on stress hormone secretion are recognized for many years, the role of endogenous cannabinoid signalling to modulate the neuroendocrine stress processing has only recently assessed (Steiner and Wotjak, 2008).

Thus, the goal of this review is to outline the current available knowledge on the role of the endocannabinoid signalling in the hypothalamic-pituitary adrenocortical (HPA) axis regulation under basal and stressful conditions. More specifically, we will show how stress exposure activating the HPA axis could be involved in the development of stress-related disorders by a dysregulation of the ECS elements. Furthermore, we try to suggest how the pharmacological modulation of the EC signalling could be a potential therapeutic target in neuropsychiatric disorders by regulating the HPA axis activity.

The endocannabinoid system (ECS) is a neuromodulatory system present in the brain and in the periphery, mediating the effects of the psychotropic phytocannabinoid Δ-9-tetrahydrocannabinol (Δ9-THC). It consists of (1) endogenous ligands anandamide (N-arachidonoyl-ethanolamine, AEA) and 2-arachidonylglycerol (2-AG); (2) the enzymes for endocannabinoid biosynthesis (N‑acyl-phosphatidylethanolamine-selective phosphodiesterase or glycerophosphodiesterase E1 and diacylglycerol lipase α or β) and enzymes for their inactivation (fatty acid amide hydrolase -FAAH- and monoacylglycerol lipase -MAGL-, respectively for AEA and 2-AG); (3) a specific and not yet identified cellular uptake mechanism and (4) the cannabinoid receptors type CB1 and CB2, which these latter are established as mediators of the biological effects induced by plant-derived, synthetic, or endogenous cannabinoids (Piscitelli and Di Marzo, 2012). However, additional “players” which are described as potential members of the ECS include the vanilloid TRPV1 channels, the putative CB1 receptor antagonist peptides like hemopressins, peroxisome proliferator- activated receptor-α (PPAR-α) and γ (PPAR-γ) ligands, such as N-arachidonoyl-dopamine (NADA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which activates both CB1 receptors and TRPV1 channels. The CB1 receptors are ubiquitously expressed in the CNS where they are predominantly found in high densities in the prefrontal cortex (PFC), basal ganglia, hippocampus and cerebellum. They are present at moderate/low densities in the periaqueductal gray (PAG), amygdala, nucleus accumbens, and thalamus. However, the CB1 receptors are also found in non-neuronal cells of the brain such as oligodendrocytes, microglia, and astrocytes (Mackie, 2005). Within these areas there are two major neuronal subpopulations expressing the CB1 receptors: the GABAergic interneurons (with high CB1 receptor levels) and glutamatergic neurons (with relatively low CB1 receptor levels) (Marsicano and Lutz, 1999), which represent the two major opposing players regulating the excitation state of the brain, GABAergic interneurons being inhibitory and glutamatergic neurons being excitatory. CB1 receptors are also in the locus coeruleus and in the dorsal raphe nucleus which are the major sources of noradrenalin (NE) and serotonin (5-HT) in the brain (Haring et al., 2007, Oropeza et al., 2007). Thus, the modulation of monoamine activity, GABA and glutamate neurons, could underlie the emotional and non-emotional effects of CB1 receptor activation.

The cannabinoid CB2 receptors, which are also activated by AEA and 2-AG, are mainly distributed in immune tissues and inflammatory cells, although they are also detected in glial cells, and to a much lesser extent, in neurons of several brain regions such as amygdala, hippocampus, cerebral cortex, hypothalamus and cerebellum (Van Sickle et al., 2005, Gong et al., 2006). The observation that ECS elements are prevalent throughout the neuroanatomical structures and circuits implicated in stress-related disorders, including hypothalamus, hippocampus, PFC, amygdala, and forebrain monoaminergic circuits, suggests the preclinical development of agents targeting this system to treat neuropsychiatric disorders.

