Role of the endocannabinoid system in regulation of the hypothalamic-pituitary-adrenocortical axis

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Abstract

The endocannabinoid system has been recognized as a major neuromodulatory system, which functions to maintain brain homoeostasis. Endocannabinoids are synthesized and released from the postsynapse and act as retrograde neuronal messengers, which bind to cannabinoid type 1 receptors at the presynapse. Here, they inhibit the release of neurotransmitters, including glutamate and GABA. By these means, endocannabinoids control the activation of various neuronal circuits including those involved in neuroendocrine stress processing. Accordingly, exogenous cannabinoids such as the major active component of marijuana, Δ9-tetrahydrocannabinol, have long been known to activate the major neuroendocrine stress response system of mammals, the hypothalamic-pituitary-adrenocortical (HPA) axis. However, the function of the endocannabinoid system in the regulation of stress hormone secretion has only recently begun to be understood. It is the focus of the present review to provide the reader with an overview of our current knowledge of the role of endocannabinoid signalling in HPA axis regulation under basal as well as under stressful conditions. This includes the specific sites of action, potential underlying neuronal pathways and interactions between behavioural and neuroendocrine stress coping. Furthermore, the potential role of HPA axis activity dysregulations, caused by deficits in the endocannabinoid system, for the pathophysiology of psychiatric diseases is discussed.

Introduction

Ever since the discovery of the cannabinoid type 1 (CB1) receptor (Matsuda et al., 1990), the first protein binding partner of the major psychoactive component of marijuana, Δ9-tetrahydrocannabinol (THC), the investigation of CB1 receptor-mediated signalling within the brain has stimulated a tremendous amount of research. Because CB1 receptors are among the most widely distributed and abundantly expressed G-protein-coupled receptors in the brain (Herkenham et al., 1990), it is not surprising that CB1 receptor signalling has profound effects on a wide variety of behavioural, vegetative and autonomic functions (Di Marzo et al., 2005). The discovery of endogenous ligands for CB1 receptors (so-called endocannabinoids; Devane et al., 1992; Mechoulam et al., 1995; Sugiura et al., 1995) paved the way for the understanding of the endocannabinoid system as a major neuromodulatory system of the brain, which influences the activity of neuronal circuits by inhibiting the release of a number of excitatory and inhibitory neurotransmitters (Piomelli, 2003; Degroot and Nomikos, 2007). Thus, endocannabinoid signaling can be expected to influence neuronal stress processing. However, even though the effects of exogenous cannabinoids on stress hormone secretion are known for many years, the role of endocannabinoid signalling for neuroendocrine stress processing has only recently begun to be deciphered (Carrier et al., 2005; Pagotto et al., 2006).

In the present review we highlight current evidence for the presence of different players of the endocannabinoid system at sites involved in hypothalamic-pituitary-adrenocortical (HPA) axis regulation. We then introduce pharmacological, genetic and neurochemical/neuroendocrine means by which exogenous and endogenous cannabinoid actions on HPA axis activity have been investigated in the past and offer perspectives for future research, followed by a compilation of the data on endocannabinoid-mediated stress hormone secretion. In this context we will provide a detailed overview of our current understanding of the role of endocannabinoid signalling for HPA axis activity under basal and stressful conditions. Finally, we summarize evidence for potential endocannabinoid-mediated interactions between behavioural and neuroendocrine stress coping, and we invite the reader to speculate on the potential role of endocannabinoid-mediated HPA axis disturbances for the development of neuropsychiatric disorders such as major depression.

Section snippets

The endocannabinoid system

Endocannabinoids are lipophilic arachidonic acid derivatives, which are primarily synthesized at the postsynapse (Di Marzo et al., 2005; Basavarajappa, 2007), from where they are released to reach across the synaptic cleft to bind to presynaptically located CB1 receptors (Piomelli, 2003). Receptor binding causes a wide variety of intracellular signalling mechanisms (Diaz-Laviada and Ruiz-Llorente, 2005), which, in the first place, serve to reduce the excitability of the presynapse and, in