Stress is recognized as an adaptive response of an organism to a real or perceived threat (i.e. stressful stimuli) in the environment which is aimed to re-establish homeostasis (McEwen, 2007). Usually, two different kinds of stressors are recognized, (a) ‘‘physiological stressors’’, where the organism is directly exposed to a physical threat (i.e.: inflammation or somatic pain), and (b) ‘‘psychological stressors’’, such as innate fear of an animal to unprotected fields or to predator odour (Herman et al., 2003). However, psychological stressors could also result in physical demands such as release of energy reservoirs to provide the basis for flight or fight, and this could explain why both physiological and psychological stressors elicit similar major stress responses. Thus, the response of vertebrates to the stressors involves (a) the activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, which results in the release of glucocorticoids (cortisol in humans and corticosterone in rodents) from the adrenal cortex into the blood stream as index of neuroendocrine response, and (b) the activation of the sympathetic-adrenergic system, which culminates in the release of adrenaline and noradrenaline from adrenal medulla and nerve terminals respectively, into the blood circulation, as index of autonomic response. The final stress response to both physiological and psychological stressors is very similar, however the brain regions involved in the integration of distinct stressors are different. More specifically, a strong involvement of higher limbic brain regions such as PFC, amygdala or hippocampus in the interpretation of psychological stressors has been supported by several evidence (Herman et al., 2005); while mid-hindbrain regions including monoaminergic brain nuclei, such as the raphe nuclei and the locus coeruleus, seem to play a role in the response to physiological stressors (Herman et al., 2003). Following the processing and integration of threatening stimuli, afferent fibres from both mid-hindbrain and limbic regions converge onto parvocellular neurons of the paraventricular nucleus (PVN) of the hypothalamus, where they trigger the release of corticotropin-releasing hormone (CRH) from axon terminals of these neurons into the capillaries of the pituitary portal vessels which target the anterior lobe of the pituitary. Here, CRH binding the CRH type 1 receptors (CRH-R1), stimulates the synthesis of adrenocorticotropic hormone (ACTH) from the precursor protein pro-opiomelanocortin (POMC) and its release into the circulation. ACTH is transported via the blood to the adrenocortical cells of the zona fasciculata of the adrenal glands and binds to the ACTH receptors (melanocortin type 2 receptors, MC2-R), stimulating the release of glucocorticoids into the blood circulation. Given the complexity of this process, different sites regulate the adequate corticosterone response to a stressor in terms of amplitude and duration. The primary brain structure responsible for the effect size of corticosterone secretion seems to be the PVN (Herman et al., 2003), however, the pituitary where the CRH signal is integrated into ACTH release (Engelmann et al., 2004) and the adrenal glands where ACTH signal is integrated into corticosterone release (Ehrhart-Bornstein et al., 1998) are involved in the fine tuning of the corticosterone response too. Besides CRH, others neuropeptide are involved in CRH secretion process, since oxytocin (OXT) and arginine–vasopressin (AVP) act synergistically with CRH to stimulate ACTH release from the pituitary (Antoni, 1993, Engelmann et al., 2004). Once a corticosterone response has been mounted and following stressor termination the HPA axis is reset by negative feedback, which occurs mainly at level of PVN and pituitary (De Kloet et al., 2005, Armario, 2006). Glucocorticoids act primarily through glucocorticoid receptors, which translocating into the nucleus activate the transcription of various stress response genes (De Kloet et al., 2005). These receptors are distinguished in type 1 glucocorticoid receptor, referred to as mineralocorticoid receptor (MR), and type 2 glucocorticoid receptor (GR). MR receptors have about a 10-fold higher affinity for corticosterone than GR receptors. Hence, MRs are activated during resting conditions, whereas GRs are occupied during the dark, active period in rodents, when basal glucocorticoid levels rise, or after stress exposure (De Kloet, 2003). Therefore, GRs seem to play a role in the stress-induced corticosterone-mediated negative feedback. GRs elicited primarily their effects on transcription, a process responsible for the delayed but not for the fast feedback HPA axis regulation, which occurs within minutes after stressor exposure (Dallman, 2005). Although the molecular mechanisms underlying the fast-feedback mechanisms of corticosterone are not fully understood it seems that endocannabinoids could be involved in feedback regulation of HPA axis activity at level of the PVN primarily via membrane-bound G-protein-coupled glucocorticoid receptors (Di et al., 2003, Malcher-Lopes et al., 2006).

The cannabinoid CB1 receptors are highly expressed in several limbic brain regions (i.e. hippocampus, amygdala and PFC) involved in HPA axis regulation, (Herkenham et al., 1990, Herkenham et al., 1991). They are also expressed at much lower levels in subcortical regions such as the bed nucleus of the stria terminalis (BNST), the PVN and in mid-hindbrain regions (Herkenham et al., 1991, Wittmann et al., 2007). Within these structures, they are located on presynaptic site of GABAergic and glutamatergic synapses and their activation leads to inhibitory effect on neurotransmitter release (Marsicano and Lutz, 1999). Although cannabinoid CB1 receptor expression in glutamatergic neurons is lower than in GABAergic neurons, the reduction of glutamate release from glutamatergic synapses by cannabinoid CB1 activation, is responsible for glucocorticoid-mediated feedback regulation of the HPA axis (Di et al., 2003). Cannabinoid CB1 receptor mRNA is co-localized with CRH mRNA both in the hypothalamic nuclei of the PVN (Cota et al., 2003) and in several extrahypothalamic areas (i.e. amygdala, PFC and BNST), which are involved in stress integration (Cota et al., 2007). Thus, we could speculate that CB1 receptor signalling at the presynaptic site might regulate the neuronal release of CRH both in limbic brain areas and at the level of the median eminence. The cannabinoid CB1 receptors are also expressed in the intermediate and anterior lobes of pituitary gland and in the external zone of the median eminence (Herkenham et al., 1991, Pagotto et al., 2001, Wittmann et al., 2007). In addition to cannabinoid CB1 receptors, the endogenous cannabinoids 2-AG and AEA have been found in the pituitary gland too (Pagotto et al., 2001). Since CB1 receptors are also expressed in adrenal gland (Ziegler et al., 2010), overall there is evidence for the pivotal role of CB1 but not CB2 receptor to regulate the HPA axis.

Section snippets

Stress exposure, endocannabinoid system and HPA axis

Stressful life events are considered as major predisposing risk factors for developing human diseases such as anxiety and depression. However, in humans the definition incorporates cognitive and emotional responses as well, where stress is defined as a condition in which the environmental demands exceed the coping abilities of the individual (Cohen et al., 1986). In order to study mechanisms involved in the aetiology of affective disorders and the effects of the potential pharmacological

Conclusive remarks and future prospective

In conclusion, the current evidence suggest that the endocannabinoid signalling is an important system involved in the neural modulation of stress response, which is in agreement with anecdotal reports from patients attesting its acute anxiolytic, antidepressant and stress-relieving effects (Iversen, 2003, Buckner et al., 2016). Preclinical data have shown that the ECS could play a role as homeostatic principle, which regulates the HPA axis activity under basal or stress-related conditions and

Acknowledgements

This work was supported by Piano triennale per la Ricerca - Linea Intervento 2, University of Catania, Italy.

Conflict of interest

The authors declare no conflict of interest.

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