The hypothalamic-pituitary-adrenocortical (HPA) axis

Stress is a highly adaptive response of an organism to challenges (i.e. stressors) in the environment that is aimed at re-establishing homoeostasis (for detailed discussions of stress concepts, see Chrousos and Gold, 1992; Pacak and Palkovits, 2001; Engelmann et al., 2004; McEwen, 2007). In general, researchers distinguish between two different types of stressors, (i) “physical stressors”, where the organism is directly exposed to a physical (systemic) threat, such as changes in cardiovascular

Means of studying the endocannabinoid system

Table 1 summarizes current research strategies aimed at investigating the physiological role of the endocannabinoid system of the brain. Initially, studies monitored consequences of exogenous CB1 agonists, such as THC, whose structure was delineated in 1964 (Gaoni and Mechoulam, 1964), or later of synthetic CB1 agonists, including WIN-55,212-2, CP-55,940 and HU-210, which were generated in the early 1990s (Howlett et al., 2002). Application of exogenous CB1 agonists induces a ubiquitous

Characteristics of the endocannabinoid system at different levels of the HPA axis

CB1 receptors are expressed in high abundance in the brain. They are prominently present in many limbic brain regions involved in HPA axis regulation, such as the prefrontal cortex, hippocampus and amygdala (Herkenham et al., 1990, Herkenham et al., 1991; Matsuda et al., 1993; Tsou et al., 1998a; Pettit et al., 1998). The receptor is also expressed in subcortical regions, such as the bed nucleus of the stria terminalis (BNST) and the PVN, however, at much lower levels (Herkenham et al., 1991;

Effects of exogenous cannabinoids on HPA axis activity

The stimulatory effects of exogenous cannabinoids on HPA axis activity are known for many decades and have been thoroughly investigated. Dewey et al. (1970) have been among the first who could demonstrate that intraperitoneal (i.p.) injection of THC decreased ascorbic acid content in the rat adrenal gland as an index of increased ACTH secretion. One year later, Kubena et al. (1971) showed that the i.p. injection of THC increases plasma corticosterone in the rat in a dose-dependent manner, which

The role of endocannabinoid signalling for HPA axis function

Table 3 summarizes our current knowledge about the effects of pharmacological or genetic inactivation of CB1 receptors on ACTH and corticosterone secretion. After several negative findings (De Fonseca et al., 1997; Navarro et al., 1997; Wenger et al., 1997), Manzanares et al. (1999) had been the first who reported that blocking CB1 receptors by SR141716 resulted in the very same net effect on HPA axis activation as administration of the exogenous cannabinoid THC. Thus, it was not before 1999

Endocannabinoid signalling and behavioural stress coping

Reviews on an involvement of the endocannabinoid system in regulation of the HPA axis can hardly go without mentioning potential implications of endocannabinoids in behavioural stress coping. At this place, we will only provide a short survey of the respective literature. Readers who are interested in more detailed information are referred to recent comprehensive review articles on this subject (Carrier et al., 2005; Hill and Gorzalka, 2005a; Viveros et al., 2005; Wotjak, 2005; Witkin et al.,

Endocannabinoid system and melancholic depression

It has been Hill and Gorzalka (2005a), who very convincingly outlined in an excellent review article the similarities between the behavioural responses of CB1 receptor-deficient mice and symptoms of melancholic depression in terms of depressed mood, anxiety, anhedonia, reduced food intake, pronounced weight loss, predominance of aversive emotional memories, hippocampal atrophy and hyperactivity of the HPA axis. The latter endophenotype deserves particular attention in the context of our

Conclusion

Animal experiments performed over the course of the past 10 years identified the endocannabinoid system of the brain as an important homoeostatic principle, which constrains HPA axis activity under basal and stress conditions and counteracts overshooting behavioural stress responses. It is likely that endocannabinoids exert their effects on ACTH and corticosterone secretion at different levels of the HPA axis. Of particular importance might be their involvement in rapid negative feedback

Acknowledgements

This work was partly supported by grants from the National Institute of Mental Health and by a PhD grant of the Boehringer Ingelheim Foundation to M.A. Steiner. We would like to thank Eric J. Nestler (Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA) for his generous support concerning the experiments leading to Fig. 1, Fig. 4 of the present review. We would like to thank Giovanni Marsicano (INSERM Bordeaux, France) and Beat Lutz (University of

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